StemCell Therapy

Research details assessment and selection of AAV regulatory cassettes that drive optimal expression of Company's novel engineered ligand-gated ion channel for the treatment of focal epilepsy

Findings inform selection process of final development candidate

SOUTH SAN FRANCISCO, Calif., May 5, 2022 /PRNewswire/ -- CODA Biotherapeutics, Inc. ("CODA"), a preclinical-stage biopharmaceutical company developing a gene therapy-mediated chemogenetic platform to treat intractable neurological disorders, today announced that preclinical data from the Company's focal epilepsy program will be featured as a poster presentation at the American Society of Gene & Cell Therapy 25th Annual Meeting being held virtually and in person, May 16-19, 2022, in Washington, D.C.

CODA Biotherapeutics, Inc. (PRNewsfoto/CODA Biotherapeutics, Inc.)

CODA's approach to treat focal epilepsy is adeno associated virus (AAV)-mediated delivery of a novel engineered ligand-gated ion channel (LGIC) that can subsequently respond to an exogenous ligand. Oral administration of this small molecule ligand, which is designed to only interact with CODA's chimeric LGIC, can be finely tuned to control the aberrant activity of neurons and suppress seizures without adverse effects. To create an effective gene delivery approach for focal epilepsy, the Company generated a series of AAV expression cassettes that could drive optimal expression of its LGIC in target cells of the hippocampus.

Michael Narachi, president and CEO of CODA, said, "Focal epilepsy is a chronic, debilitating neurologic disorder that is characterized by unpredictable seizures initiated from a specific location in the brain and affects millions of people around the world. Recurrent seizures can result in cognitive and emotional deficits, with current interventions offering limited efficacy and multiple side effects. This research details the analysis and selection process of AAV regulatory cassettes that should drive optimal expression of our LGIC for the treatment of focal epilepsy. We look forward to advancing our assessment of these two selected cassettes in epilepsy models to inform the final decision of our development candidate in focal epilepsy."

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Title: Assessment of AAV Regulatory Cassettes with Optimal Hippocampal Neuron Expression for the Treatment of Focal EpilepsyDate: May 16, 2022 5:30-6:30 PM ETSession: Neurological Diseases IPoster Board Number: M-158Abstract Number: 277Location: Hall D, Walter E. Washington Convention CenterPresenter: Edward Yeh

The first round of selection was performed in vitro with 23 unique expression cassettes containing various combinations of regulatory elements including, enhancer, promoter, intron, 5' untranslated region, 3' untranslated region, and polyA tail. Plasmids with inverted terminal repeats (ITRs) flanking the regulatory cassettes driving LGIC expression were transfected in SKNAS neuroblastoma cells, as well as HeLa cells to determine which cassettes were able to target the cells more efficiently and provide high levels of LGIC expression. Analysis by Droplet Digital PCR (ddPCR) and ELISA showed varying levels of expression, with the highest observed in cassettes containing the cytomegalovirus (CMV) promoter followed by those with various tissue-specific promoters. For the second round of selection, nine expression cassettes chosen from the first round were packaged into AAV9 vectors and transduced in neonatal rat hippocampal mixed cultures. Analysis by ddPCR revealed high levels of LGIC mRNA expression from CaMKII- and Syn-driven cassettes, which were comparable to the strong, ubiquitous CAG promoter. CaMKII and Syn are both excitatory neuron-specific promoters.

Finally, the highest expressing cassettes from round two were assessed in vivo in male Sprague Dawley rat hippocampi by AAV9-mediated directed injection. mRNA analysis using ddPCR and immunofluorescence for cellular tropism demonstrated high levels of expression from human versions of the Syn- and CaMKII-driven cassettes. Further assessment of the two selected cassettes, one driven by the pan-neuronal hSyn promoter and the other by CaMKII promoter, will be performed in an animal model of focal epilepsy to finalize the development candidate.

Abstracts can be accessed via the conference website at annualmeeting.asgct.org

First Applications of the CODA Platform: Focal Epilepsy and Chronic Neuropathic PainEpilepsy is one of the most common chronic neurological diseases and, according to the Centers for Disease Control, affects more than 65 million people around the world of which 3.4 million are in the U.S. Epilepsy is characterized by unpredictable seizures and the term "focal" epilepsy is used to describe seizures that initiate from a specific location in the brain, typically in one hemisphere. Focal epilepsy represents approximately 60 percent of all epilepsy (National Institute of Neurological Disorders and Strokes). According to the World Health Organization, recurrent seizures disrupt normal brain functions, lead to neuronal loss, and result in cognitive and emotional deficits. Patients suffer from stigmatization, social isolation, combined with disability, educational underachievement, and poor employment outcomes. The Epilepsy Foundation estimates that one-third of people with epilepsy live with uncontrollable seizures because no available treatments are effective.

According to a study published in the Journal of Pain Research, 10 percent of the U.S. population suffers from neuropathic pain an estimated 30 million Americans. Neuropathic pain is caused by damage or disease of the sensory system, leading to chronic debilitation and loss of quality of life. Current pharmacological therapies for chronic neuropathic pain, such as opioids, anticonvulsants, and tricyclic anti-depressants, are not always effective and can have side effects, including the potential for addiction.

About the CODA PlatformCODA Biotherapeutics is developing a paradigm-shifting gene therapy approach by deploying a chemogenetic strategy for treating neurological disorders. The Company's innovative treatment aims to modulate specific neuronal circuits via adeno-associated virus (AAV)-mediated delivery of an engineered, inhibitory receptor by standard-of-care neurosurgical procedures. The receptor is designed to be quiescent in the transduced cells but will specifically and dose-dependently inhibit neurons when exposed to a novel, orally bioavailable small-molecule agonist. CODA expects this treatment will produce substantially improved and durable results while potentially avoiding off-target/adverse effects of currently available treatments.

About CODA Biotherapeutics CODA Biotherapeutics, Inc., is a preclinical-stage biopharmaceutical company developing an innovative gene therapy platform to treat intractable neurological disorders, with an initial focus on epilepsy, movement disorders, and neuropathic pain. The Company is creating the ability to control neurons with its revolutionary chemogenetics-based technology. CODA is located in South San Francisco, CA. For more information, please visit http://www.codabiotherapeutics.com.

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SOURCE CODA Biotherapeutics, Inc.

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