Scientists Unravel the Secrets of 37 Key Genes Linked to Reproductive Health and Longevity SciTechDaily
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Scientists Unravel the Secrets of 37 Key Genes Linked to Reproductive Health and Longevity - SciTechDaily
Exosomes Are Being Hyped as a Silver Bullet Therapy. Scientists Say No. Singularity Hub
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Exosomes Are Being Hyped as a Silver Bullet Therapy. Scientists Say No. - Singularity Hub
Using technology first designed by Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology, researchers at the UNC School of Medicine have engineered a molecular technology that can turn off pain receptors.
Pain is meant to be a defense mechanism. It creates a strong sensation to get us to respond to a stimulus and prevent ourselves from further harm. But, sometimes injuries, nerve damage, or infections can cause long-lasting, severe bouts of pain that can make daily life unbearable.
What if there was a way to simply turn off pain receptors? UNC School of Medicine researchers Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology, and Grgory Scherrer, PharmD, PhD, associate professor of cell biology and physiology and the UNC Neuroscience Center, have just proved that it is possible.
Using a tool designed by Roth in the early 2000s, the labs have created a new system that reduces acute and tissue-injury-induced inflammatory pain in mouse models. Hye Jin Kang, PhD, an alumnus of the Roth Lab and now associate professor at Yonsei University in Korea, was first author on the research paper. Their results were published in Cell.
What we have developed is potentially a gene therapy approach for chronic pain, said Roth, who is also a member of UNC Lineberger Comprehensive Cancer Center. The idea is that we could deliver this chemogenetic tool through a virus to the neurons that sense the pain. Then, you could just take an inert pill and turn those neurons off, and the pain will literally disappear.
Neuroscientists have been on a decades-long endeavor to build a comprehensive map of the human brain. If every type of cell and every neural pathway could be identified, researchers could make large strides in neurological research including the ability to turn regions of the brain on and off to parse out their functions or mimic drug therapy.
In the 90s, Roth, then professor of biochemistry at Case Western Reserve University (with secondary appointments in Psychiatry, Oncology, and Neurosciences), wanted to find a way to make new, powerful therapeutics that could stop diseases without incurring dissuading side effects. It was a tall order, pharmacologically-speaking. So, Roth decided to use an up-and-coming technique called directed molecular evolution, which essentially uses chemically engineered molecules to speed up the evolution process in nature.
What I realized, and what a lot of people realized, is, if you could make an engineered receptor that had some of the same signaling properties as a drug of interest, and if you could put it in a particular brain region or cell type, then you could mimic the effects of the drug, said Roth, who is now the project director of the NIMH Psychoactive Drug Screening Program. We made some several attempts in the 90s, as did other people, without a great deal of success.
Roth perfected the chemogenetic technology in 2005. With yeast as his model organism, he engineered an artificial protein receptor that could only be unlocked by clozapine N-oxide, a synthetic drug-like compound that had been rendered inert by removing all its therapeutic qualities.
The tool, which is also termed designer receptors exclusively activated by designer drugs, or DREADDs, acts as a molecular lock and key that can only be activated when an inert drug-like compound is introduced to the body. Once activated, the technology can turn neurons on or shut them off, effectively giving researchers the ability to make highly selective changes to the nervous system.
The techniques were revealed to the scientific community in March 2007 in the Proceedings of the National Academy of Sciences. Since then, Roths technology has been used by thousands of researchers worldwide to study the functions of neurons and develop new medications to treat complex neuropsychiatric conditions from depression and substance abuse to epilepsy and schizophrenia.
Every neuron in our body that is not part of central nervous system (CNS) belongs to the peripheral nervous system, or PNS. This division of the nervous system is responsible for relaying our five sensations to the CNS, allows our muscles to move, and aids in involuntary process such as digestion, breathing, and heart beats.
Relatively few studies have been done on the use of chemogenetics in the PNS, simply because of technical difficulty. The CNS and PNS are so intertwined on a cellular, chemical, and genetic level, that it is challenging for researchers to apply their technology solely to the PNS.
Many of the genes that are expressed in the peripheral nervous system are also expressed in the central nervous system, particularly in the brain, said Scherrer, who is also an associate professor in the UNC Department of Pharmacology. We had to perform a multitude of analyses and tests to isolate both a receptor and drug-like compound that only operate in the periphery.
However, after seven long years, the Roth and Scherrer labs found success. Researchers based their new system off of hydroxycarboxylic acid receptor 2 (HCA2), a type of receptor implicated in anti-inflammation. HCA2 receptors are expressed in the PNS and are usually activated by vitamin B3. Using mouse models, researchers altered the HCA2 receptors so that they could only bind to FCH-2296413, an inert drug-like compound that only acts within the PNS.
The chemogenetic system, termed mHCAD, is designed to interfere with nociceptors, making it more difficult for the sensory neurons to transmit pain information to the spinal cord and brain. To be more specific, mHCAD reduces their ability to fire off their electrical and chemical messages. A more intense, more painful stimulus will be needed to cause the perception of pain.
Although the technology is still far from human use, Roth and Scherrer have already thought about how the technology would best be delivered in the body: through gene therapy. Researchers successfully injected mHCAD into a mouse model using genetic technology created by colleague and gene therapy pioneer Jude Samulski, PhD, a distinguished professor of pharmacology at the UNC School of Medicine. The gene therapy leverages the infectious abilities of the adeno-associated virus (AAV), allowing researchers to deliver mHCAD into the pain neurons of interest.
In 2013, the National Institutes of Health formed a partnership between Federal and non-Federal partners with a common goal of mapping every human brain cell and every neural circuit through innovative neurotechnologies called the Brain Research Through Advancing Innovative Neurotechnologies Initiative, or BRAIN Initiative.
Roths chemogenetic technology has played a big role in the BRAIN Initiative. To date, tens of thousands of shipments of viruses and plasmids from the Roth lab have been distributed leading to many thousand publications. Now that the technology has expanded to the peripheral nervous system, researchers can better study the neurons that produce the perception of touch, temperature, body position, pain, and more.
There are dozens of classes of PNS neurons that we dont fully understand, said Scherrer. By using this new innovative tool, we can then define cellular targets that we can engage with to treat diseases. Its going to be an important tool to increase our knowledge in the somatosensory field and beyond.
