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Enrollment Ongoing in PROPEL Trial for Prevail’s Gene Therapy PR001

PR001 trial enrollment continuing

Enrollment in the Phase 1/2 PROPEL trial, evaluating the safety, tolerability, and early efficacy of PR001 — a one-time gene therapy — for Parkinson’s disease associated with mutations in the GBA1 gene, is progressing at two centers in New York and patient dosing is continuing.

Prevail Therapeutics, which is developing the therapy, expects to present early interim results in the second half of 2020.

This first in-human study (NCT04127578) of PR001 expects to enroll 16 people with moderate-to-severe Parkinson’s with confirmed GBA1 mutations. More information on locations and contacts can be found at the trial’s page here; additional study locations are expected in Chicago and New York.

People with GBA1 mutations have up to a five-fold higher risk of developing Parkinson’s disease. Indeed, estimates point to a link to GBA1 mutations in 7 to 10% of all Parkinson’s cases.

The GBA1 gene contains the information necessary to produce the enzyme beta-glucocerebrosidase (GCase) — an important component of cells’ recycling factories, called lysosomes. Lack of this enzyme, or its faulty activity, will make cells accumulate toxic substances inside them, which may contribute to the neurodegeneration seen in Parkinson’s disease.

PR001 was designed as a single-dose gene therapy to provide nerve cells with a fully working copy of the GBA1 gene. This new method uses a modified and harmless version of an adeno-associated virus (AAV9) to deliver the gene to cells, which will then be able to recover GCase function.

This gene therapy is expected to ease Parkinson’s symptoms caused by the mutations in the GBA1 gene.

The investigational therapy was well-tolerated in preclinical studies in mice and primates with Parkinson’s disease. PR001 also was found to promote an increase in GCase enzyme activity, which resulted in reduced accumulation of toxic fatty molecules, and improvements in motor function.

In this double-blind Phase 1/2 trial, participants will be randomly assigned to receive two escalating doses of PR001 — a low and a high dose — or placebo, given as a single injection. The gene therapy is injected directly into one of the subarachnoid cisterns, or brain chambers filled with cerebrospinal fluid (CSF), which surrounds the brain and spinal cord.

The study will run for five years. During the first year, the researchers will assess PR001‘s safety and tolerability, and its impact on biomarkers of disease activity in the CSF and clinical efficacy measures. One specific biomarker the team will exam are changes in GCase enzyme activity levels in the blood and CSF.

Participants in the trial will continue to be followed for an additional four years after its conclusion to monitor safety as well as selected biomarkers and efficacy measures.

An update on the trial’s clinical progress was presented recently at the Cowen & Co. Annual Healthcare Conference in Boston.

The U.S. Food and Drug Administration granted fast track designation to PR001 in July 2019 for the treatment of people with Parkinson’s disease associated with GBA1 gene mutations. This designation accelerates a therapy’s development and may help expedite its approval by providing more frequent meetings with the FDA and discussions about the therapy’s development plan.

“We believe the PROPEL trial makes PR001 the first potentially disease-modifying gene therapy for PD-GBA patients to enter clinical trials,” Asa Abeliovich, MD, PhD, founder and CEO of Prevail, said in a press release.

“Its ongoing progress brings us a step closer to new treatment options for patients living with PD-GBA,” Abeliovich said. “We are excited about the potential of PR001 to slow or stop disease progression for PD-GBA patients.”

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Study Shows Age-dependent Spread Of Alpha-synuclein From Gut to Brain in Mice

gut Parkinson's alpha-synuclein

Aggregates of the Parkinson’s disease-associated protein alpha-synuclein can spread from the gut to the brain in mice, but this process is dependent on aging, likely as a result of altered protein dynamics, a new study suggests.

The study, “Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice,” was published in Nature Neuroscience.

Parkinson’s disease is characterized by aggregates of alpha-synuclein in the nervous system, particularly in dopamine-producing neurons in the brain. However, how these aggregates form in the first place isn’t fully understood.

