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Archive for the ‘Gene therapy’ Category

Chiesi dumps uniQure’s hemophilia B gene therapy – FierceBiotech

Tuesday, August 1st, 2017

Chiesi has cut its ties to uniQures hemophilia B gene therapy. The split gives uniQure full rights to AMT-060 but leaves it without a partner to cofund R&D as it closes in on the start of a pivotal trial.

Italian drugmaker Chiesi picked up the rights to commercialize AMT-060 in certain markets in 2013 as part of a deal that also gave it a piece of Glybera, the gene therapy that made history by coming to market in Europe only to flop commercially. Chiesi backed out of the Glybera agreement earlier this year and has now completed its split from uniQure by terminating the hemophilia B pact.

Amsterdam, the Netherlands-based uniQure framed the termination as it reacquiring the rights to AMT-060, rather than Chiesi dumping the program. But as the deal will see money transfer from Chiesi to uniQure and the former stated a shift in priorities prompted it to sever ties to AMT-060, it seems clear the Italian drugmaker wanted to exit the agreement.

That leaves uniQure facing the prospect of taking AMT-060 into a pivotal trial without the financial support of a partner. Chiesi and uniQure have evenly shared R&D costs since 2013. The loss of the support of Chiesi will add $3 million to uniQures outlay this year, although the Dutch biotech still thinks it has enough cash to take it into 2019.

After a trying time on public markets dotted with stock drops following unfavorable comparisons to Spark Therapeutics rival hemophilia B program, uniQure is less well equipped to raise more money than in the past. But uniQure CEO Matthew Kapusta spun the regaining of full rights to the gene therapy as a boost for the company.

We believe uniQure is better positioned to accelerate the global clinical development plan, maximize shareholder return on our pipeline and take advantage of new potential opportunities related to the program, Kapusta said in a statement.

If the potential opportunities are to include a deal covering AMT-060, uniQure must persuade a potential partner of the merits of its asset. UniQure has sought to focus attention on the durable clinical benefits associated with AMT-060 but investors have fixated on Sparks clear advantage in terms of Factor IX activity.

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Philly drug maker seeks approval in EU for gene therapy – Philly.com

Tuesday, August 1st, 2017

Philadelphia gene therapy company Spark Therapeutics has applied to the European Medicines Agency for approval to sell its treatment of rare inherited blindness in the European Union.

The experimental therapy, Luxturna, or voretigene neparvovec, is under priority review with the U.S. Food and Drug Administration, with a possible approval date of Jan. 12, 2018.

Spark was spun out of Childrens Hospital of Philadelphia, based on research led by Katherine A. High, Sparks cofounder, president, and chief scientific officer. If approved, it would be the first gene therapy for a genetic disease in the United States.

With Luxturna now in regulatory review on both sides of the Atlantic, we are building out our medical and commercial infrastructure to bring the drug to patients, said John Furey, Sparks chief operating officer. For the first time, adults and children, who otherwise would progress to complete blindness, have hope for a potential treatment option that may restore their vision, he said.

About 3,500 people in the United States and Europe live with the disease.

The review period will begin in Europe once the agency validates the application, Spark said.

Published: August 1, 2017 3:01 AM EDT | Updated: August 1, 2017 11:40 AM EDT

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Gene Therapy Treats Muscular Dystrophy in Dogs, Provides Hope for Humans – Wall Street Pit

Tuesday, August 1st, 2017

There is new hope for human patients with Duchenne muscular dystrophy. Results released in the journal Nature Communications describe a promising gene therapy performed on dogs. Twelve Golden Labrador dogs were subjected to a breakthrough gene therapy technology and, after two years, the dogs are healthy and appears to be illness-free. Researchers are optimistic about the implication of this study on humans.

Duchenne muscular dystrophy (or DMD) is a hereditary condition characterized by muscle weaknesses and muscle degeneration. Among nine types of muscular dystrophy, DMD is the most severe and life-threatening. Dystrophin protein is vital for muscles to function properly and the absence of this protein makes muscles fragile and easily damaged. At early stages, DMD will affect muscles in the shoulder, upper arms, thighs and hips that are vital to movement and balance. Patients experience muscle weaknesses by age 4 and then start losing the ability to walk by age 12. Later on, DMD will weaken the heart and respiratory muscles. For DMD cases, the average life expectancy is 26 years, with only a few patients living beyond 40.

Duchenne muscular dystrophy was named after French neurologist Guillaume Benjamin Amand Duchenne who described the illness in the 1860s. It was only in 1986 that researchers discovered a specific gene in the X chromosome that is responsible for normal dystrophin production. If a human has inherited the mutated or defective gene, that human can be ill with DMD or be a carrier of the defective gene.

Duchenne muscular dystrophy affects 1 in 5,000 boys at birth but is rare among girls. Girls, which have XX composition, are less likely affected than boys with XY composition as the dystrophin gene is located in the X chromosome. When a young girl inherits a defective dystrophin gene from one parent, she will be DMD-free if she gets a normal gene from her other parent or DMD-affected if she gets another defective gene. However, a DMD-free girl with a defective gene is still a carrier and can pass that gene to her children. On the other hand, it only takes one defective gene for boys to be affected with DMD.

There are no cures for Duchenne muscular dystrophy. Drugs, physical therapy and corrective surgery have been the primary tools for dealing with DMD but researchers are now pursuing newer technologies as possible treatment routes. The team of researchers from Genethon, the AFM-Telethon laboratory, INSERN (UMR 1089, Nantes) and the Royal Holloway of University of London collaborated for a promising gene therapy study conducted on twelve Golden Labrador dogs. The dogs were injected one-time with a gene for microdystrophin, a compressed version of dystrophin. Microdystrophin gene is used instead of dystrophin gene as the latter is too large to fit into a carrier virus that will be injected into a dogs body.

Golden Labrador dogs are chosen for this study as these breed is prone to DMD. Injecting the microdystrophin gene is expected to restore a dogs ability to normally produce dystrophin protein. The chosen dogs were not expected to live beyond six months but they are still alive two years since the study commenced. The dogs have shown improved ability to walk, run and jump. Buoyed by these positive results, researchers hope their study will pave the way in starting human clinical trials in the near future.

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Vectors in gene therapy – Wikipedia

Wednesday, July 12th, 2017

Gene therapy utilizes the delivery of DNA into cells, which can be accomplished by several methods, summarized below. The two major classes of methods are those that use recombinant viruses (sometimes called biological nanoparticles or viral vectors) and those that use naked DNA or DNA complexes (non-viral methods).

All viruses bind to their hosts and introduce their genetic material into the host cell as part of their replication cycle. This genetic material contains basic 'instructions' of how to produce more copies of these viruses, hacking the body's normal production machinery to serve the needs of the virus. The host cell will carry out these instructions and produce additional copies of the virus, leading to more and more cells becoming infected. Some types of viruses insert their genome into the host's cytoplasm, but do not actually enter the cell. Others penetrate the cell membrane disguised as protein molecules and enter the cell.

There are two main types of virus infection: lytic and lysogenic. Shortly after inserting its DNA, viruses of the lytic cycle quickly produce more viruses, burst from the cell and infect more cells. Lysogenic viruses integrate their DNA into the DNA of the host cell and may live in the body for many years before responding to a trigger. The virus reproduces as the cell does and does not inflict bodily harm until it is triggered. The trigger releases the DNA from that of the host and employs it to create new viruses.

The genetic material in retroviruses is in the form of RNA molecules, while the genetic material of their hosts is in the form of DNA. When a retrovirus infects a host cell, it will introduce its RNA together with some enzymes, namely reverse transcriptase and integrase, into the cell. This RNA molecule from the retrovirus must produce a DNA copy from its RNA molecule before it can be integrated into the genetic material of the host cell. The process of producing a DNA copy from an RNA molecule is termed reverse transcription. It is carried out by one of the enzymes carried in the virus, called reverse transcriptase. After this DNA copy is produced and is free in the nucleus of the host cell, it must be incorporated into the genome of the host cell. That is, it must be inserted into the large DNA molecules in the cell (the chromosomes). This process is done by another enzyme carried in the virus called integrase.

Now that the genetic material of the virus has been inserted, it can be said that the host cell has been modified to contain new genes. If this host cell divides later, its descendants will all contain the new genes. Sometimes the genes of the retrovirus do not express their information immediately.

One of the problems of gene therapy using retroviruses is that the integrase enzyme can insert the genetic material of the virus into any arbitrary position in the genome of the host; it randomly inserts the genetic material into a chromosome. If genetic material happens to be inserted in the middle of one of the original genes of the host cell, this gene will be disrupted (insertional mutagenesis). If the gene happens to be one regulating cell division, uncontrolled cell division (i.e., cancer) can occur. This problem has recently begun to be addressed by utilizing zinc finger nucleases[1] or by including certain sequences such as the beta-globin locus control region to direct the site of integration to specific chromosomal sites.