Media contact:Kendall Daniels Rovinsky, Communications Specialist, UNC Health | UNC School of Medicine
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Researchers Create Gene Therapy with Potential to Treat Peripheral Pain ...
July 27, 2020, by NCI Staff
CRISPR is a highly precise gene editing tool that is changing cancer research and treatment.
Credit: Ernesto del Aguila III, National Human Genome Research Institute
Ever since scientists realized that changes in DNA cause cancer, they have been searching for an easy way to correct those changes by manipulating DNA. Although several methods of gene editing have been developed over the years, none has really fit the bill for a quick, easy, and cheap technology.
But a game-changer occurred in 2013, when several researchers showed that a gene-editing tool called CRISPR could alter the DNA of human cells like a very precise and easy-to-use pair of scissors.
The new tool has taken the research world by storm, markedly shifting the line between possible and impossible. As soon as CRISPR made its way onto the shelves and freezers of labs around the world, cancer researchers jumped at the chance to use it.
CRISPR is becoming a mainstream methodology used in many cancer biology studies because of the convenience of the technique, said Jerry Li, M.D., Ph.D., of NCIs Division of Cancer Biology.
Now CRISPR is moving out of lab dishes and into trials of people with cancer. In a small study, for example, researchers tested a cancer treatment involving immune cells that were CRISPR-edited to better hunt down and attack cancer.
Despite all the excitement, scientists have been proceeding cautiously, feeling out the tools strengths and pitfalls, setting best practices, and debating the social and ethical consequences of gene editing in humans.
Like many other advances in science and medicine, CRISPR was inspired by nature. In this case, the idea was borrowed from a simple defense mechanism found in some microbes, such as bacteria.
To protect themselves against invaders like viruses, these microbes capture snippets of the intruders DNA and store them away as segments called CRISPRs, or clustered regularly interspersed short palindromic repeats. If the same germ tries to attack again, those DNA segments (turned into short pieces of RNA) help an enzyme called Cas find and slice up the invaders DNA.
After this defense system was discovered, scientists realized that it had the makings of a versatile gene-editing tool. Within a handful of years, multiple groups had successfully adapted the system to edit virtually any section of DNA, first in the cells of other microbes, and then eventually in human cells.
CRISPR consists of a guide RNA (RNA-targeting device, purple) and the Cas enzyme (blue). When the guide RNA matches up with the target DNA (orange), Cas cuts the DNA. A new segment of DNA (green) can then be added.
Credit: National Institute of General Medical Sciences, National Institutes of Health
In the laboratory, the CRISPR tool consists of two main actors: a guide RNA and a DNA-cutting enzyme, most commonly one called Cas9. Scientists design the guide RNA to mirror the DNA of the gene to be edited (called the target). The guide RNA partners with Cas andtrue to its nameleads Cas to the target. When the guide RNA matches up with the target gene's DNA, Cas cuts the DNA.
What happens next depends on the type of CRISPR tool thats being used. In some cases, the target gene's DNA is scrambled while it's repaired, and the gene is inactivated. With other versions of CRISPR, scientists can manipulate genes in more precise ways such as adding a new segment of DNA or editing single DNA letters.
Scientists have also used CRISPR to detect specific targets, such as DNA from cancer-causing viruses and RNA from cancer cells. Most recently, CRISPR has been put to use as an experimental testto detect the novel coronavirus.
Scientists consider CRISPR to be a game-changer for a number of reasons. Perhaps the biggest is that CRISPR is easy to use, especially compared with older gene-editing tools.
Before, only a handful of labs in the world could make the proper tools [for gene editing]. Now, even a high school student can make a change in a complex genome using CRISPR, said Alejandro Chavez, M.D., Ph.D., an assistant professor at Columbia University who has developed several novel CRISPR tools.
CRISPR is also completely customizable. It can edit virtually any segment of DNA within the 3 billion letters of the human genome, and its more precise than other DNA-editing tools.
And gene editing with CRISPR is a lot faster. With older methods, it usually [took] a year or two to generate a genetically engineered mouse model, if youre lucky, said Dr. Li. But now with CRISPR, a scientist can create a complex mouse model within a few months, he said.
Another plus is that CRISPR can be easily scaled up. Researchers can use hundreds of guide RNAs to manipulate and evaluate hundreds or thousands of genes at a time. Cancer researchers often use this type of experiment to pick out genes that might make good drug targets.
And as an added bonus, its certainly cheaper than previous methods, Dr. Chavez noted.
With all of its advantages over other gene-editing tools, CRISPR has become a go-to for scientists studying cancer. Theres also hope that it will have a place in treating cancer, too. But CRISPR isnt perfect, and its downsides have made many scientists cautious about its use in people.
A major pitfall is that CRISPR sometimes cuts DNA outside of the target genewhats known as off-target editing. Scientists are worried that such unintended edits could be harmful and could even turn cells cancerous, as occurred in a 2002 study of a gene therapy.
If [CRISPR] starts breaking random parts of the genome, the cell can start stitching things together in really weird ways, and theres some concern about that becoming cancer, Dr. Chavez explained. But by tweaking the structures of Cas and the guide RNA, scientists have improved CRISPRs ability to cut only the intended target, he added.
Another potential roadblock is getting CRISPR components into cells. The most common way to do this is to co-opt a virus to do the job. Instead of ferrying genes that cause disease, the virus is modified to carry genes for the guide RNA and Cas.
Slipping CRISPR into lab-grown cells is one thing; but getting it into cells in a person's bodyis another story. Some viruses used to carry CRISPR can infect multiple types of cells, so, for instance, they may end up editing muscle cells when the goal was to edit liver cells.
Researchers are exploring different ways to fine-tune the delivery of CRISPR to specific organs or cells in the human body. Some are testing viruses that infect only one organ, like the liver or brain. Others have created tiny structures callednanocapsules that are designed to deliver CRISPR components to specific cells.
Because CRISPR is just beginning to be tested in humans, there are also concerns about how the bodyin particular, the immune systemwill react to viruses carrying CRISPR or to the CRISPR components themselves.
