Prevail’s Gene Therapy Candidate PR001 Granted FDA Fast Track Status

PR001 Fast Track

The U.S. Food and Drug Administration (FDA) has granted Fast Track designation to Prevail Therapeutics’ lead gene therapy candidate, PR001, for the treatment of people with Parkinson’s disease associated with GBA1 gene mutations.

Fast Track status will support and expedite the clinical development, regulatory review, and potential marketing approval of PR001.

The FDA’s decision follows its acceptance of Prevail’s Investigational New Drug application in June. That IND acceptance will allow the company to initiate a Phase 1/2 clinical trial to assess PR001’s safety and tolerability.

Prevail expects to launch the trial, and start dosing patients, during the second half of 2019.

“We are pleased that the FDA has granted Fast Track Designation for PR001, which underscores the unmet need of patients with Parkinson’s disease with a GBA1 mutation,” Asa Abeliovich, MD, PhD, founder and CEO of Prevail, said in a press release.

People who carry a mutated GBA1 gene can have up to 5 times higher risk of developing Parkinson’s disease. Even though it remains unclear what links the two conditions, it is estimated that 7 to 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 enzyme is essential for the digestion and recycling of different types of molecules and cellular debris in tiny vesicles called lysosomes. If GCase activity is impaired in any way, toxic substances accumulate inside cells, particularly as people age, leading to excessive inflammation and —probably, scientists say — the neurodegeneration seen in Parkinson’s disease.

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

Studies in mice and primates with Parkinson’s disease demonstrated that PR001 was well-tolerated. The gene therapy was found to promote an increase in GCase enzyme activity in mice. That resulted in reduced accumulation of fatty molecules, and improvements in motor function.

“With no treatments available that modify the progressive course or the underlying disease process of Parkinson’s disease, a potential disease-modifying therapy like PR001 could significantly transform the lives of patients with this disease,” Abeliovich said.

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Mutation Plays a Role in Fatty Plaque Formation in Brain, Study Suggests

Mutation and brain plaque

A common Parkinson’s gene mutation plays a role in the formation of fatty plaque in the brain that can destroy nerve cells controlling movement, a study suggests.

The research, “GBA1 deficiency negatively affects physiological α-synuclein tetramers and related multimers,” was published in the Proceedings of the National Academy of Sciences.

Five to 10 percent of Parkinson’s patients have a mutation of the GBA1 gene. It generates an enzyme responsible for breaking down a large fat molecule into smaller ones called ceramides.

Fat molecules are the glue that helps proteins maintain a complex design in cell membranes.   The GBA1 enzyme is supposed to ensure that the glue is strong enough to hold the mosaic together.

In addition to ensuring cell membrane integrity, the enzyme is also responsible for the normal functioning of the cell’s recycling system.

Johns Hopkins researchers used the gene editing technology CRISPR-Cas9 to remove the enzyme from lab-grown brain cells. As expected, its depletion led to an accumulation of a fatty molecule called glucosylceramide and increased cell stress.

Strikingly, when glucosylceramide levels rose, the number of stable alpha-synuclein tetramers — a hallmark of Parkinson’s disease — fell.

Researchers then treated the modified brain cells with Zavesca (miglustat), an approved therapy for the treatment of Gaucher disease type 1 that prevents fatty molecule buildups.

The treatment led to cells recovering their levels of alpha-synuclein tetramers. This suggested that high levels of glucosylceramide destabilize the cell membrane mix. The result is alpha-synuclein tetramers falling out of the mosaic and breaking into single alpha-synucleins, the researchers said.

To further assess the potential of targeting GBA1 to treat Parkinson’s, the team used brain cells collected from a patient with a mutated GBA1 gene. These cells had lower than normal GBA1 activity and higher than normal levels of glucosylceramide. The result was an  accumulation of alpha-synuclein monomers.

Once more, treatment with Zavesca promoted alpha-synuclein stability and tetramer formation, while preventing the accumulation of alpha-synuclein fibrils that is characteristic of Parkinson’s disease. In addition, the researchers showed that increasing the amount of functional GBA1 with gene therapy also promoted alpha-synuclein stability.

“We believe this study gives us a better understanding of the effects of GBA1 mutation and its role in the development and progress of Parkinson’s disease,” Dr. Han Seok Ko, an associate professor of neurology at the Johns Hopkins University School of Medicine’s  Institute for Cell Engineering, said in a press release.

The team plans to continue study the enzyme’s effect on alpha-synuclein and nerve cell health.

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Source: Parkinson's News Today