Gene therapy trials using retroviral vectors to treat X-linked severe combined immunodeficiency (X-SCID) represent the most successful application of gene therapy to date. More than twenty patients have been treated in France and Britain, with a high rate of immune system reconstitution observed. Similar trials were restricted or halted in the USA when leukemia was reported in patients treated in the French X-SCID gene therapy trial.[citation needed] To date, four children in the French trial and one in the British trial have developed leukemia as a result of insertional mutagenesis by the retroviral vector. All but one of these children responded well to conventional anti-leukemia treatment. Gene therapy trials to treat SCID due to deficiency of the Adenosine Deaminase (ADA) enzyme (one form of SCID)[2] continue with relative success in the USA, Britain, Ireland, Italy and Japan.

Adenoviruses are viruses that carry their genetic material in the form of double-stranded DNA. They cause respiratory, intestinal, and eye infections in humans (especially the common cold). When these viruses infect a host cell, they introduce their DNA molecule into the host. The genetic material of the adenoviruses is not incorporated (transient) into the host cell's genetic material. The DNA molecule is left free in the nucleus of the host cell, and the instructions in this extra DNA molecule are transcribed just like any other gene. The only difference is that these extra genes are not replicated when the cell is about to undergo cell division so the descendants of that cell will not have the extra gene. As a result, treatment with the adenovirus will require readministration in a growing cell population although the absence of integration into the host cell's genome should prevent the type of cancer seen in the SCID trials. This vector system has been promoted for treating cancer and indeed the first gene therapy product to be licensed to treat cancer, Gendicine, is an adenovirus. Gendicine, an adenoviral p53-based gene therapy was approved by the Chinese food and drug regulators in 2003 for treatment of head and neck cancer. Advexin, a similar gene therapy approach from Introgen, was turned down by the US Food and Drug Administration (FDA) in 2008.

Concerns about the safety of adenovirus vectors were raised after the 1999 death of Jesse Gelsinger while participating in a gene therapy trial. Since then, work using adenovirus vectors has focused on genetically crippled versions of the virus.

The viral vectors described above have natural host cell populations that they infect most efficiently. Retroviruses have limited natural host cell ranges, and although adenovirus and adeno-associated virus are able to infect a relatively broader range of cells efficiently, some cell types are refractory to infection by these viruses as well. Attachment to and entry into a susceptible cell is mediated by the protein envelope on the surface of a virus. Retroviruses and adeno-associated viruses have a single protein coating their membrane, while adenoviruses are coated with both an envelope protein and fibers that extend away from the surface of the virus. The envelope proteins on each of these viruses bind to cell-surface molecules such as heparin sulfate, which localizes them upon the surface of the potential host, as well as with the specific protein receptor that either induces entry-promoting structural changes in the viral protein, or localizes the virus in endosomes wherein acidification of the lumen induces this refolding of the viral coat. In either case, entry into potential host cells requires a favorable interaction between a protein on the surface of the virus and a protein on the surface of the cell. For the purposes of gene therapy, one might either want to limit or expand the range of cells susceptible to transduction by a gene therapy vector. To this end, many vectors have been developed in which the endogenous viral envelope proteins have been replaced by either envelope proteins from other viruses, or by chimeric proteins. Such chimera would consist of those parts of the viral protein necessary for incorporation into the virion as well as sequences meant to interact with specific host cell proteins. Viruses in which the envelope proteins have been replaced as described are referred to as pseudotyped viruses. For example, the most popular retroviral vector for use in gene therapy trials has been the lentivirus Simian immunodeficiency virus coated with the envelope proteins, G-protein, from Vesicular stomatitis virus. This vector is referred to as VSV G-pseudotyped lentivirus, and infects an almost universal set of cells. This tropism is characteristic of the VSV G-protein with which this vector is coated. Many attempts have been made to limit the tropism of viral vectors to one or a few host cell populations. This advance would allow for the systemic administration of a relatively small amount of vector. The potential for off-target cell modification would be limited, and many concerns from the medical community would be alleviated. Most attempts to limit tropism have used chimeric envelope proteins bearing antibody fragments. These vectors show great promise for the development of "magic bullet" gene therapies.

A replication-competent vector called ONYX-015 is used in replicating tumor cells. It was found that in the absence of the E1B-55Kd viral protein, adenovirus caused very rapid apoptosis of infected, p53(+) cells, and this results in dramatically reduced virus progeny and no subsequent spread. Apoptosis was mainly the result of the ability of EIA to inactivate p300. In p53(-) cells, deletion of E1B 55kd has no consequence in terms of apoptosis, and viral replication is similar to that of wild-type virus, resulting in massive killing of cells.

A replication-defective vector deletes some essential genes. These deleted genes are still necessary in the body so they are replaced with either a helper virus or a DNA molecule.

[3]

Replication-defective vectors always contain a transfer construct. The transfer construct carries the gene to be transduced or transgene. The transfer construct also carries the sequences which are necessary for the general functioning of the viral genome: packaging sequence, repeats for replication and, when needed, priming of reverse transcription. These are denominated cis-acting elements, because they need to be on the same piece of DNA as the viral genome and the gene of interest. Trans-acting elements are viral elements, which can be encoded on a different DNA molecule. For example, the viral structural proteins can be expressed from a different genetic element than the viral genome.

[3]

The Herpes simplex virus is a human neurotropic virus. This is mostly examined for gene transfer in the nervous system. The wild type HSV-1 virus is able to infect neurons and evade the host immune response, but may still become reactivated and produce a lytic cycle of viral replication. Therefore, it is typical to use mutant strains of HSV-1 that are deficient in their ability to replicate. Though the latent virus is not transcriptionally apparent, it does possess neuron specific promoters that can continue to function normally[further explanation needed]. Antibodies to HSV-1 are common in humans, however complications due to herpes infection are somewhat rare.[4] Caution for rare cases of encephalitis must be taken and this provides some rationale to using HSV-2 as a viral vector as it generally has tropism for neuronal cells innervating the urogenital area of the body and could then spare the host of severe pathology in the brain.

Non-viral methods present certain advantages over viral methods, with simple large scale production and low host immunogenicity being just two. Previously, low levels of transfection and expression of the gene held non-viral methods at a disadvantage; however, recent advances in vector technology have yielded molecules and techniques with transfection efficiencies similar to those of viruses.[5]

This is the simplest method of non-viral transfection. Clinical trials carried out of intramuscular injection of a naked DNA plasmid have occurred with some success; however, the expression has been very low in comparison to other methods of transfection. In addition to trials with plasmids, there have been trials with naked PCR product, which have had similar or greater success. Cellular uptake of naked DNA is generally inefficient. Research efforts focusing on improving the efficiency of naked DNA uptake have yielded several novel methods, such as electroporation, sonoporation, and the use of a "gene gun", which shoots DNA coated gold particles into the cell using high pressure gas.[6]

Electroporation is a method that uses short pulses of high voltage to carry DNA across the cell membrane. This shock is thought to cause temporary formation of pores in the cell membrane, allowing DNA molecules to pass through. Electroporation is generally efficient and works across a broad range of cell types. However, a high rate of cell death following electroporation has limited its use, including clinical applications.

More recently a newer method of electroporation, termed electron-avalanche transfection, has been used in gene therapy experiments. By using a high-voltage plasma discharge, DNA was efficiently delivered following very short (microsecond) pulses. Compared to electroporation, the technique resulted in greatly increased efficiency and less cellular damage.

The use of particle bombardment, or the gene gun, is another physical method of DNA transfection. In this technique, DNA is coated onto gold particles and loaded into a device which generates a force to achieve penetration of the DNA into the cells, leaving the gold behind on a "stopping" disk.

Sonoporation uses ultrasonic frequencies to deliver DNA into cells. The process of acoustic cavitation is thought to disrupt the cell membrane and allow DNA to move into cells.

In a method termed magnetofection, DNA is complexed to magnetic particles, and a magnet is placed underneath the tissue culture dish to bring DNA complexes into contact with a cell monolayer.