Some wonder whether the immune system could attack Cas (a bacterial enzyme that is foreign to human bodies) and destroy CRISPR-edited cells. Twenty years ago, a patient died after his immune system launched a massive attack against the viruses carrying a gene therapy he had received. However, newer CRISPR-based approaches rely on viruses that appear to be safer than those used for older gene therapies.
Another major concern is that editing cells inside the body could accidentally make changes to sperm or egg cells that can be passed on to future generations. But for almost all ongoing human studies involving CRISPR, patients cells are removed and edited outside of their bodies. This ex vivo approach is considered safer because it is more controlled than trying to edit cells inside the body, Dr. Chavez said.
However, one ongoing study is testing CRISPR gene editing directly in the eyes of people with a genetic disease that causes blindness, called Leber congenital amaurosis.
The first trial in the United States to test a CRISPR-made cancer therapy was launched in 2019 at the University of Pennsylvania. The study, funded in part by NCI, is testing a type of immunotherapy in which patients own immune cells are genetically modified to better see and kill their cancer.
The therapy involves making four genetic modifications to T cells, immune cells that can kill cancer. First, the addition of a synthetic gene gives the T cells a claw-like protein (called a receptor) that sees NY-ESO-1, a molecule on some cancer cells.
Then CRISPR is used to remove three genes: two that can interfere with the NY-ESO-1 receptor and another that limits the cells cancer-killing abilities. The finished product, dubbed NYCE T cells, were grown in large numbers and then infused into patients.
The first trial of CRISPR for patients with cancer tested T cells that were modified to better "see" and kill cancer.CRISPR was used to remove three genes: two that can interfere with the NY-ESO-1 receptor and another that limits the cells cancer-killing abilities.
Credit: National Cancer Institute
We had done a prior study of NY-ESO-1directed T cells and saw some evidence of improved response and low toxicity, said the trials leader, Edward Stadtmauer, M.D., of the University of Pennsylvania. He and his colleagues wanted to see if removing the three genes with CRISPR would make the T cells work even better, he said.
The goal of this study was to first find out if the CRISPR-made treatment was safe. It was tested in two patients with advanced multiple myeloma and one with metastatic sarcoma. All three had tumors that contained NY-ESO-1, the target of the T-cell therapy.
Initial findings suggest that the treatment is safe. Some side effects did occur, but they were likely caused by the chemotherapy patients received before the infusion of NYCE cells, the researchers reported. There was no evidence of an immune reaction to the CRISPR-edited cells.
Only about 10% of the T cells used for the therapy had all four of the desired genetic edits. And off-target edits were found in the modified cells of all three patients. However, none of the cells with off-target edits grew in a way that suggested they had become cancer, Dr. Stadtmauer noted.
The treatment had a small effect on the patients cancers. The tumors of two patients (one with multiple myeloma and one with sarcoma) stopped growing for a while but resumed growing later. The treatment didn't work at all for the third patient.
It'sexciting that the treatment initially worked for the sarcoma patientbecause solid tumors have been a much more difficult nut to crack with cellular therapy," Dr. Stadtmauer said. "Perhaps [CRISPR] techniques will enhance our ability to treat solid tumors with cell therapies.
Although the trial shows that CRISPR-edited cell therapy is possible, the long-term effects still need to be monitored, Dr. Stadtmauer continued. The NYCE cells are safe for as long as weve been watching [the study participants]. Our plan is to keep monitoring them for years, if not decades, he said.
While the study of NYCE T cells marked the first trial of a CRISPR-based cancer treatment, there are likely more to come.
This [trial] was really a proof-of-principle, feasibility, and safety thing that now opens up the whole world of CRISPR editing and other techniques of [gene] editing to hopefully make the next generation of therapies, Dr. Stadtmauer said.
Other clinical studies of CRISPR-made cancer treatments are already underway. A few trials are testing CRISPR-engineered CAR T-cell therapies, another type of immunotherapy. For example, one company is testing CRISPR-engineered CAR T cells in people with B cell cancers and people with multiple myeloma.
There are still a lot of questions about all the ways that CRISPR might be put to use in cancer research and treatment. But one thing is for certain: The field is moving incredibly fast and new applications of the technology are constantly popping up.
People are still improving CRISPR methods, Dr. Li said. Its quite an active area of research and development. Im sure that CRISPR will have even broader applications in the future.
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How CRISPR Is Changing Cancer Research and Treatment
Patients with Leber hereditary optic neuropathy (LHON) due to the MT-ND4 gene variant treated with the gene therapy lenadogene nolparvovec in one eye showed a sustained improvement in best-corrected visual acuity (BCVA) in both eyes up to 5 years after treatment, the long-term RESTORE study showed.
Among 55 patients who completed the 5-year follow-up, bilateral vision improvement was similar to what was observed at the 2-year mark, with a mean change in BCVA of -0.4 logMAR (more than +4 lines) for treated eyes and -0.4 logMAR (+4 lines) for eyes treated with sham (difference -0.05, 95% CI -0.15 to 0.04, P=0.27), reported Patrick Yu-Wai-Man, MD, PhD, of the University of Cambridge in England, and colleagues.
In addition, an improvement of at least -0.3 logMAR (+3 lines) from the nadir in at least one eye was observed in 66.1% of patients, they noted in JAMA Ophthalmology.
The findings suggest that vision improvement "is likely to be a lasting effect," co-author Jos-Alain Sahel, MD, PhD, of the Centre Hospitalier National D'Ophtalmologie des Quinze Vingts in Paris, told MedPage Today. However, Sahel -- a co-founder of the company that makes the gene therapy -- said it may still take several years to get the treatment approved in the U.S.
LHON is a rare inherited disease that damages the optic nerve, and is estimated to affect one in 50,000 people. According to Sahel, patients with the condition have normal vision early in life but typically develop problems as teenagers or young adults. One eye and then the other loses vision, he said, and most patients become legally blind.
Sahel explained that lenadogene nolparvovec, an adeno-associated virus (AAV)-based ocular gene therapy, was designed to correct the genetic defect that causes LHON.
The initial RESCUE and REVERSE trials, patients from which comprise RESTORE, showed that vision in treated eyes improved at 2 years, but, unexpectedly, so did vision in untreated(sham) eyes, said Sahel, who noted that about 60% to 70% of patients were able to regain some level of vision.
