Potential One-time Gene Therapy for Parkinson’s Linked to GBA Mutations to Enter Clinical Trial

Parkinson's gene therapy trial

A potential gene therapy for Parkinson’s disease associated with mutations in the GBA1 gene, PR001, will move into clinical testing in patients after the U.S. Food and Drug Administration (FDA) accepted an application for the therapy, Prevail Therapeutics announced.

FDA acceptance of the company’s Investigational New Drug (IND) application allows Prevail to initiate a Phase 1/2 clinical trial assessing PR001’s safety and tolerability in Parkinson’s patients with disease-causing GBA1 mutations. Prevail expects to open the trial and begin dosing this year.

People with mutations in the GBA1 gene have a higher risk — possibly as high as five-fold — of developing Parkinson’s disease. Even though the exact relationship between both conditions is not clear, it is estimated that 7%–10% of all Parkinson’s cases are related to GBA1 mutations.

The GBA1 gene holds the instructions to produce the enzyme beta-glucocerebrosidase (GCase) that is active in lysosomesspecial compartments within cells that digest and recycle different types of molecules. If beta-glucocerebrosidase does not work as intended, toxic substances accumulate inside cells, particularly as people age, leading to excessive inflammation and —probably — the neurodegeneration seen in Parkinson’s disease.

PR001 is intended to be a disease-modifying and single-dose gene therapy for patients with mutations in this gene. It uses a modified and harmless version of an adeno-associated virus (AAV9) to deliver a fully working copy of the GBA1 gene to nerve cells. This should allow for long-lasting expression of functional beta-glucocerebrosidase, easing disease symptoms caused by the mutated gene.

AAV-9 has been widely used in various gene therapies both approved and in clinical testing, including Zolgensma, a recently approved gene therapy to treat spinal muscular atrophy. The viral construct appears to be safe and can effectively cross the blood-brain barrier, a semipermeable membrane that separates blood from cerebrospinal fluid and protects the brain from viruses and other “invaders” entering via the bloodstream.  

“We are pleased that the FDA has accepted the IND for our first program, which we believe has the potential to transform the lives of patients with Parkinson’s disease with a GBA1 mutation,” Asa Abeliovich, MD, PhD, founder and CEO of Prevail, said in a press release.

“At Prevail, our goal is to halt the progression of serious neurodegenerative diseases by applying precision medicine to the development of gene therapies. Our active IND brings us a step closer to achieving that goal, and we look forward to entering this new phase as a clinical-stage company,” he added.

Prevail, based in New York City, was founded in 2017 through a collaboration between Abeliovich,  OrbiMed and The Silverstein Foundation for Parkinson’s with GBA.

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New Mouse Model Targets Parkinson’s Disease Mechanisms, New Therapies

Parkinson's mouse studies

Researchers have generated a new mouse model that can be used for in-depth studies of disease mechanisms and new therapeutic possibilities for Parkinson’s disease.

Although the function of the protein α-synuclein is unknown, its accumulation in clumps known as Lewy bodies, hallmarks of Parkinson’s disease, suggests this protein plays a role in the pathology of neurodegeneration.

Mutations in GBA1, the gene coding for the enzyme lysosomal glucocerebrosidase 1 (GBA1), have been suggested to play a role in Parkinson’s pathology by enhancing the accumulation of α-synuclein and, consequently, the amount of Lewy bodies. This so-called GBA1-associated Parkinsonism is characterized by an early onset and more severe symptoms of the disease.

The study, “D409H GBA1 mutation accelerates the progression of pathology in A53T α-synuclein transgenic mouse model“, published the journal Acta Neuropathologica Communications, investigated the link between GBA1 mutations and Parkinson’s disease.

By crossing mice that had a GBA1 mutation (known as the D409H mutation) with mice commonly used as models for Parkinson’s disease, researchers created mice with elevated levels of α-synuclein, suggesting that GBA1 plays a role in controlling levels of this protein.

These mice also had a shortened life-span and an earlier onset of neurological disease phenotypes, suggesting that GBA1 plays a role in the pathology of Parkinson’s disease. In fact, in depth-analysis revealed that the GBA1 mutation led to loss of dopaminergic neurons, exacerbated neuroinflammation and endoplasmic reticulum stress, a cellular process that reflects α-synuclein aggregation.

According to researchers these results “indicate that GBA1 deficiency due to D409H GBA1 mutation that contributes to α-synuclein accumulation, exacerbates neuronal vulnerability in neurodegenerative processes.”

This model can be used as a tool to study “the possible mechanisms underlying neurodegeneration due to GBA1 mutations and to test the efficacy of potential treatment against GBA1-associated PD and Dementia with Lewy bodies (DLB),” the researchers stated.

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Source: Parkinson's News Today