Hydrodynamic delivery involves rapid injection of a high volume of a solution into vasculature (such as into the inferior vena cava, bile duct, or tail vein). The solution contains molecules that are to be inserted into cells, such as DNA plasmids or siRNA, and transfer of these molecules into cells is assisted by the elevated hydrostatic pressure caused by the high volume of injected solution.[7][8][9]

The use of synthetic oligonucleotides in gene therapy is to deactivate the genes involved in the disease process. There are several methods by which this is achieved. One strategy uses antisense specific to the target gene to disrupt the transcription of the faulty gene. Another uses small molecules of RNA called siRNA to signal the cell to cleave specific unique sequences in the mRNA transcript of the faulty gene, disrupting translation of the faulty mRNA, and therefore expression of the gene. A further strategy uses double stranded oligodeoxynucleotides as a decoy for the transcription factors that are required to activate the transcription of the target gene. The transcription factors bind to the decoys instead of the promoter of the faulty gene, which reduces the transcription of the target gene, lowering expression. Additionally, single stranded DNA oligonucleotides have been used to direct a single base change within a mutant gene. The oligonucleotide is designed to anneal with complementarity to the target gene with the exception of a central base, the target base, which serves as the template base for repair. This technique is referred to as oligonucleotide mediated gene repair, targeted gene repair, or targeted nucleotide alteration.

To improve the delivery of the new DNA into the cell, the DNA must be protected from damage and positively charged. Initially, anionic and neutral lipids were used for the construction of lipoplexes for synthetic vectors. However, in spite of the facts that there is little toxicity associated with them, that they are compatible with body fluids and that there was a possibility of adapting them to be tissue specific; they are complicated and time consuming to produce so attention was turned to the cationic versions.

Cationic lipids, due to their positive charge, were first used to condense negatively charged DNA molecules so as to facilitate the encapsulation of DNA into liposomes. Later it was found that the use of cationic lipids significantly enhanced the stability of lipoplexes. Also as a result of their charge, cationic liposomes interact with the cell membrane, endocytosis was widely believed as the major route by which cells uptake lipoplexes. Endosomes are formed as the results of endocytosis, however, if genes can not be released into cytoplasm by breaking the membrane of endosome, they will be sent to lysosomes where all DNA will be destroyed before they could achieve their functions. It was also found that although cationic lipids themselves could condense and encapsulate DNA into liposomes, the transfection efficiency is very low due to the lack of ability in terms of endosomal escaping. However, when helper lipids (usually electroneutral lipids, such as DOPE) were added to form lipoplexes, much higher transfection efficiency was observed. Later on, it was figured out that certain lipids have the ability to destabilize endosomal membranes so as to facilitate the escape of DNA from endosome, therefore those lipids are called fusogenic lipids. Although cationic liposomes have been widely used as an alternative for gene delivery vectors, a dose dependent toxicity of cationic lipids were also observed which could limit their therapeutic usages.

The most common use of lipoplexes has been in gene transfer into cancer cells, where the supplied genes have activated tumor suppressor control genes in the cell and decrease the activity of oncogenes. Recent studies have shown lipoplexes to be useful in transfecting respiratory epithelial cells.

Polymersomes are synthetic versions of liposomes (vesicles with a lipid bilayer), made of amphiphilic block copolymers. They can encapsulate either hydrophilic or hydrophobic contents and can be used to deliver cargo such as DNA, proteins, or drugs to cells. Advantages of polymersomes over liposomes include greater stability, mechanical strength, blood circulation time, and storage capacity.[10][11][12]

Complexes of polymers with DNA are called polyplexes. Most polyplexes consist of cationic polymers and their fabrication is based on self-assembly by ionic interactions. One important difference between the methods of action of polyplexes and lipoplexes is that polyplexes cannot directly release their DNA load into the cytoplasm. As a result, co-transfection with endosome-lytic agents such as inactivated adenovirus was required to facilitate nanoparticle escape from the endocytic vesicle made during particle uptake. However, a better understanding of the mechanisms by which DNA can escape from endolysosomal pathway, i.e. proton sponge effect,[13] has triggered new polymer synthesis strategies such as incorporation of protonable residues in polymer backbone and has revitalized research on polycation-based systems.[14]

Due to their low toxicity, high loading capacity, and ease of fabrication, polycationic nanocarriers demonstrate great promise compared to their rivals such as viral vectors which show high immunogenicity and potential carcinogenicity, and lipid-based vectors which cause dose dependence toxicity. Polyethyleneimine[15] and chitosan are among the polymeric carriers that have been extensively studies for development of gene delivery therapeutics. Other polycationic carriers such as poly(beta-amino esters)[16] and polyphosphoramidate[17] are being added to the library of potential gene carriers. In addition to the variety of polymers and copolymers, the ease of controlling the size, shape, surface chemistry of these polymeric nano-carriers gives them an edge in targeting capability and taking advantage of enhanced permeability and retention effect.[18]

A dendrimer is a highly branched macromolecule with a spherical shape. The surface of the particle may be functionalized in many ways and many of the properties of the resulting construct are determined by its surface.

In particular it is possible to construct a cationic dendrimer, i.e. one with a positive surface charge. When in the presence of genetic material such as DNA or RNA, charge complimentarity leads to a temporary association of the nucleic acid with the cationic dendrimer. On reaching its destination the dendrimer-nucleic acid complex is then taken into the cell via endocytosis.

In recent years the benchmark for transfection agents has been cationic lipids. Limitations of these competing reagents have been reported to include: the lack of ability to transfect some cell types, the lack of robust active targeting capabilities, incompatibility with animal models, and toxicity. Dendrimers offer robust covalent construction and extreme control over molecule structure, and therefore size. Together these give compelling advantages compared to existing approaches.

Producing dendrimers has historically been a slow and expensive process consisting of numerous slow reactions, an obstacle that severely curtailed their commercial development. The Michigan-based company Dendritic Nanotechnologies discovered a method to produce dendrimers using kinetically driven chemistry, a process that not only reduced cost by a magnitude of three, but also cut reaction time from over a month to several days. These new "Priostar" dendrimers can be specifically constructed to carry a DNA or RNA payload that transfects cells at a high efficiency with little or no toxicity.[citation needed]

Inorganic nanoparticles, such as gold, silica, iron oxide (ex. magnetofection) and calcium phosphates have been shown to be capable of gene delivery.[19] Some of the benefits of inorganic vectors is in their storage stability, low manufacturing cost and often time, low immunogenicity, and resistance to microbial attack. Nanosized materials less than 100nm have been shown to efficiently trap the DNA or RNA and allows its escape from the endosome without degradation. Inorganics have also been shown to exhibit improved in vitro transfection for attached cell lines due to their increased density and preferential location on the base of the culture dish. Quantum dots have also been used successfully and permits the coupling of gene therapy with a stable fluorescence marker.

Cell-penetrating peptides (CPPs), also known as peptide transduction domains (PTDs), are short peptides (< 40 amino acids) that efficiently pass through cell membranes while being covalently or non-covalently bound to various molecules, thus facilitating these molecules entry into cells. Cell entry occurs primarily by endocytosis but other entry mechanisms also exist. Examples of cargo molecules of CPPs include nucleic acids, liposomes, and drugs of low molecular weight.[20][21]

CPP cargo can be directed into specific cell organelles by incorporating localization sequences into CPP sequences. For example, nuclear localization sequences are commonly used to guide CPP cargo into the nucleus.[22] For guidance into mitochondria, a mitochondrial targeting sequence can be used; this method is used in protofection (a technique that allows for foreign mitochondrial DNA to be inserted into cells' mitochondria).[23][24]

Due to every method of gene transfer having shortcomings, there have been some hybrid methods developed that combine two or more techniques. Virosomes are one example; they combine liposomes with an inactivated HIV or influenza virus. This has been shown to have more efficient gene transfer in respiratory epithelial cells than either viral or liposomal methods alone. Other methods involve mixing other viral vectors with cationic lipids or hybridising viruses.

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Gene Therapy Retrovirus Vectors Explained

Wednesday, July 12th, 2017

A retrovirus is any virus belonging to the viral family Retroviridae. All The genetic material in retroviruses is in the form of RNA molecules, while the genetic material of their hosts is in the form of DNA. When a retrovirus infects a host cell, it will introduce its RNA together with some enzymes into the cell. This RNA molecule from the retrovirus must produce a DNA copy from its RNA molecule before it can be considered part of the genetic material of the host cell. Retrovirus genomes commonly contain these three open reading frames that encode for proteins that can be found in the mature virus. Group-specific antigen (gag) codes for core and structural proteins of the virus, polymerase (pol) codes for reverse transcriptase, protease and integrase, and envelope (env) codes for the retroviral coat proteins (see figure 1).Figure 1. Genome organisation of retroviruses.

The process of producing a DNA copy from an RNA molecule is termed reverse transcription. It is carried out by one of the enzymes carried in the virus, called reverse transcriptase. After this DNA copy is produced and is free in the nucleus of the host cell, it must be incorporated into the genome of the host cell. That is, it must be inserted into the large DNA molecules in the cell (the chromosomes). This process is done by another enzyme carried in the virus called integrase (see figure 2).