"Most of them didn't regain full vision, but several of them regained a good level of autonomy and the ability to read at least large print or medium print," he added. Some patients were able to drive again, take part in sports, and go back to college.
This follow-up study showed that vision benefits persisted over 3 years beyond the initial studies, Sahel concluded, noting that no patients had permanent complications from the gene therapy, and inflammation occurring in some patients was manageable.
In an accompanying commentary, Hendrik Scholl, MD, of Medical University of Vienna, and Bence Gyrgy, MD, PhD, of the University of Basel in Switzerland, said that the initial results of the RESCUE and REVERSE trials were "somewhat puzzling."
The studies didn't meet their primary outcomes -- a difference in visual acuity between treated and untreated eyes -- since vision in both eyes improved, they wrote. "One possibility [for this] is that the vector is trafficking from one eye to the other."
Another possibility is the analysis may be misleading because the authors chose to track visual changes from nadir, which "may represent a 1-time event due to poor effort or poor fixation."
The commentary authors recommended that "if investigators insist on using change from nadir, at a minimum, they should require 2 consecutive visits that confirm the stability of this nadir visit and, more importantly and primarily, consider BCVA changes from baseline."
The RESCUE and REVERSE Long-Term Follow-up Study (RESTORE) was conducted from 2018 to 2022 and tracked 62 of the 76 patients with LHON due to the MT-ND4 gene variant who took part in the initial two trials; 55 patients completed the 5-year follow-up. Mean age at treatment was 35.9, and 79% were men.
The mean baseline BCVA was 1.5 logMAR in the lenadogene nolparvovec group and 1.4 logMAR in sham eyes; after 2 years, the mean changes were -0.05 logMAR (+1 line) and 0.01 logMAR (-0 line), respectively (difference -0.03, 95% CI -0.16 to 0.09, P=0.60).
Over the 3-year follow-up period, intraocular inflammation occurred in four patients with eight events in eyes treated with lenadogene nolparvovec and one event in an eye treated with sham.
Sahel acknowledged that the gene therapy is likely to be expensive. In 2021, its manufacturer said the bilateral treatment would cost $725,000 per patient.
What's next? "Most likely in the U.S. and in some countries in Europe, there will be a need for a confirmatory study to be performed," he said, in light of the unusual initial results that didn't allow comparison of treated and untreated eyes.
The company plans further studies, he added, and he expects approval in the U.S. to come in 3 to 4 years.
Randy Dotinga is a freelance medical and science journalist based in San Diego.
Disclosures
GenSight Biologics, maker of lenadogene nolparvovec, funded the study, with support from multiple sources including the U.K. National Institute of Health Research, U.K. Medical Research Council, Fight for Sight, Isaac Newton Trust, Moorfields Eye Charity, Addenbrooke's Charitable Trust, and others.
Yu-Wai-Man reported receiving consultant fees from GenSight Biologics, Chiesi, and Neurophth, and research support from GenSight Biologics and Santhera.
Sahel reported being a co-founder and shareholder of GenSight Biologics; receiving grants from Laboratoire d'Excellence (LabEx) Lifesenses, Institut Hospitalo-Universitaire FOReSIGHT, the NIH, Research to Prevent Blindness, Light4Deaf, and the European Research Council; having a patent related to gene therapy for LHON; a personal financial interest in Pixium, GenSight Biologics, Sparing Vision, Prophesee, Chronolife, Tilak, VegaVect, Avista, Tenpoint, and SharpEye; receiving consultant fees from Tenpoint and Avista; and serving on the board of GenSight and Sparing Vision.
Other study authors reported multiple and various disclosures, including relationships with GenSight Biologics.
Scholl reported being chief medical officer of Belite Bio and relationships with the Swiss National Science Foundation, Wellcome Trust, Droia, Janssen (Johnson & Johnson), Okuvision, Boehringer Ingelheim, Alnylam, Belite Bio, F. Hoffmann-La Roche, ViGeneron, and Novo Nordisk.
Gyrgy reported relationships with Sphere, Cove, and the Swiss National Science Foundation.
Primary Source
JAMA Ophthalmology
Source Reference: Yu-Wai-Man P, et al "Five-year outcomes of lenadogene nolparvovec gene therapy in Leber hereditary optic neuropathy" JAMA Ophthalmol 2024; DOI: 10.1001/jamaophthalmol.2024.5375.
Secondary Source
JAMA Ophthalmology
Source Reference: Scholl HPN, Gyrgy B "Single-eye gene therapy for Leber hereditary optic neuropathy" JAMA Ophthalmol 2024; DOI: 10.1001/jamaophthalmol.2024.5618.
