We are pioneering the development of novel gene therapies that target the root genetic causes of Parkinson’s disease, frontotemporal dementia, Alzheimer’s disease, ALS, 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 disease.
Leveraging recent breakthroughs in human genetics and the transformative success of AAV-based gene therapy, our goal is to use a precision medicine approach to slow or stop the progression of neurodegenerative diseases. We are particularly focused on neurodegenerative diseases caused by 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.
Our approach centers on selecting patient populations with particular genetic mutations whom we believe can be treated by increasing or decreasing the expression of a particular gene through gene therapy. Each of our gene therapy candidates is intended to be a one-time treatment to correct the key underlying genetic mutation that we believe drives disease progression.
LYSOSOMAL DYSFUNCTION AND NEURODEGENERATION
Lysosomes are membrane-bound organelles found in all cells. 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, resulting in toxicity and inflammation, which we believe causes neurodegenerative disease.
Mutations in Lysosomal Genes Cause Lysosomal Dysfunction Leading to Toxicity, Inflammation and Neurodegenerative Disease
Gene therapy breakthroughs present new hope for patients with neurodegenerative diseases. 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.
We are 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.
We have chosen to use AAV9 for our initial programs based on its transformational biological properties and track record. AAV9 is uniquely well-suited to deliver genetic material to the brain, and has demonstrated efficacy, acceptable safety, and broad brain-wide biodistribution in third-party clinical trials in other disease areas, including for one FDA approved treatment.
We have exclusive worldwide license agreements with REGENXBIO to develop and commercialize gene therapy products using REGENXBIO’s NAV AAV9 vector to deliver the genes contained in PR001, PR006 and PR004.
Parkinson's Disease with GBA1 Mutations (PD-GBA)
Parkinson’s disease is a severe and progressive neurodegenerative disorder that affects more than seven million people worldwide and up to one million people in the United States. Although Parkinson’s has historically been characterized as a movement disorder, patients can suffer from a range of non-motor symptoms, including psychosis, dementia and cognitive impairment. Pathologically, Parkinson’s disease is characterized by the presence of abnormal clumps of a protein called α-Synuclein that form in neurons throughout the brain. These protein aggregates are known as Lewy bodies.
There are currently no approved therapies that modify the course of Parkinson’s disease or the underlying pathological process.
Large-scale genetic studies have recently identified dozens of causative and risk genes for Parkinson’s disease. Many of these genes are involved in the normal functioning of lysosomes — so-called “recycling centers” in cells that contain enzymes responsible for degrading proteins, lipids and sugars to regulate metabolic function.
Lysosomal dysfunction plays a role in many types of neurogenerative diseases. In particular, mutations in the GBA1 gene — which helps to regulate lysosomal activity — are now known to be the single largest genetic risk factor for developing Parkinson’s disease, causing a subtype of the disorder known as PD-GBA. It is estimated that as many as seven to ten percent of Parkinson’s patients worldwide, and some 90,000 patients in the United States, carry at least one GBA1 mutation. GBA1 encodes the lysosomal enzyme beta-glucocerebrosidase (GCase), which is needed for the disposal and recycling of glycolipids — a type of cellular lipid component that is known to accumulate with aging. Mutations in the GBA1 gene lead to a deficiency of GCase. Without sufficient levels of the enzyme, lysosomes in brain cells cannot do their jobs, and inflammation and neurodegeneration ensue. GBA1 mutations lead to earlier onset of Parkinson’s disease, more severe symptoms, and increased likelihood of progression to dementia.
We are developing PR001 for the treatment of neuronopathic Gaucher disease, as well as Parkinson’s disease with GBA1 mutations.
Neuronopathic Gaucher Disease (nGD)
Gaucher disease is a lysosomal storage disorder caused by mutations in both copies of the GBA1 gene, which can have a wide range of effects on organs throughout the body. Gaucher disease has three subtypes, which vary by the presence or absence of neurological symptoms, severity of symptoms, age of onset and age at death.