Now that the genetic material of the virus is incorporated and has become part of the genetic material of the host cell, we can say that the host cell is now modified to contain a new gene. If this host cell divides later, its descendants will all contain the new genes. Sometimes the genes of the retrovirus do not express their information immediately.

Retroviral vectors are created by removal op the retroviral gag, pol, and env genes. These are replaced by the therapeutic gene. In order to produce vector particles a packaging cell is essential. Packaging cell lines provide all the viral proteins required for capsid production and the virion maturation of the vector. These packaging cell lines have been made so that they contain the gag, pol and env genes. Early packaging cell lines contained replication competent retroviral genomes and a single recombination event between this genome and the retroviral DNA vector could result in the production of a wild type virus. Following insertion of the desired gene into in the retroviral DNA vector, and maintainance of the proper packaging cell line, it is now a simple matter to prepare retroviral vectors (see figure 3).

One of the problems of gene therapy using retroviruses is that the integrase enzyme can insert the genetic material of the virus in any arbitrary position in the genome of the host. If genetic material happens to be inserted in the middle of one of the original genes of the host cell, this gene will be disrupted (insertional mutagenesis). If the gene happens to be one regulating cell division, uncontrolled cell division (i.e., cancer) can occur. This problem has recently begun to be addressed by utilizing zinc finger nucleases or by including certain sequences such as the beta-globin locus control region to direct the site of integration to specific chromosomal sites.

Gene therapy trials to treat severe combined immunodeficiency (SCID) were halted or restricted in the USA when leukemia was reported in three of eleven patients treated in the French X-linked SCID (X-SCID) gene therapy trial. Ten X-SCID patients treated in England have not presented leukemia to date and have had similar success in immune reconstitution. Gene therapy trials to treat SCID due to deficiency of the Adenosine Deaminase (ADA) enzyme continue with relative success in the USA, Italy and Japan.

As a reaction to the adverse events in the French X-SCID gene therapy trial, the Recombinant DNA Advisory Committee (RAC) sent a letter to Principal Investigators Conveying RAC Recommendations in 2003. In addition, the RAC published conclusions and recommendations of the RAC Gene Transfer Safety Symposium in 2005. A joint working party of the Gene Therapy Advisory Committee and the Committee on Safety of Medicines (CSM) in the UK lead to the publication of an updated recommendations of the GTAC/CSM working party on retroviruses in 2005.

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FDA advisers endorse what could be 1st US gene therapy – ABC News

Wednesday, July 12th, 2017

A panel of cancer experts Wednesday recommended approval of what could become the first gene therapy available in the U.S.

The Food and Drug Administration advisory panel voted 10-0 in favor of an advanced leukemia treatment developed by the University of Pennsylvania and Novartis Corp. The FDA usually follows recommendations of its expert panels, but isn't obligated to do so.

The therapy could be the first of a wave of treatments custom-made to target a patient's cancer. Called CAR-T, it involves removing immune cells from a patients' blood, reprogramming them to create an army of cells that can zero in on and destroy cancer cells, and injecting them back into the patient.

"This is a major advance," said panel member Dr. Malcolm A. Smith of the National Cancer Institute. He said the treatment is "ushering in a new era."

The vote came after lengthy discussion and impassioned pleas from the fathers of two young patients whose lives were saved by the therapy. The one-time leukemia treatment would be for children and young adults with the most common form of childhood cancer, known as ALL.

"Our daughter was going to die and now she leads a normal life," said Tom Whitehead, of Philipsburg, Pennsylvania. His daughter Emily, now 12, was the first child to receive the experimental therapy, five years ago. "We believe when this treatment is approved, it will save thousands of children's lives around the world."

After decades of setbacks and disappointments in efforts to fix, replace, or change genes to cure diseases, several companies are near the finish line in a race to bring CAR-T and other types of gene therapy to patients. Kite Pharma also has a CAR-T therapy in FDA review and Juno Therapeutics and others are in late stages of testing.

Novartis is seeking approval to use the treatment for patients aged 3 to 25 with a blood cancer called acute lymphoblastic leukemia whose disease has spread or failed to respond to standard treatment. That happens to more than 600 patients in the U.S. each year. At that point, they have limited options all more toxic than the CAR-T therapy and survival chances are slim. ALL accounts for a quarter of all cancers in children under age 15.

In a key test, results were far better than chemotherapy and even newer types of cancer drugs. Of the 52 patients whose results were analyzed, 83 percent had complete remission, meaning their cancer vanished. Most patients suffered serious side effects but nearly all recovered.

CAR-T therapy starts with filtering key immune cells called T cells from a patient's blood. In a lab, a gene is then inserted into the T cells that prompts them to grow a receptor that targets a special marker found on some blood cancers. Millions of copies of the new T cells are grown in the lab and then injected into the patient's bloodstream where they can seek out and destroy cancer cells. Doctors call it a "living drug" permanently altered cells that continue to multiply in the body into an army to fight the disease.

During the patient testing, the whole process took about 16 weeks, which can be too long a wait for some desperately ill patients, the FDA advisers noted during the meeting in Silver Spring, Maryland. Drug company officials said they can now produce a treatment and get it to a patient in about three weeks.

Novartis said in a statement that it has long believed CAR-T therapy could "change the cancer treatment paradigm."

The cost of CAR-T therapy is likely to be hundreds of thousands of dollars, but it's only given once. Typically, cancer patients take one or more drugs until they stop working, then switch to other drugs, so treatment and side effects can go on for years.

The treatment's short-term side effects, including fever and hallucinations, are often intense as the body's revved up immune system goes on the attack. The long-term side effects of the treatment are unknown. It's also unclear if patients whose cancer goes into remission will be cured or will have their cancer return eventually. The FDA panel recommended that patients who get the treatment be monitored for 15 years.

Other biotech and pharmaceutical companies are developing types of gene therapy to treat solid cancers and rare gene-linked diseases. A few products have been approved elsewhere one for head and neck cancer in China in 2004 and two in Europe, most recently GlaxoSmithKline's Strimvelis. That was approved last year for a deadly condition called severe combined immunodeficiency and launched with a $670,000 price tag.

UniQure's Glybera was approved for a rare enzyme disorder. It was used only once in five years, likely due to its $1 million-plus price tag, so uniQure is pulling it from the market.

Follow Linda A. Johnson at https://twitter.com/LindaJonPharma

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South Korea OKs First-in-Class Gene Therapy for Osteoarthritis – Genetic Engineering & Biotechnology News

Wednesday, July 12th, 2017

South Koreas Ministry of Food and Drug Safety said today that it has approved the countrys first gene therapy for osteoarthritis, the lead product candidate of a Maryland-based regenerative medicine company.

Invossa-K Inj. was developed by Maryland-based TissueGene, whose Korean licensee, Kolon Life Sciences, won approval for the injectable treatment. According to the company, Invossa is a first-in-class cell-mediated gene therapy designed to treat moderate (Kellgren and Lawrence grade 3) knee osteoarthritis through regeneration of cartilage.

Invossa uses allogeneic human cartilage cells engineered to express transforming growth factor TGF-1. TissueGenes platform technology involves transducing the cells with a retroviral vector engineered to express TGF-1 at a specific therapeutic level and duration of time.

The modified cell lines are further selected and screened for cellular expression characteristics intended to minimize patient immune response to the injected cellsthen mixed with unmodified cells to create cartilage regeneration via Invossa, as well as bone, disc, and nerve regeneration through the companys other product candidates.

Invossa is designed for a single injection directly into the knee joint, allowing the cells to induce repair and regeneration of tissue by secreting therapeutic growth factors. The gene therapyincluded in GENs recent roundup of Top Trends in Tissue Engineeringis an alternative to surgery for arthritis patients, according to Kolon.

Kolon has said injection of Invossa has been shown in Phase III trials in Korea to ease the symptoms of about 84% of patientswhile 88% of U.S. patients treated with the gene therapy in Phase 2 trials reported improved symptoms for up to two years.

Invossa is being assessed in a Phase III trial in the U.S. after TissueGene and the FDA came to agreement on a Special Protocol Assessment (SPA) for the study. The company is seeking agency approval for the gene therapy as the first disease-modifying osteoarthritis drug (DMOAD).

Kolon has also inked an exclusive licensing and development agreement with Mitsubishi Tanabe Pharma to market the drug in Japan. Under that deal, Mitsubishi Tanabe agreed to pay approximately $24 million upfront plus up to $410 million in payments tied to achieving development, regulatory, and commercial milestones, plus double-digit sales royalties.