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Gene Therapy Shows Long-Term Vision Benefits in Rare Eye Disease
1Bluebird BioSomerville, MA, USAGene therapies for genetic diseasesZynteglo, Skysona, LyfgeniaPublic (BLUE)Multiple approved gene therapies for rare diseases. Patents (20202024): 15 total (10 gene, 1 vector, 4 cancer)2NovartisBasel, SwitzerlandPioneer: CAR-T (Kymriah), Zolgensma (SMA)Kymriah, ZolgensmaPublicRobust pipeline, global CGT leader. Patents (20202024): 95 total (47 gene, 8 vector, 40 cancer)3Gilead Sciences/Kite PharmaFoster City, CA, USACAR-T therapies for oncologyYescarta, TecartusPublic (GILD)Leading CAR-T franchise in oncology. Patents (20202024): 40 total (6 vector, 34 cancer). 2024 sales data strong: Q2: $521M combined, Q3: ~$485M, steady performance.4Bristol Myers SquibbNew York, NY, USAMultiple CAR-T approvalsAbecma, BreyanziPublic (BMY)Deep CAR-T pipeline, oncology focus. Patents (20202024): 164 total (92 gene, 12 vector, 60 cancer). Q3 2024 total revenue +8% YoY to $11.9B; growth portfolio (incl. 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Funding Status: Late Stage Venture, Last Funding Date: May 24, 2023, Last Funding Amount: $401,000,000 (Series D), Total Funding Amount: $1,246,000,000, Top Investors: Novo Nordisk, Fidelity, Vertex Ventures, Invus, Surveyor Capital30Sana BiotechnologySeattle, WA, USAEx/in vivo CGTNonePublic (SANA)Fusogenix, hypoimmune platforms31Fate TherapeuticsSan Diego, CA, USAiPSC immunotherapiesNonePublic (FATE)Off-the-shelf NK & T-cell therapies. Patents (20202024): 7 total (7 cancer)32Poseida TherapeuticsSan Diego, CA, USAGene editing allogeneic CAR-TNonePublic (PSTX)* Roche is acquiringNon-viral gene editing (piggyBac). Patents (20202024): 20 total (11 gene, 3 vector, 6 cancer)33Caribou BiosciencesBerkeley, CA, USACRISPR-edited cell therapiesNonePublic (CRBU)chRDNAs for precision CRISPR editing. Patents (20202024): 48 total (4 gene, 33 vector, 11 cancer)34CellectisParis, FranceTALEN-based allogeneic CAR-TNonePublic (CLLS)TALEN gene editing, off-the-shelf CAR-T. Patents (20202024): 91 total (12 gene, 20 vector, 59 cancer)35MeiraGTxLondon, UKAAV for ocular & neuroNonePublic (MGTX)Vertically integrated gene therapy company. Patents (20202024): 15 total (10 vector, 5 gene*). Additional Funding Info (for Tmunity Therapeutics Rank #35): M&A, Last Funding Date: Oct 31, 2019, $75,000,000 (Series B), Total Funding Amount: $220,000,000, Top Investors: Gilead Sciences, Andreessen Horowitz, University of Pennsylvania, Kleiner Perkins, Lilly Asia Ventures364D Molecular TherapeuticsEmeryville, CA, USAEngineered AAV vectorsNonePublic (FDMT)Custom AAV capsids for multiple indications. Patents (20202024): 34 total (34 gene)37Abeona TherapeuticsNew York, NY, USARare disease gene therapiesNonePublic (ABEO)Focus on RDEB and CLN138Adverum BiotechnologiesRedwood City, CA, USAAAV ocular gene therapyNonePublic (ADVM)Wet AMD gene therapy. Patents (20202024): 26 total (23 gene, 3 vector)39Generation BioCambridge, MA, USANon-viral genetic medicinesNonePublic (GBIO)Closed-ended DNA platform40Dyno TherapeuticsCambridge, MA, USAAI-driven AAV engineeringNonePrivateAI to optimize AAV capsids41MetagenomiEmeryville, CA, USANovel CRISPR systemsNonePublic (MGX)Metagenomic enzyme discovery for gene editing. Patents (20202024): 11 total (1 gene, 10 vector)42EdiGeneBeijing, ChinaGene editing & therapyNonePrivateCRISPR-based therapies in development. Patents (20202024): 6 total (6 vector)43CelularityFlorham Park, NJ, USAPlacental-derived cell therapiesNonePublic (CELU)Off-the-shelf NK cell therapies44Rubius TherapeuticsCambridge, MA, USARed Cell TherapeuticsNonePublic (RUBY)Engineering RBCs for immuno-oncology. Patents (20202024): 8 total (7 gene, 1 cancer)45ArcellxGermantown, MD, USAControllable CAR-TNonePublic (ACLX)ARC-sparX platform. Patents (20202024): 5 total (5 cancer)46AstraveusParis, FranceCGT manufacturing solutions (with innovation)NoneSeed 10.4MMicrofluidic platform for scalable manufacturing. Funding Status: Seed, Last Funding Date: Oct 24, 2023, 10,400,000 (Grant), Total Funding Amount: 28,872,000, Top Investors: Bpifrance, EASME EU Executive Agency for SMEs, Johnson & Johnson Innovation JJDC, Bpifrance Large Venture, M Ventures47Inceptor BioRaleigh, NC, USACell therapy for tough cancersNoneEarly Stage VentureDiversified cell therapy pipeline. Funding Status: Early Stage Venture, Last Funding Date: Oct 20, 2022, $15,875,000 (Debt Financing), Total Funding Amount: $87,645,000, Top Investors: Kineticos Ventures, Kineticos Disruptor Fund48Tevogen BioWarren, NJ, USAOff-the-shelf T-cell therapiesNonePublic (TVGN)Allogeneic T-cells for viral infections/cancer. Funding Status: IPO, Last Funding Date: May 10, 2024, $36,000,000 (Post-IPO Debt), Total Funding Amount: $58,000,000, Top Investors: HMP Partners49CSL BehringMelbourne, AustraliaGlobal biotech in immunology/heme/CGTNonePublic (CSL)Hemophilia B gene therapy & plasma products50CRISPR TherapeuticsZug, Switzerland & Boston, MACRISPR/Cas9 gene editing therapiesExa-cel (with Vertex)Public (CRSP)Pipeline in hemoglobinopathies, oncology. Patents (20202024): 57 total (46 gene, 6 vector, 5 cancer)51ImmunoACTMumbai, IndiaAdvanced CGT startupNone800M CorporateCAR-T development for emerging markets. Funding Status: Corporate Round (Unlisted as IPO/M&A), Last Funding Date: May 31, 2023, 800,000,000, Total Funding Amount: 1,397,500,000, Top Investors: Laurus Labs52Coave TherapeuticsParis, FranceGene therapies for ocular/CNSNonePrivate (33.1M Series B)AAV-ligand conjugates53Celyad OncologyBelgiumAllogeneic CAR-T for oncologyNonePublic (CYAD)shRNA-based allogeneic CAR-T54Chimeron BioPhiladelphia, PA, USASelf-amplifying RNA therapeuticsNone$4.33M fundingChaESAR RNA platform55Deep GenomicsToronto, CanadaAI-driven RNA therapeuticsNone$241M totalBigRNA AI for RNA drug design56DendreonSeal Beach, CA, USACellular immunotherapy for prostate cancerPROVENGECommercial revenueAutologous cell therapy pioneer57Editas MedicineCambridge, MA, USACRISPR-based gene editing therapiesNone~$931.6M raisedIn vivo & ex vivo CRISPR platform. Patents (20202024): 48 total (21 gene, 26 vector, 1 cancer)58eGenesisCambridge, MA, USAGene-edited xenotransplantationNone$191M Series DMulti-gene-edited porcine