Type 1 Gaucher disease has widely varying symptoms, including spleen and liver enlargement, low blood counts, bleeding problems, and bone pain and damage. Patients with Type 1 Gaucher disease are also at very high risk of developing PD-GBA, due to the genetic connection between the diseases. Enzyme replacement therapies (ERTs) are approved for the treatment of Type 1 Gaucher disease but are only effective in treating only the peripheral symptoms of disease, since they cannot cross the blood brain barrier.
Type 2 Gaucher disease, the most severe form, strikes infants and toddlers. It causes rapid and irreversible brain damage beginning in the first six months of life; patients typically die by age two.
Type 3 Gaucher disease can present in either childhood or adulthood. It involves neurological symptoms such as gaze and motor abnormalities, ataxia, spasticity and seizures, as well as symptoms that affect other organs.
We are developing PR001 for the treatment of Type 2 and Type 3 Gaucher disease, as well as Parkinson’s disease with GBA1 mutations.
Frontotemporal Dementia with GRN Mutations (FTD-GRN)
Frontotemporal dementia (FTD) is the second most common cause of dementia in people under the age of 65 (after Alzheimer’s disease), affecting 50,000 to 60,000 patients in the U.S. and 80,000 to 110,000 in the European Union. FTD is characterized by the progressive degeneration of the frontal and temporal lobes of the brain, which control decision-making, behavior, emotion and language. Although clinical presentation varies, the disease progresses more rapidly than Alzheimer’s, and death typically occurs three to ten years after the onset of symptoms.
There are currently no approved therapies for FTD.
Several forms of FTD are known to be caused by genetic mutations, which are increasingly well understood. One important example is the GRN gene, which encodes a protein called progranulin that is needed for the normal functioning of lysosomes, microglia, and neurons. Most people carry two normal copies of the GRN gene. Patients with FTD-GRN have mutations in one of their GRN genes that causes them to produce about half as much progranulin as healthy people. This reduction in progranulin lead to age-dependent lysosomal dysfunction, inflammation of the brain, and neurodegeneration.
We are developing PR006 for the treatment of FTD-GRN.
Supporting Publications: PR001
Defects in trafficking bridge Parkinson's disease pathology and genetics.
Abeliovich A, Gitler AD (2016) Nature
Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations.
Alcalay RN et al. (2015) Brain
Glucocerebrosidase mutations and synucleinopathies: toward a model of precision medicine.
Blandini et al. (2019) Mov Disord
The risk of Parkinson's disease in type 1 Gaucher disease.
Bultron G et al. (2010) J Inherit Metab Dis
Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's.
Liu G (2016) Ann Neurol
Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies.
Mazzulli JR et al. (2011) Cell
Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease.
Robak LA et al. (2017) Brain
Glucosylsphingosine promotes α-synuclein pathology in mutant GBA-associated Parkinson's disease.
Taguchi YV et al. (2017) J Neurosci
A "dose" effect of mutations in the GBA gene on Parkinson's disease phenotype.
Thaler A (2017) Parkinsonism Relat Disord
Supporting Publications: PR006
Progranulin Gene Therapy Improves Lysosomal Dysfunction and Microglial Pathology Associated with Frontotemporal Dementia and Neuronal Ceroid Lipofuscinosis.
Arrant AE et al. (2018) J Neurosci
Progranulin plasma levels predict the presence of GRN mutations in asymptomatic subjects and do not correlate with brain atrophy: results from the GENFI study.
Galimberti D et al. (2018) Neurobiol Aging
Restoring neuronal progranulin reverses deficits in a mouse model of frontotemporal dementia
Arrant AE et al. (2017) Brain
Lipidomic and Transcriptomic Basis of Lysosomal Dysfunction in Progranulin Deficiency.
Evers BM et al. (2017) Cell Rep
Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.
Lui H et al. (2016) Cell
Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study.
Le Ber I et al. (2008) Brain
Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21.
Cruts M et al. (2006) Nature