In Korea, Mundipharma plans to market and distribute Invossa to general and semiprivate hospitals, while Kolon focuses on general practitioners, under an agreement announced April 11.

With the Korean drug ministrys approval, Invossa became the 29th South Koreandeveloped novel therapy approved by the countrys drug regulatory agencyand one of only four cell gene therapies to have ever been approved globally. The others were approved to treat immunodeficiency diseases, genetic disorders, and cancer.

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South Korea OKs First-in-Class Gene Therapy for Osteoarthritis - Genetic Engineering & Biotechnology News

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FDA cancer advisers consider what would be first gene therapy in US – Chicago Sun-Times

Wednesday, July 12th, 2017

An experimental therapy for treating children and young adults with advanced leukemia could be the first gene therapy approved in the United States, potentially opening the door to a wave of treatments custom-made to target a patients cancer.

A panel of cancer experts that advises the federal Food and Drug Administration panel is holding a hearing Wednesday to discuss the treatment developed by the University of Pennsylvania and Novartis Corp.

The drugmaker is seeking approval to use the one-time treatment for children and young adults.

Called CAR-T, it involves removing immune cells from patients blood, genetically altering them in effect, reprogramming them to create an army of attack cells and then putting them back in the patients to fight these blood cancers.

The therapy could pave the way for other individualized, custom-made cancer treatments. Dr. Carl June, the Penn scientist who led the development of this immunotherapy, told the Washington Post it would be a true living drug.

The panel is reviewing the safety, effectiveness and production of the treatment. It will vote on whether to recommend FDA approval. The federal agency typically goes along with the recommendations of its advisory panels.

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FDA cancer advisers consider what would be first gene therapy in US - Chicago Sun-Times

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New Gene Therapy Shows Promise for Dire Cancer Cases – 41 NBC News

Wednesday, July 12th, 2017

Dimas Padilla, 43, of Kissimmee, is in remission from non-Hodgkins lymphoma after receiving an experimental cancer therapy called CAR-T. Here, he poses with his wife, Johanna Padilla. NBC News

Its worked well in patients who had no other options after going through rounds of chemo and bone marrow transplants. More than one-third of patients who got the treatment 39 percent are tumor-free nine months later, researchers will tell a meeting of the American Association for Cancer Research that starts this weekend.

These are patients who really are without hope, Locke said.

Patients who at best could expect to have a one in 10 chance of having a complete disappearance of their lymphoma, he added. So the results are really exciting and remarkable.

More than 80 percent of the 101 patients who got the treatment were still alive six months later. Only about half the patients who (went) on this study could expect to even be alive six months after the therapy, Locke said.

Padilla is one of them. When the cancer came back most recently time, his lymph nodes were bulging. They were so bad that they moved my vocal cords to the side and I was without my voice for almost three months, he said.

They kept growing and my face was swelling, and I thought I was going to choke while I was sleeping.

Padilla was among the last patients enrolled in the trial.

Once they infused the cells in my body, within two to three days all my lymph nodes started melting like ice cubes, he said.

The treatment is no cake walk. Just as with a bone marrow transplant, the patients immune system must be damaged so that the newly engineered T-cells can do their work. That involves some harsh chemotherapy.

Its so harsh that it killed three of the patients in the trial. Padilla says he still has some memory loss from his bout with the chemo.

Related:

Cancer Moonshot Panel Says Focus on Immune Therapies

I had some fevers and I was shaking and a little bit of memory loss but it was temporary, he said. I will say that it was pretty intense for like a week, but in my second week, second week and a half, I was starting to feel more normal. I was able to start walking and the shaking was not as bad as it was in the beginning, he said.

And when he got the news that his lymphoma was gone at least for now Padilla was delighted.

I kissed my wife. I probably kissed the doctor, he said.

The company developing the treatment, Kite Pharma, sought Food and Drug Administration approval for the therapy on Friday.

It carries the tongue-twisting name of axicabtagene ciloleucel, and its the first commercial CAR-T product to get into the FDA approval process.

Its far too early to say any of the patients were cured, Locke cautions. And such a difficult treatment course is really only for patients in the most desperate condition.

The patients in this trial were really without options, he said.

But Locke is sold on the approach. This is a revolution. Its a revolution in cancer care. This is the tip of the iceberg, he said.

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FDA panel to focus on safety of Novartis gene therapy drug – Reuters

Wednesday, July 12th, 2017

(Reuters) - The U.S. Food and Drug Administration will ask a panel of advisors to focus on the safety of Novartis AG's experimental gene therapy drug when it meets to review the product on Wednesday.

The keenly anticipated preliminary review of the leukemia treatment, posted on the FDA's website on Monday, comes two days ahead of the advisory panel meeting, which will discuss the drug and vote on whether the benefits exceed the risks.

If approved, the drug, tisagenlecleucel, would be the first gene therapy to be approved in the United States. The FDA is not obliged to follow the recommendations of its advisors but typically does so.

The panel's decision could have significant implications not only for Novartis but for companies making similar drugs, including Kite Pharma Inc. Juno Therapeutics Inc and bluebird bio Inc.

The drugs use a new technology known as CAR-T, or chimeric antigen receptor T-cell therapy, which harnesses the body's own immune cells to recognize and attack malignant cells.

If approved they are expected to cost up to $500,000 and generate billions of dollars for their developers. Success would also help advance a cancer-fighting technique that scientists have been trying to perfect for decades.

Novartis is applying for approval in the first instance to treat B-cell acute lymphoblastic leukemia (ALL), the most common type of childhood cancer in the United States.

A clinical trial showed that 83 percent of patients who had relapsed or failed chemotherapy achieved complete or partial remission three months post infusion. Patients with ALL who fail chemotherapy typically have only a 16 to 30 percent chance of survival.

The FDA said it is not asking the panel to focus on whether the drug works, as it successfully met the main goal of the clinical trial. The panel will be asked only to focus on the short-term and long-term safety risks.

About half the patients experienced a serious complication known as cytokine release syndrome (CRS) which occurs when the body's immune system goes into overdrive. Doctors were able to manage the condition and it caused no patient deaths.

The FDA also raised concerns that the drug may cause secondary malignancies to occur and said long-term safety monitoring may be needed to address this concern.

Novartis is also testing its drug in diffuse large b-cell Lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, as is Kite. Part of the competitive landscape will include which company is best able to manufacture its drugs efficiently and reliably.

Reporting by Toni Clarke in Washington; Editing by Nick Zieminski

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uniQure Presents New Clinical Data in Hemophilia B Patients Demonstrating Therapeutic Efficacy of AAV5 Gene … – GlobeNewswire (press release)

Tuesday, July 11th, 2017

July 11, 2017 06:30 ET | Source: uniQure N.V.

LEXINGTON, Mass. and AMSTERDAM, the Netherlands, July 11, 2017 (GLOBE NEWSWIRE) -- uniQure N.V. (NASDAQ:QURE), a leading gene therapy company advancing transformative therapies for patients with severe medical needs, today presented new clinical data demonstrating that the presence of pre-existing anti-AAV5 neutralizing antibodies (NABs) does not predict the potential efficacy of AAV5-mediated gene transfer in patients with hemophilia B. Clinically meaningful factor IX (FIX) activity levels from the ongoing Phase I-II trial of AMT-060 were observed at NAB titers up to 1:341, determined as corresponding up to the 90th percentile of a healthy control population. NABs were quantified in the blood sera of these patients using a highly sensitive assay. These clinical data were presented today in a poster presentation at the 26th Biennial Congress of theInternational Society on Thrombosis and Hemostasis(ISTH), taking place this week in Berlin, Germany.

The presence of pre-existing NABs to adeno-associated virus (AAV) vectors has long posed a critical challenge for the clinical application of gene therapies, as patients who currently screen positive for NABs are generally excluded from treatment. Researchers from uniQure recently presented data in non-human primates suggesting that AAV5 could successfully mediate gene transfer in the presence of NABs at levels as high as 1:1031.

In a poster presentation at the ISTH meeting, a re-analysis was described of pre-gene transfer screening samples from the 10 patients who have been treated in the ongoing Phase I/II trial of AMT-060 for hemophilia B. The patients had tested negative for preexisting anti-AAV5 NAbs using a green fluorescent proteinbased (GFP) assay before receiving treatment. These samples were later re-assessed using a highly sensitive luciferase-based (LUC) NAB assay. Anti-AAV5 NABs were detected retrospectively in three patients who had been treated with the low dose (5x1012 gc/kg) of AMT-060. However, all three patients presented increases in FIX expression and, especially, the patient with the highest NAB level (titer 1:341) had the highest FIX-activity (steady-state FIX 6.8% of normal; latest FIX measurement 10.7% of normal) among all five patients treated in the low-dose cohort. None of the three patients who tested positive for NAB titers, experienced over time elevations in liver enzymes post gene transfer, FIX activity loss, or clinically relevant T-cell responses to the capsid.