organs59EyevensysParis, FranceNon-viral gene therapy for eye diseasesNone$44.1M fundingElectroporation-based ocular gene delivery60Ferring PharmaceuticalsSaint-Prex, SwitzerlandADSTILADRIN for bladder cancerADSTILADRINPrivate; $500M royalty dealGene therapy in oncology61Forte BiosciencesDallas, TX, USAAnti-CD122 mAb for autoimmuneNone$53M private placementTargeting IL-2 pathway disorders62GenascencePalo Alto, CA, USAGene therapy for osteoarthritisNoneFDA Fast Track GNSC-001IL-1Ra gene therapy for OA63GenSight BiologicsParis, FranceGene therapies for retinal diseasesNonePublic (SIGHT.PA)Mitochondrial targeting, optogenetics64Cabaletta BioPhiladelphia, PA, USAT-cell therapies for autoimmune diseaseNonePublic (CABA)CAART for B-cell-mediated conditions65Capricor TherapeuticsSan Diego, CA, USACell & exosome-based therapies (DMD)NonePublic (CAPR)StealthX exosome platform66RegeneronTarrytown, NY, USAExpanding in CGT, advanced biologicsNone (CGT)Public (REGN)Acquired cell therapy programs, DB-OTO gene therapy67RiboKunshan, ChinaRNAi therapeuticsNoneMultiple RMB roundsGalNAc RNAi for liver/CV/metabolic68TakedaTokyo, JapanGlobal pharma investing in CGTNonePublic (TAK)Cell therapy facility, gene therapy collaborations69Ultragenyx PharmaceuticalNovato, CA, USARare & ultra-rare diseases (gene therapy)NonePublic (RARE)Diverse biologics/gene therapy pipeline70VinetiSan Francisco, CA, USAPersonalized therapy management platformNoneSeries A-C fundingSoftware for CGT supply chain71VericelCambridge, MA, USACell therapies for cartilage & burnsMACI, Epicel, NexoBridPublic (VCEL)Strong revenue, expanding indications72Verve TherapeuticsBoston, MA, USAGene editing for cardiovascular diseaseNonePublic (VERV)Base editing for LDL-C/triglycerides73Vivet TherapeuticsParis, FranceGene therapies for metabolic diseasesNonePrivateVTX-801 for Wilson disease (Phase 1/2)74Voyager TherapeuticsCambridge, MA, USAGene therapies for neurological diseasesNonePublic (VYGR)TRACER capsids, partnered CNS programs75Sangamo TherapeuticsBrisbane, CA, USAZinc finger & AAV gene therapiesNonePublic (SGMO)ZFN platform, Fabry, hemophilia programs76SQZ BiotechnologiesWatertown, MA, USACell therapy for HPV16+ tumorsNonePublic (SQZ)AAC & eAPC platforms, strategic restructuring77Arrowhead PharmaceuticalsPasadena, CA, USARNAi therapeutics (cardiometabolic & more)NonePublic (ARWR)SiRNA pipeline, strong partnerships78Alnylam PharmaceuticalsCambridge, MA, USARNAi therapies for various diseasesOnpattro, Givlaari, Oxlumo, AmvuttraPublic (ALNY)RNAi pioneer with multiple approved products. Patents (20202024): 73 total (73 gene)79Aspen NeuroscienceSan Diego, CA, USAAutologous iPSC for Parkinsons diseaseNonePrivate (> $220M raised)iPSC-based personalized cell therapy80American Gene Technologies (AGT)Rockville, MD, USAGene therapy for HIV & rare diseasesNone~$78M fundingHIV functional cure in Phase 181Ionis PharmaceuticalsCarlsbad, CA, USAAntisense therapiesSpinraza, Tegsedi, WaylivraPublic (IONS)Antisense leader, broad pipeline. Patents (20202024): 62 total (60 gene, 2 vector)82Allogene TherapeuticsSouth San Francisco, CA, USAAllogeneic CAR T therapiesNonePublic (ALLO)Off-the-shelf CAR T for hematologic & solid tumors83NexImmuneGaithersburg, MD, USAAIM nanoparticle immunotherapyNonePublic (NEXI)Artificial Immune Modulation platform84NextCureBeltsville, MD, USAImmunomedicines for oncologyNonePublic (NXTC)B7-H4 ADC, immunotherapy pipeline85Oxford BiomedicaOxford, UKVector platform (Lentiviral), integrated innovationNonePublic (LSE:OXB)Leading lentiviral vector developer & collaborator86Pluri Inc.Haifa, Israel3D cell-based technology across industriesNonePublic (PLUR)3D cell expansion platform87ReNeuronBridgend, UKExosome-based therapeuticsNonePublic (RENE.L)CustomEX platform for targeted delivery88Arcturus TherapeuticsSan Diego, CA, USAmRNA medicines & vaccinesNonePublic (ARCT)Self-amplifying mRNA vaccines/therapies. Patents (20202024): 23 total (23 gene)89Silence TherapeuticsLondon, UKRNAi therapeutics targeting liver genesNonePublic (SLN)GalNAc-siRNA pipeline90BioNTechMainz, GermanymRNA-based immunotherapiesComirnaty (COVID-19 vaccine)Public (BNTX)mRNA cancer immunotherapies, global leader. Patents (20202024): 36 total (29 gene, 7 vector)91ModernaCambridge, MA, USAmRNA therapeutics & vaccinesSpikevax (COVID-19 vaccine)Public (MRNA)Expanding mRNA platform to rare diseases. Patents (20202024): 140 total (124 gene, 16 vector)92CureVacTbingen, GermanymRNA therapeutics & vaccinesNonePublic (CVAC)mRNA platform for prophylactic & therapeutic use. Patents (20202024): 65 total (56 gene, 9 vector)93Inovio PharmaceuticalsPlymouth Meeting, PA, USADNA medicines (cancer, infectious diseases)NonePublic (INO)Electroporation delivery of DNA plasmids. Patents (20202024): 28 total (25 gene, 3 vector)94Senti BiosciencesSouth San Francisco, CA, USAGene circuit-engineered cell & gene therapiesNonePublic (SNTI)Programmable gene circuits for cell therapies95Graphite BioSouth San Francisco, CA, USACRISPR gene editing therapiesNonePublic (GRPH)Precise gene correction for genetic diseases96Century TherapeuticsPhiladelphia, PA, USAAllogeneic iPSC-derived cell therapiesNonePublic (IPSC)iPSC platform for NK & T-cell therapies97ArsenalBioSan Francisco, CA, USAProgrammable cell therapies for cancerNonePrivateEngineered T-cells with synthetic biology98Homestead BioPharmaHouston, TX, USAGene therapies targeting AML & cancersNonePrivateEarly-stage gene therapy for oncology99Anew MedicalOmaha, NE, USACGT for cancer/neurologicalNoneIPO $15MDeveloping gene/cell therapies for CNS & cancer. Funding Status: IPO, Last Funding Date: May 26, 2023, $15,000,000 (Post-IPO Debt), Total Funding Amount: $15,000,000, Top Investors: Gaensel Energy Group100AmbuleroMiami, FL, USAVascular gene therapiesNoneSeed $5.5MGene therapies for vascular/ischemic diseases. Funding Status: Seed, Last Funding Date: Jan 25, 2021, $5,500,000 (Seed), Total Funding Amount: $5,500,000, Top Investors: Orphinic Scientific
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100 cell and gene therapy leaders to watch in 2025
Julie AndersonOmaha World-Herald
After more than four decades of infusing himself with the blood clotting factor his body cant make, Chad Stevens decided it was time to try something new.