One proposed hypothesis is that these aggregates don’t initially form in the brain, but in the enteric nervous system (ENS) — the nervous system of the gut. This hypothesis is supported by the fact that many people with Parkinson’s experience gastrointestinal symptoms, such as constipation, years before the onset of motor symptoms. The idea is that, from the gut, the aggregates could “spread up” to the brain through the vagus nerve.

“The vagus nerve is a physical connection between neurons in the gut and neurons in the brain,” study co-author Collin Challis, PhD, a former postdoctoral researcher at California Institute of Technology (Caltech), said in a press release. “If these damaging protein clusters first originate in gut neurons, then in the future we may be able to diagnose [Parkinson’s disease] earlier and potentially use gene delivery to restore functions to the cells so that they can clean up the aggregates.”

In the new study, researchers injected alpha-synuclein aggregates into the lining of the intestinal tract in mice. This led to numerous Parkinson’s-associated changes in the gut, including increased production of inflammatory molecules (e.g. IL-6), gastrointestinal dysfunction, and increased activation of neurons in the ENS, indicating an inflammatory response.

The researchers then looked to see whether the aggregates had spread into the central nervous system (CNS, comprising the brain and spinal cord). Interestingly, initial experiments did not reveal significant aggregate accumulation in the CNS, nor were there sustained motor impairments of the sort that would be expected if this system was modeling Parkinson’s disease.

But, crucially, these experiments were done in young adult mice (8-10 weeks old), and the biggest risk factor for developing Parkinson’s is aging. Thus, the researchers repeated the experiment in older (16-month-old) mice.

In these mice, as in the younger mice, injecting alpha-synuclein into the gut lining led to gut dysfunction. But, unlike in the young mice, older mice also developed motor deficits resembling Parkinson’s disease. Furthermore, the older mice did have alpha-synuclein aggregates in their brainstems, supporting the idea that the aggregates “spread up.”

Additionally, the older mice had significantly reduced levels of dopamine in their brains, which was not observed in the younger mice following alpha-synuclein injection.

The reason for this age-related difference may come down to how protein-regulating systems in the body change with age.

The researchers demonstrated that older mice express significantly less of the gene GBA1, which encodes for the protein glucocerebrosidase (GCase). This protein plays a critical role in the molecular machinery that cells use to recycle proteins, so the researchers proposed that the age-associated decrease in GCase levels could allow alpha-synuclein aggregates to spread in a way that is limited in younger animals.

In keeping with this idea, the researchers found that, when they increased GCase levels in the guts of young adult mice through gene therapy using a variant of adeno-associated virus (AAV) as a delivery system, gut-related problems associated with alpha-synuclein were diminished, though not entirely resolved. As such, although GCase dysfunction probably isn’t the only factor, it likely plays a role in alpha-synuclein pathology.

“Our results propose mechanisms that may underlie the etiology of sporadic [Parkison’s disease] and highlight GBA1 as a therapeutic target for prodromal [early], peripheral synucleinopathy,” the researchers wrote.

“Interestingly,” they noted, “[disease-causing alpha-synuclein] also inhibits GCase function.” As such, it’s possible that there is a feedback loop wherein increasing alpha-synuclein leads to decreased GCase function, which in turn leads to further increases in alpha-synuclein, until a threshold is crossed, spilling over into disease.

“Mutations in the gene that encodes GCase are responsible for Gaucher disease and a risk factor in [Parkinson’s disease],” said Viviana Gradinaru, PhD, a professor at Caltech and co-author of the study. “Our work shows that this gene can be delivered by AAVs to rescue gastric symptoms in mice, and emphasizes that peripheral neurons are a worthwhile target for treating [Parkinson’s disease], in addition to the brain.”

Overall, the researchers said, “[O]ur findings suggest that age-related declines in protein homeostasis, including diminished GCase function, may promote susceptibility to [disease causing alpha-synuclein] in the ENS and support the gut-to-brain hypothesis of [the biology of] synucleinopathy.”

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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