These clinical data show that hemophilia B patients presenting with neutralizing antibodies may be considered eligible for AAV5-mediated gene transfer, stated Matthew Kapusta, chief executive officer at uniQure. This development potentially expands the applicability of AAV5 gene therapies to nearly all hemophilia B patients. We believe these factors contribute to making AAV5 a potential best-in-class vector for delivering gene therapies more effectively and safely to a greater portion of patients in need of treatment.

About uniQure uniQure is delivering on the promise of gene therapy single treatments with potentially curative results. We are leveraging our modular and validated technology platform to rapidly advance a pipeline of proprietary and partnered gene therapies to treat patients with hemophilia, Huntingtons disease and cardiovascular diseases. http://www.uniQure.com

uniQure Forward-Looking Statements This press release contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as "anticipate," "believe," "could," "estimate," "expect," "goal," "intend," "look forward to", "may," "plan," "potential," "predict," "project," "should," "will," "would" and similar expressions. Forward-looking statements are based on management's beliefs and assumptions and on information available to management only as of the date of this press release. These forward-looking statements include, but are not limited to, statements regarding the development of our gene therapy product candidates, including the future development of AMT-060, the success of our collaborations and the risk of cessation, delay or lack of success of any of our ongoing or planned clinical studies and/or development of our product candidates. Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including, without limitation, risks associated with corporate reorganizations and strategic shifts, collaboration arrangements, our and our collaborators clinical development activities, regulatory oversight, product commercialization and intellectual property claims, as well as the risks, uncertainties and other factors described under the heading "Risk Factors" in uniQures 2016 Annual Report on Form 10-K filed on March 15, 2017. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and we assume no obligation to update these forward-looking statements, even if new information becomes available in the future.

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uniQure Presents New Clinical Data in Hemophilia B Patients Demonstrating Therapeutic Efficacy of AAV5 Gene ... - GlobeNewswire (press release)

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BioMarin’s Investigational Gene Therapy for Hemophilia A at 6e13 … – PR Newswire (press release)

Tuesday, July 11th, 2017

BioMarin Pharmaceutical Inc. (NASDAQ: BMRN) announced today an update to its previously reported interim results of an open-label Phase 1/2 study of BMN 270, an investigational gene therapy treatment for severe hemophilia A. The updated results will be presented by John Pasi, Ph.D. F.R.C.P, at Barts and the London School of Medicine and Dentistry and Haemophilia Clinical Director at Barts Health NHS Trust and primary investigator for the BMN 270 Phase 1/2 clinical trial, during an oral presentation at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress being held July 8-13, 2017 in Berlin, Germany. Professor Pasi will present the data in a late breaking abstract on July 11, 2017, which will be the only clinical data in gene therapy for hemophilia A to be presented at the meeting.

In the open-label Phase 1/2 study, a total of 15 patients with severe hemophilia A1(defined by the World Federation of Hemophilia (WFH) as having Factor VIII activity levels less than 1%, expressed as a percentage of normal factor activity in blood) received a single dose of BMN 270, seven of whom were treated at a dose of 6e13 vg/kg and an additional six of whom were subsequently treated at a lower dose of 4e13 vg/kg. The other two patients in the study were treated at lower doses as part of dose escalation in the study and did not achieve therapeutic efficacy. According to the WFH rankings of severity of hemophilia A, the normal range of Factor VIII activity levels for people without disease is between 50% and 150%, expressed as a percentage of normal factor activity in blood, and the mild hemophilia A range of Factor VIII activity levels is between 5% and 40%. (See Table 6 for further information on severity levels)

As of the May 31, 2017 data cutoff, all patients at the 6e13 vg/kg dose had reached 52 weeks of post-treatment follow-up. Median and mean Factor VIII levels from week 20 through 52 for the 6e13 vg/kg dose cohort have been consistently within the normal levels post treatment as a percentage calculated based on the numbers of International Units per deciliter (IU/dL) of plasma. (See Table 1). At one year after dosing, the median and mean Factor VIII levels of the 6e13 vg/kg cohort continue to be above 50%. (See Table 6)

Table 1: Factor VIII Levels (%) of 6e13 vg/kg Dose Patients* by Visit (N=7)

Week**

20

24

28

32

36

40

44

48

52

6e13 vg/kg Dose

N***

7

7

7

6

7

7

7

7

7

Median

Factor VIII Level**** (%)

97

101

122

99

99

111

105

105

89

Mean

Factor VIII Level**** (%)

118

129

123

122

116

124

122

106

104

Range

(low, high)

(12, 254)

(12, 227)

(15, 257)

(26, 316)

(31, 273)

(17, 264)

(20,242)

(23,196)

(20, 218)

*All patients had severe hemophilia A, defined as less than 1% of Factor VIII activity levels, expressed as a percentage of normal factor activity in blood. **Weeks were windowed by +/- 2 weeks ***For week 32, one patient had no Factor VIII reading ****Bolded numbers are in the normal range of Factor VIII as defined by the World Federation of Hemophilia, http://www.wfh.org/en/page.aspx?pid=643 (link current as of June 30, 2017). Factor VIII levels are determined by one-stage assay.

The median and mean Factor VIII levels from week 8 to 24 for all patients observed at the 4e13 vg/kg dose are in the mild level. Three of these subjects who have been observed for 24 weeks are at the upper end of mild. (See Table 2 for Factor VIII levels and Table 6 for severity levels)

Table 2: Factor VIII Levels (%) of 4e13 vg/kg Dose Patients* by Visit (N=6)

Week**

4

8

12

16

20

24

4e13 vg/kg Dose

n

6

6

6

3

3

3

Median

Factor VIII Level*** (%)

4

15

21

35

37

33

Mean

Factor VIII Level*** (%)

5

13

19

33

38

33

Range

(low, high)

(2,10)

(3,21)

(6,32)

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Breakthrough Nanorod Tech Could Deliver Gene Therapy Directly to Cancer Cells – Technology Networks

Tuesday, July 11th, 2017

A new method efficiently transfers genes into cells, then activates them with light. This could lead to gene therapies for cancers

Mineko Kengaku, Tatsuya Murakami, and their colleagues from Kyoto Universitys Institute for Integrated Cell-Material Sciences (iCeMS) have developed a new method that modifies the surface of nanorods, making them more efficient in transporting cancer-killing genes into cells.

The method involves coating gold nanorods, which produce heat when exposed to a near-infrared laser, with the lipids oleate and DOTAP. The lipids enhance the nanorods' ability to interact with and penetrate cells.

The team also developed a gene carrier, known as a plasmid vector, which includes a heat shock protein that is activated in response to heat.

First, the vector was bound to the enhanced green fluorescent protein (EGFP) gene, and then transferred into mammalian cells by the lipid-coated gold nanorods. Exposing cells to near-infrared laser for ten seconds heated up the gold nanorods, turning on the EGFP gene. Surrounding, non-targeted cells showed little to no EGFP expression.

A protein called TRAIL was then added to the plasmid vector. TRAIL induces cell death in cancer cell lines. Infrared illumination of cells transfected by TRAIL-carrying nanorods led to a high cell death rate in surrounding cancer cells.

The lipid-coated gold nanorods could potentially help with molecular cancer therapies.

This new system provides a unique opportunity for site-directed, light-inducible transgene expression in mammalian cells by a near-infrared laser, with minimal phototoxicity, conclude the researchers in their study published in the journal Scientific Reports.

This article has been republished frommaterialsprovided by Kyoto University. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference

Nakatsuji, H., Kawabata, G. K., Kurisu, J., Imahori, H., Murakami, T., & Kengaku, M. (2017). Surface chemistry for cytosolic gene delivery and photothermal transgene expression by gold nanorods. Scientific reports, 7(1), 4694.

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Pioneering gene therapy patients stay on track, boosting Spark’s … – Endpoints News

Tuesday, July 11th, 2017

After rattling investors with early signs of an immune reaction in a couple of cases as well as an unexpected infusion for a suspected knee bleed, Spark Therapeutics $ONCE says that its early Phase I/II study for its hemophilia B gene therapy is staying on track, slashing the rate of annual infusions and the bleed rate among the 10 patients on the pioneering therapy SPK-9001.

The annual infusion rate has new dropped 99%, down to a mean of 1 compared to 67.5 ahead of treatment. Five of the 10 are now past the one-year mark since their treatment, with no bleeding issues. The group of 10 posted an average bleed rate of 0.4 compared to 11.1 ahead of once-and-done therapy.