Stevens, 63, suffers from hemophilia B, a bleeding disorder caused by a genetic mutation that affects production of a type of protein known as factor 9. Over the years, bleeds have damaged his joints. His ankles have been fused, his knees and elbows have severe damage. And successfully hitting a vein to infuse himself as he got older wasnt getting any easier.
In mid-October, Stevens traveled from his home town of Newdale, Idaho, to Omahas Nebraska Medical Center, where he became the hospitals first patient to receive the first gene therapy approved for his condition.
Called Hemgenix, the therapy doesnt fix the damaged gene. Instead, a modified virus delivers the working gene to the liver, providing the instructions his body needs to make the factor on its own. The medical center is the first hospital in the region to become an administration site for the therapy, according to drug-maker CSL Behring.
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Since then, Stevens hasnt had any bleeds or needed to infuse clotting factor. He said he hopes the therapy will provide enough to take him from severe hemophilia to a milder version that might require infusions only for a severe trauma or surgery.
Thats really promising, Stevens said. I hate to get too excited about it, because you never know whats going to happen. But Im quite thrilled with it.
So is Dr. Alex Nester, a hematologist with Nebraska Medicine who specializes in benign or non-cancerous blood conditions, including bleeding disorders and sickle cell disease.
Its incredible, he said. Its (been) a dream in the hemophilia community for 20-plus years.
The treatment, approved by the Food and Drug Administration in 2022, is one of a number of gene therapies that have trickled out in recent years for a variety of genetic conditions. The FDA approved a separate gene therapy for hemophilia A last year. The agency also has approved two gene therapies for sickle cell disease, another inherited blood disorder that causes red blood cells to become misshapen, block blood flow and cause painful episodes.
Kim Phelan, CEO of The Coalition for Hemophilia B, said the lasting advantages of the gene therapy include reduced joint damage, fewer hospitalizations and a better quality of life for people with hemophilia.
An estimated 7,000 people in the U.S. have hemophilia B, and approximately 17,000 have hemophilia A, which involves a different blood clotting factor.
After more than 25 years of anticipation and hope, individuals with hemophilia now have access to a groundbreaking therapy that offers the potential for greater independence and a more normalized life, she said.
Gene therapy at Nebraska Medicine
At Nebraska Medicine, the addition of the gene therapy builds on the work of the team involved in bone marrow transplants and cellular therapies, including CAR-T, or chimeric antigen receptor T-cell therapy. That treatment involves removing patients immune cells from their bodies and genetically engineering them to recognize and attack their cancer.
Dr. Matthew Lunning, medical director of gene and cellular therapy at Nebraska Medicine, said earlier this fall that the team has used CAR-T to treat hundreds of lymphoma and leukemia patients since the late 2010s.
Earlier this year, he and his team used CAR-T for the first time to treat an Omaha woman with lupus, an autoimmune disease, as part of a multi-site clinical trial. He credited Nebraska Medicines leaders for making the investment required to offer such ground-breaking therapies.
Still, gene therapies, according to news reports, have been somewhat slow to catch on. In the case of hemophilia, Nester said he suspects that may be a result of the complex modern history of the condition.
By the 1980s, he said, hemophilia patients who suffered trauma were given a concentrated form of the missing proteins when they needed help getting their blood to clot. But many contracted infections such as HIV and hepatitis C from contaminated blood products, which killed thousands of those with severe disease. Later, the products were purified but still were reserved for cases of active bleeding. As a result, older patients like Stevens suffered significant joint damage.
In the 1990s, researchers began producing a recombinant version of the missing proteins in hamster cells, similar to the way insulin is made. Children diagnosed with hemophilia could dose themselves with clotting factors to prevent bleeds, he said. That resulted in a generation with no bleeding episodes for years at a time and without the joint damage suffered by older patients.
You dont need a lot of these factors to live a pretty normal life, said Nester, also an assistant professor of medicine in UNMCs oncology and hematology division.
That also means younger patients may have less interest for now in a more permanent solution, he said. Some also may be holding off for newer versions of the gene therapy that are in the pipeline.
Stevens said his parents, on the other hand, were told he probably wouldnt survive his teens. Between his mother and her three sisters, three had children with hemophilia, a total of seven. He was the youngest. He is now the sole survivor. Several died from bleeds and a couple died of complications of AIDs due to the contaminated clotting factor relied on at the time.
It took a big toll on the hemophilia community, he said. It just decimated it, really. So us older ones are pretty lucky to have survived all of that.
Issues with earlier blood products, however, also have made older patients skeptical about new treatments. We like to wait and see how the products are doing out there before you jump on it, he said.
Cost of treatment can run into the millions
Patients also have to weigh the cost. The price for the one-time treatment reportedly was set at $3.5 million.
