Prevail is developing a pipeline of potentially disease-modifying AAV9-based gene therapies for the treatment of genetically-defined neurodegenerative diseases.
PR001 is being developed as a potentially disease-modifying, single-dose gene therapy for Parkinson’s disease with GBA1 mutation (PD-GBA) and neuronopathic Gaucher disease. PD-GBA and Gaucher disease share the same underlying genetic mechanism, and we believe they represent a continuum of disease.
GBA1 encodes the lysosomal enzyme, beta-glucocerebrosidase, or GCase, which is required for the disposal and recycling of glycolipids, a type of cellular lipid component that is known to accumulate with aging. PD-GBA patients have a mutation in one chromosomal copy of GBA1 and Gaucher disease patients have mutations in both chromosomal copies of GBA1. These mutations lead to a deficiency of GCase, causing the accumulation of glycolipids, which is toxic and causes inflammation. This results in lysosomal dysfunction and aggregation of the protein α-Synuclein in cells, which we believe leads to the inflammation and neurodegeneration present in PD-GBA and neuronopathic Gaucher disease patients.
PR001 utilizes an AAV9 viral vector to deliver the GBA1 gene, which encodes GCase, to a patient’s cells.
The initial new drug (IND) application for PR001 in PD-GBA has been accepted by the U.S. Food and Drug Administration (FDA) and we plan to initiate our Phase 1/2 trial in 2019. A Phase 1/2 trial in neuronopathic Gaucher disease is also expected to begin in 2019.
PR006 is our gene therapy candidate being developed for patients with frontotemporal dementia with a GRN mutation (FTD-GRN).
Frontotemporal dementia (FTD) is the most common cause of dementia in people under age 60 and results from the progressive degeneration of the frontal and temporal lobes of the brain, which control decision-making, behavior, emotion and language. FTD progresses rapidly after the onset of symptoms and there are currently no approved treatments. FTD is estimated to impact 50,000 to 60,000 people in the U.S. and 80,000 to 110,000 individuals in the European Union.
Progranulin is a glycoprotein encoded in humans by the GRN gene. Progranulin is found both extracellularly and in lysosomes. It is expressed by astroglia and microglia, which are immune cells that reside in the brain. Healthy levels of progranulin are necessary for cellular processes such as lysosomal function, neuronal survival and normal microglial activities. In FTD-GRN patients, reduced levels of progranulin lead to lysosomal dysfunction and ineffective protein degradation and recycling, which causes neurodegeneration.
PR006 is designed to increase progranulin levels in FTD-GRN patients by delivering a healthy GRN gene using an AAV9 vector.
PR004 is a gene therapy in preclinical development for patients with certain synucleinopathies. PR004 utilizes an AAV9 vector to deliver the GBA1 gene, which encodes glucocerebrosidase (GCase), and a molecule that suppresses expression of α-Synuclein.