Singling out the first patient, whos now past the 18-month mark, researchers say hes had zero bleeds with no Factor IX infusions. Both cases of elevated liver enzymes indicating an immune response to the delivery vector were resolved with steroids and neither have had bleeds or the need for infusions.

Spark has now accumulated close to 10 years of patient responses to its therapy, an important first step in laying out the potential for gene therapy to end hemophilia.

The latest update arrived at a scientific conference in Berlin marked by the dramatic showdown between Shire and its rival Roche, which fielded more newly contested boasts about its would-be hemophilia blockbuster emicizumab. Alnylam and Sanofi also stepped up with a promising look at the latest Phase II data on their RNAi approach underscoring some significant gains in the field for a variety of new approaches to the rare blood disorder.

We continue to be encouraged by the SPK-9001 clinical trial results observed to date, with all participants having discontinued routine infusions of factor IX concentrates, said Katherine A. High, M.D., president and chief scientific officer at Spark Therapeutics. The growing body of data showing a sustained response is a promising sign for this investigational hemophilia B gene therapy program.

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Gene therapy in hemophilia advances with big drops in patient bleeding rates – STAT

Tuesday, July 11th, 2017

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First gene therapy ‘a true living drug’ on the cusp of FDA … – Washington Post

Tuesday, July 11th, 2017

PHILADELPHIA When doctors saw the report on Bill Ludwigs bone-marrow biopsy, they thought it was a mistake and ordered the test repeated. But the results came back the same: His lethal leukemia had been wiped out by an experimental treatment never used in humans.

We were hoping for a little improvement, remembers the 72-year-old retired New Jersey corrections officer, who had battled the disease for a decade. He and his oncologist both broke down when she delivered the good news in 2010. Nobody was hoping for zero cancer.

The pioneering therapy with Ludwig and a few other adults at the University of Pennsylvania hospital paved the way for clinical trials with children. Six-year-old Emily Whitehead, who was near death, became the first pediatric recipient in 2012. Like Ludwig, she remains cancer-free.

Such results are why the treatment is on track to become the first gene therapy approved by the Food and Drug Administration. An FDA advisory committee will decide Wednesday whether to recommend approval of the approach, which uses patients own genetically altered immune cells to fight blood cancers.

If the panel gives the nod, the agency probably will follow suit by the end of September. That would open the latest chapter in immunotherapy a true living drug, says Penn scientist Carl June, who led its development.

The CAR T-cell treatment, manufactured by the drug company Novartis, initially would be available only for the small number of children and young adults whose leukemia doesnt respond to standard care. Those patients typically have a grim prognosis, but in the pivotal trial testing the therapy in almost a dozen countries, 83 percent of patients went into remission. A year later, two-thirds remained so.

And childhood leukemia is just the start for a field that has attracted intense interest in academia and industry. Kite Pharma of Santa Monica, Calif., has applied for FDA approval for aggressive non-Hodgkin lymphoma, and a similar Novartis application is close behind. Researchers also are exploring CAR T-cell therapys use for multiple myeloma and chronic lymphocytic leukemia, the disease that afflicted Ludwig. Theyre also tackling a far more difficult challenge using the therapy for solid tumors in the lungs or brain, for example.

The excitement among doctors and researchers is palpable. Were saving patients who three or four years ago we were at our wits end trying to keep alive, said Stephen Schuster, the Penn oncologist who is leading a Novartis lymphoma study. Both the study and a Kite trial have shown that the treatment can put about one-third of adults with advanced disease those who have exhausted all options into remission.

Yet along with the enthusiasm come pressing questions about safety, cost and the complexity of the procedure.

It involves extracting white blood cells called T cells the foot soldiers of the immune system from a patients blood, freezing and sending them to Novartiss sprawling manufacturing plant in Morris Plains, N.J. There, a crippled HIV fragment is used to genetically modify the T cells so they can find and attack the cancer. The cells then are refrozen and sent back to be infused into the patient.

Once inside the persons body, the T-cell army multiplies astronomically.

Novartis hasnt disclosed the price for its therapy, but analysts are predicting $300,000 to $600,000 for a one-time infusion. Brad Loncar, whose index fund focuses on cancer immunotherapy treatment, hopes the cost doesnt prompt a backlash. CAR-T is not the EpiPen, he said. This is truly pushing the envelope and at the cutting edge of science.

The biggest concerns, however, center on safety. The revved-up immune system becomes a potent cancer-fighting agent but also a dangerous threat to the patient. Serious side effects abound, raising concerns about broad use.

Treating patients safely is the heart of the rollout, said Stephan Grupp of the Childrens Hospital of Philadephia, who as director of its Cancer Immunotherapy Program led early pediatric studies as well as Novartiss global trial. The efficacy takes care of itself, but safety takes a lot of attention.

One of the most common side effects is called cytokine release syndrome, which causes high fever and flulike symptoms that in some cases can be so dangerous that the patient ends up in intensive care. The other major worry is neurotoxicity, which can result in temporary confusion or potentially fatal brain swelling. Juno Therapeutics, a biotech firm in Seattle, had to shut down one of its CAR T-cell programs because five patients died of brain swelling. Novartis has not seen brain swelling in its trials, company officials said.

To try to ensure patient safety, Novartis isnt planning a typical product rollout, with a drug pushed as widely and aggressively as possible. The company instead will designate 30to 35 medical centers to administer the treatment. Many of them took part in the clinical trial, and all have gotten extensive training by Grupp and others.

Grupp said he and his staff learned about the side effects of CAR T-cell therapy and what to do about them through terrifying experience that began five years ago with Emily Whitehead.

The young girl, who had relapsed twice on conventional treatments for acute lymphoblastic leukemia, was in grave condition. Grupp suggested to her parents that she become the first child to get the experimental therapy.

I said, Surely, this has been tried on kids somewhere else in the world, recalled her father, Thomas Whitehead of Philipsburg, Pa. But Steve said, Nope, some adults got it, but that was a different kind of leukemia.

After getting the therapy, Emilys fever soared, her blood pressure plummeted, and she ended up in a coma and on a ventilator for two weeks in the hospitals intensive care unit. Convinced his patient would not survive another day, a frantic Grupp got rushed lab results that suggested a surge of interleukin 6 was causing her immune system to relentlessly hammer her body. Doctors decided to give Emily an immunosuppressant drug called tocilizumab.

She was dramatically better within hours. She woke up the next day, her 7th birthday. Tests showed her cancer was gone.

The approval of CAR T-cell therapy would represent the second big immunotherapy advance in less than a decade. In 2011, the FDA cleared the first agent in a new class of drugs called checkpoint inhibitors. It has approved four more since then.

There are big differences between the two approaches. The checkpoint inhibitors are targeted at solid tumors, such as advanced melanoma, lung and bladder cancer, while CAR-T cell therapy has been aimed at blood disorders. And although checkpoint inhibitors are off the shelf, with every patient getting the same drug, the other is customized to an individual. Many immunotherapy experts think the greatest progress against cancer will occur when researchers figure out how to combine the approaches.

For the Penn team, the CAR T-cell story goes back decades, starting at the then-National Naval Medical Center in Bethesda, where June and a postdoc fellow named Bruce Levine worked on new HIV treatments. In the process, they figured out a way to turbocharge T cells to make them more powerful and plentiful.

The pair moved to Philadelphia in 1999 and dove into cancer research. Two years later, Junes wife died of ovarian cancer, something he has credited as spurring him to work even harder in the field. In the years that followed, researchers across the country, including at Memorial Sloan Kettering Cancer Center in New York and Fred Hutchinson Cancer Research Center in Seattle racked up an array of tantalizing discoveries involving T cells.

Fast-forward to 2010, when Ludwig, who lives in Bridgeton, N.J. became Penns first patient to receive CAR T-cell therapy. Two other men got the treatment not long after. One is still in remission; the other relapsed and died.

But after those three patients, the Penn researchers ran out of money for more treatments. To try to raise interest and funding, they decided to publish the results of their work. The article that appeared in the New England Journal of Medicine in August 2011 created a firestorm, June said one that brought them new resources. David Porter, a Penn oncologist working with June, was on vacation in western Maryland and had to stop at a Kohls to buy a dress shirt for the immediate TV interviews.

The pediatric trial opened the following spring with Whitehead. Six months later, Penn licensed its technology to Novartis in exchange for financial support, which included a new cell-manufacturing facility on campus.

With FDA approval seeming imminent, the researchers who were so instrumental in the therapys development and testing are almost giddy. Grupp is especially pleased that the advance will be available first to children. Usually everything is developed first for adults, he noted recently, and children are an afterthought.