A spokesperson for CSL Behring said the company has seen an acceleration in the number of people being infused with the therapy since its approval, which the company attributes to its outreach to patients and work with insurers. Some 90% now cover the therapy, and the company also offers a program to help patients with copays. She declined to say, however, how many patients have received the therapy.
But Nester said clotting factors also are costly. Depending on the patient, the source of their factor and their insurance, it may run a half a million dollars a year to keep nothing from happening, he said.
Meanwhile, he said, researchers have seen that the majority of patients who have received the gene therapy are making 10% or more of the normal levels of the missing clotting factor even five years after being treated. That means their bodies are producing at least the preventative dose.
Patients still may have a bleeding episode after twisting their ankle or maybe needing a dose before surgery, Nester said, but, generally speaking, spontaneous bleeds or bleeds associated with minor trauma are gone.
Not every hemophilia patient will qualify for the treatment, however, he said. Patients cant have antibodies to either the virus or the factor theyre missing.
Stevens said his infusions probably cost closer to three-quarters of a million dollars a year. So far, the cost of his gene therapy has been covered. Previously employed in banking in Boise, he retired and applied for Social Security disability benefits on the advice of his doctor after his pain and mobility issues had made it nearly impossible for him to get out of his chair at work.
He moved back to Newdale, population 325, in eastern Idaho. But he didnt like being on disability, because he wasnt giving back. He was elected to the City Council and appointed mayor, a post he continues to hold.
It was just a pleasure to be contributing again, Stevens said.
Since receiving the therapy, he said, he seems to be moving a little better, and his knee isnt bothering him as much. Since the damage was done at an earlier age, he doesnt think the therapy will do much to repair it.
But if we can keep it from getting any worse, Stevens said, thats the goal.
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A new gene therapy can reverse the effects of heart failure and restore heart function in a large animal model.
The therapy increases the amount of blood the heart can pump and dramatically improves survival, in what a paper describing the results calls an unprecedented recovery of cardiac function.
Currently, heart failure is irreversible. In the absence of a heart transplant, most medical treatments aim to reduce the stress on the heart and slow the progression of the often-deadly disease.
But if the gene therapy shows similar results in future clinical trials, it could help heal the hearts of the 1 in 4 people alive today who will eventually develop heart failure.
The results appear in npj Regenerative Medicine.
The researchers were focused on restoring a critical heart protein called cardiac bridging integrator 1 (cBIN1). They knew that the level of cBIN1 was lower in heart failure patientsand that, the lower it was, the greater the risk of severe disease.
When cBIN1 is down, we know patients are not going to do well, says Robin Shaw, director of the Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI) at the University of Utah and a co-senior author on the study. It doesnt take a rocket scientist to say, What happens when we give it back?'
To try and increase cBIN1 levels in cases of heart failure, the researchers turned to a harmless virus commonly used in gene therapy to deliver an extra copy of the cBIN1 gene to heart cells. They injected the virus into the bloodstream of pigs with heart failure. The virus moved through the bloodstream into the heart, where it delivered the cBIN1 gene into heart cells.
For this heart failure model, heart failure generally leads to death within a few months. But all four pigs that received the gene therapy in their heart cells survived for six months, the endpoint of the study.
Importantly, the treatment didnt just prevent heart failure from worsening. Some key measures of heart function actually improved, suggesting the damaged heart was repairing itself.
Shaw emphasizes that this kind of reversal of existing damage is highly unusual.
In the history of heart failure research, we have not seen efficacy like this, Shaw says. Previous attempted therapies for heart failure have shown improvements to heart function on the order of 5-10%. cBIN1 gene therapy improved function by 30%. Its night and day, Shaw adds.
The treated hearts efficiency at pumping blood, which is the main measure of the severity of heart failure, increased over timenot to fully healthy levels, but to close that of healthy hearts. The hearts also stayed less dilated and less thinned out, closer in appearance to that of non-failing hearts.
Despite the fact that, throughout the trial, the gene-transferred animals experienced the same level of cardiovascular stress that had led to their heart failure, the treatment restored the amount of blood pumped per heartbeat back to entirely normal levels.
Even though the animals are still facing stress on the heart to induce heart failure, in animals that got the treatment, we saw recovery of heart function and that the heart also stabilizes or shrinks, says TingTing Hong, associate professor of pharmacology and toxicology and CVRTI investigator at the University of Utah and co-senior author on the study. We call this reverse remodeling. Its going back to what the normal heart should look like.
The researchers think that cBIN1s ability to rescue heart function hinges on its position as a scaffold that interacts with many of the other proteins important to the function of heart muscle.
cBIN1 serves as a centralized signaling hub, which actually regulates multiple downstream proteins, says Jing Li, associate instructor at CVRTI and first author on the study. By organizing the rest of the heart cell, cBIN1 helps restore critical functions of heart cells.
cBIN1 is bringing benefits to multiple signaling pathways, Li adds.
Indeed, the gene therapy seemed to improve heart function on the microscopic level, with better-organized heart cells and proteins. The researchers hope that cBIN1s role as a master regulator of heart cell architecture could help cBIN1 gene therapy succeed and introduce a new paradigm of heart failure treatment that targets heart muscle itself.
Along with industry partner TikkunLev Therapeutics, the team is currently adapting the gene therapy for use in humans and intend to apply for FDA approval for human clinical trial in fall of 2025. While the researchers are excited about the results so far, the therapy still has to pass toxicology testing and other safeguards. And, like many gene therapies, it remains to be seen if it will work for people who have picked up a natural immunity to the virus that carries the therapy.
But the researchers are optimistic. When you see large animal data thats really close to human physiology, it makes you think, Hong says. This human disease, which affects more than six million Americansmaybe this is something we can cure.
Funding for this study came from the National Institutes of Health and the Nora Eccles Treadwell Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Conflict of interest statement: The University of Utah has submitted a provisional patent application: Methods for rehabilitating heart failure using gene therapy (US 63/088, 123, Hong and Shaw), which has been licensed by TikkunLev Therapeutics Inc. Hong and Shaw received a Sponsored Research Award and stock options from TikkunLev Therapeutics Inc. Stavros Drakos, also an author on the study, is a consultant for Abbott and has received research support from Novartis.
Source: University of Utah
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