Prevail Therapeutics is pioneering the development of novel gene therapies that target the root genetic causes of Parkinson’s disease and other neurodegenerative disorders.
We seek to treat patient populations with urgent unmet needs, who currently have no available therapies to modify the progressive course of their diseases.
Leveraging recent breakthroughs in human genetics and the transformative success of AAV-based gene therapy, our goal is to cure neurodegenerative diseases. Prevail is particularly focused on lysosomal dysfunction; our hypothesis is that restoring healthy lysosomal function in the cells of a patient’s central nervous system could stop the progression of the patient’s neurodegenerative disease.
About Gene Therapy
Gene therapy breakthroughs present new hope for patients with Parkinson’s disease and related disorders. Over the past decades, simply reaching the intended target was a major challenge for any neurological drug, due in part to the presence of the blood-brain barrier. Advances in gene therapy technology allow for the efficient and widespread delivery of gene therapies to the central nervous system.
Prevail is developing adeno-associated virus (AAV)-based gene therapies for the treatment of neurodegenerative diseases. AAVs are small, non-replicating viruses that are not known to cause disease in humans. AAVs can be used as shuttle vectors to deliver engineered DNA (transgene) cargos to human cells. AAV-based vectors have shown substantial promise in achieving stable, long-lasting transgene expression. Many clinical trials of AAV-based gene therapies are currently ongoing, and one AAV-based gene therapy has been approved in the United States.
Prevail has in-licensed exclusive worldwide rights from REGENXBIO, a leading clinical-stage gene therapy company, to develop and commercialize gene therapy products using REGENXBIO’s NAV AAV9 vector for Parkinson’s disease and other related neurodegenerative disorders.
About Parkinson's Disease
Parkinson’s disease is a chronic, progressive neurodegenerative disorder that affects more than 10 million people worldwide. While Parkinson’s disease is a movement disorder that is most commonly characterized by resting tremor, bradykinesia, rigidity and gait difficulty, it is now known to impact other aspects of nervous system function, and patients can suffer from a range of disturbances such as in sleep, cognition and blood pressure. Pathologically, Parkinson’s disease is defined by inclusions called Lewy bodies, which are found within neurons and are comprised predominantly of an aggregated protein called alpha-synuclein.
Gene mapping in recent years has led to the identification of dozens of genetic variations across the human genome that are risk factors for Parkinson’s disease. For example, mutations in the glucocerebrosidase (GBA1) gene are now known to play an important role in Parkinson’s disease risk. It is estimated that up to 10 percent of patients with Parkinson’s disease in the United States carry such GBA1 mutations and risk-associated variants. GBA1 encodes the enzyme glucocerebrosidase, which is required for the disposal and recycling of glycolipids, a type of cellular lipid component that is known to accumulate with aging and can be toxic at elevated levels. Prevail is focused on developing gene therapies that directly address genetic causes of Parkinson’s disease, such as GBA1.
About Lysosomal Dysfunction and Neurodegeneration
Lysosomes are membrane-bound organelles found in essentially all human cell and tissue types. Lysosomes serve as the cell’s “recycling center,” as enzymes within the lysosome act to degrade proteins, lipids and sugars that come in from the cell’s cytoplasm (through autophagic trafficking) or its exterior (through endosomal trafficking). Lysosomes play an especially critical role in long-lived cells, such as neurons, and in the aging process. Deficiencies in various lysosomal enzymes can induce the accumulation of toxic materials in the cells, which in severe cases, can lead to rare childhood illnesses, called lysosomal storage disorders.
Human genetic studies, including genome-wide association and deep sequencing studies that compare patients with a particular neurodegenerative disease to healthy controls, have identified a number of genes that are highly associated with several neurodegenerative diseases, including Parkinson’s disease. Many of these identified risk genes are known to play a role in lysosomal function and trafficking.
Our hypothesis is that restoring healthy lysosomal function in the cells of a patient’s central nervous system could stop the progression of neurodegenerative disease.
Supporting PublicationsDefects in trafficking bridge Parkinson's disease pathology and genetics.
Abeliovich A, Gitler AD (2016) NatureGlucocerebrosidase activity in Parkinson's disease with and without GBA mutations.
Alcalay RN et al. (2015) BrainGlucocerebrosidase mutations and synucleinopathies: toward a model of precision medicine.
Blandini et al. (2019) Mov DisordThe risk of Parkinson's disease in type 1 Gaucher disease.
Bultron G et al. (2010) J Inherit Metab DisSpecifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's.
Liu G (2016) Ann NeurolGaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies.
Mazzulli JR et al. (2011) CellExcessive burden of lysosomal storage disorder gene variants in Parkinson's disease.
Robak LA et al. (2017) BrainGlucosylsphingosine promotes α-synuclein pathology in mutant GBA-associated Parkinson's disease.
Taguchi YV et al. (2017) J NeurosciA "dose" effect of mutations in the GBA gene on Parkinson's disease phenotype.
Thaler A (2017) Parkinsonism Relat Disord