Read more:

This is not the end: Using immunotherapy and a genetic glitch to give cancer patients hope

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For a 6-year-old with cancer, a future staked on medicines hottest field

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First gene therapy 'a true living drug' on the cusp of FDA ... - Washington Post

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Vineti to fast-track cell and gene therapy tech with $14 million first … – Healthcare IT News

Wednesday, June 21st, 2017

San Francisco-based Vineti, a cell and gene therapy software and analytics company, has closed on Series A funding round that pulled together nearly $14 million.

Backing came from General Electric Ventures, Mayo Clinic and new investor Draper Fisher Jurvetson.

The company will use the funds to continue growing its team and to deliver cloud-based software to improve patient access. It also plans to speed its work on life-saving treatment delivery and to promote safety and FDA compliance for individualized cell therapies.

The Vineti platform integrates logistics, manufacturing and clinical data.

Physicians, medical researchers and pharmaceutical companies are working together to develop successful therapies, transitioning from a one-size-fits-all model to individualized treatments for each patient, Vineti CEO Amy DuRoss said in a statement. But, the process for administering these treatments is broken and outdated, restricting access to terminal patients and creating unnecessary risk.

DuRoss added that Vineti developed the platform to ensure treatments reach the patients who need them the most. She added that many patients who are excellent candidates dont have access to the most innovative therapies and discovery timelines are more challenging than necessary.

GE Ventures formed Vineti based on customer requests to bridge the technology gap between individualized cell therapies and production.

Modern technology solutions to address complex production and delivery processes are lacking. GE Ventures, Mayo Clinic and DFJ have invested in Vineti to rectify these problems.

Vineti is led by DuRoss, Chief Strategy Officer Heidi Hagen and CTO Razmik Abnous.

Twitter: @Bernie_HITN Email the writer: bernie.monegain@himssmedia.com

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Vineti to fast-track cell and gene therapy tech with $14 million first ... - Healthcare IT News

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Sarepta signs another Duchenne gene therapy pact as it aims for wider treatment – FierceBiotech

Wednesday, June 21st, 2017

Sarepta Therapeutics has penned its second DMD gene therapy pact this year as it announces a tie-up with Frances Genethon, a nonprofit R&D org.

The research collaborationwill see the Franco-American pair jointly develop treatments for Duchenne muscular dystrophy and comes after Sareptas first FDA approval for DMD with its controversial med Exondys 51 (eteplirsen).

RELATED: FDA expert lashes out at 'worrisome' Sarepta approval in JAMA

Sarepta is looking to tap into Genethons preclinical microdystrophin gene therapy approach, which can target the majority of patients with DMD. Its current med can only treat certain patients, namely those with the mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13% of the population with DMD.

It is hoping that with new tie-ups, it could produce a gene therapy that could treat many more, if not all, patients with the disease, although this is still some years off. DMD is a rare genetic disorder characterized by progressive muscle deterioration and weakness. The disease primarily affects young boysand occurs in about one out of every 3,600 male infants worldwide.

This builds on the pacts announced at the start of the year at the JPM conference, which saw it sign a deal with the Nationwide Childrens Hospital, which also focuses on the microdystrophin gene therapy program, as well as another form of gene therapy.

An initial phase 1/2a trial for the microdystrophin gene therapy is slated to begin at the end of the year and will be done at Nationwide Childrens. It also penned an exclusive license agreement with Nationwide for their Galgt2 gene therapy program, originally developed by researcher Paul Martin. This early-stage program aims to research a potential surrogate gene therapy approach to DMD, whereby the gene therapy looks to induce genes that make proteins that can perform a similar function as dystrophin. The goal will be to produce a muscle cell that can function normally even when dystrophin is absent, Sarepta said at the time.

Under the terms of its latest collaboration, Genethon will be responsible for the early development work. Sarepta has the option to co-develop Genethons microdystrophin program, which includes exclusive U.S. commercial rights. Financial terms, as is becoming more common with these pacts, have not been disclosed.

RELATED: With Exondys 51 approved, Sarepta chief Ed Kaye to bow out

Our agreement with Genethon strengthens our ongoing commitment to patients and is aligned with our strategy of building the industrys most comprehensive franchise in DMD, said Ed Kaye, Sareptas outgoing chief. This partnership brings together our collective experience in Duchenne drug development and Genethons particular expertise in gene therapy for rare diseases. We look forward to working with Genethon given their knowledge, large infrastructure and state-of the-art manufacturing capabilities to advance next generation therapies for DMD.

Frederic Revah, CEO of Genethon, added: Microdystrophin-based gene therapy is a very promising approach with potential application to a large majority of Duchenne patients. In order to accelerate the development of a treatment, we are very pleased to partner with Sarepta Therapeutics, which has demonstrated commitment and success for innovative therapies for Duchenne muscular dystrophy. This partnership brings together the highly complementary and synergistic expertises of Sarepta and Genethon, to the benefit of the patients.

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Sarepta signs another Duchenne gene therapy pact as it aims for wider treatment - FierceBiotech

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Mayo Clinic Ventures funds new cancer-fighting cell, gene therapy … – Post-Bulletin

Wednesday, June 21st, 2017

SAN FRANCISCO, Calif. Mayo Clinic Ventures has partnered with a California-based company to make cancer-fighting gene therapies available to the public.

Vineti, a pioneering cell and gene therapy software and analytics company, announced Tuesday that it had completed its initial round of funding raising $13.75 million aimed at delivering "the first cloud-based software solution to improve patient access, accelerate life-saving treatment delivery, and promote safety and regulatory compliance for individualized cell therapies."

The funding was provided by Mayo Clinic Ventures, GE Ventures, DFJ and LifeForce Capital. It's just the 15th company that Mayo Clinic Ventures has backed since it was formed, according to Andy Danielson, vice chairman of Mayo Clinic Ventures.

"One thing with Vineti that we liked is that we have a commitment to cell and gene therapies at Mayo," Danielson told TechCrunch.com. "Vineti will make the gene and cell therapy production process more efficient and as a result, less costly. It's all part of the equation of making these therapies more affordable and opening them up to a greater number of people."

The targeted cancer therapy under development by Vineti is part of a thriving field that conducted more than 800 clinical trials in 2016 while investing nearly $6 billion. It's all aimed at positively impacting the oncology field, the largest market in medicine that's expected to grow to $165 billion by 2021.

The first two cell therapies are expected to hit the market later this year.

Vineti touts its plans as one that "integrates logistics, manufacturing and clinical data to improve product performance overall and enable faster, broader access for patients."

"Physicians, medical researchers and pharmaceutical companies are working together to develop successful therapies, transitioning from a one-size-fits-all model to individualized treatments for each patient," said Amy DuRoss, CEO at Vineti. "Now, the process for creating and delivering these treatments can be as innovative as the therapies themselves. We are developing the Vineti platform to help these treatments reach the patients who need them the most, and are confident the partnership between our advances technologies and leading medical research will deliver better outcomes across the globe."

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Mayo Clinic Ventures funds new cancer-fighting cell, gene therapy ... - Post-Bulletin

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Gene therapy: What you need to know – BioPharma Dive

Wednesday, June 21st, 2017

British drugmaker GlaxoSmithKline made headlines last year when it won approval for its gene therapy Strimvelis in Europe. But, due to a small patient population and high price tag, the drug has only been used once. So far, despite higher levels of safety and efficacy than previous iterations, the new wave of gene therapies still face commercial hurdles.

Spark Therapeutics looks set to be the next company to take on this challenge in the U.S. The biotech is currently awaiting approval of its treatment for a rare genetic form of blindness a potential one-time cure. Yet pricing will be the most closely watched aspect of this therapy, likely serving as an early barometer of what might be sustainable for a pipeline of treatments still in development.

While gene therapy offers the promise of cures and new ways of revolutionizing treatment of genetic diseases, society remains a long way from fully realizing those advances.

After decades of setbacks, a slew of next-gen gene therapies are ready to hit the U.S. market, prompting questions about manufacturing and pricing. Read More >>

A pricing conundrum and ethical decisions are clouding an already hazy path to market for many gene therapy drugs and providers. Read More >>

With an approval of Spark Therapeutics' gene therapy for a rare eye disease rapidly approaching, new questions about pricing are being raised. Read More >>

In a field shaped by small patient populations and eye-popping cost considerations, understanding gene therapy's promise and challenges comes down, in part, to the numbers. Read More >>

While many are optimistic about gene editing's ability to cure disease, it seems not enough realize the more dangerous aspects of treatment. Read More >>

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Gene therapy: What you need to know - BioPharma Dive

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