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First Trial Begins Testing Drug in People with GBA Mutation

First Trial Begins Testing Drug in People with GBA Mutation

Sanofi Genzyme has started a clinical trial for a drug targeting cellular dysfunction seen in people with Parkinson's disease (PD) and a GBA mutation. This study is a major step for PD research as it is the first drug trial where one's genetic information determines eligibility and is testing a potential therapy to slow or stop disease progression.

"I think of this as precision medicine for Parkinson's," Pablo Sardi, PharmD, PhD, research and development director in neuroscience at Sanofi wrote to news and information site Alzforum. Dr. Sardi announced the study at the Society for Neuroscience conference in November.

Precision or personalized medicine means developing and testing therapies based on one's molecular profile rather than on a clinical diagnosis. As we learn more about genetic mutations that may cause Parkinson's disease and the cellular dysfunction associated with those mutations, the research field moves to create more targeted treatments that may have greater success.

"We will only get to true cures if we can move away from historical clinical disease definitions, based purely on symptoms, to one more nuanced and linked to underlying biology, genetics and pathology," wrote MJFF leaders in a recent editorial in the journal Personalized Medicine.

Listen to a podcast or watch a webinar on Parkinson's personalized medicine.

Targeting Dysfunction Seen with GBA Mutations
GBA mutations cause dysfunction in the glucocerebrosidase (GCase) protein, which can lead to build-up of the protein alpha-synuclein. Clumps of alpha-synuclein (Lewy bodies) are seen in brain cells of everyone with Parkinson's disease, and scientists believe Lewy bodies harm cells, causing symptoms and progression. Read more about the connection between GBA, GCase and PD.

The Sanofi trial is testing a drug (GZ/SAR402671) against a partner of GCase and alpha-synuclein. GCase normally breaks down fatty substances (lipids). Build-up of one lipid (glucosylceramide) -- due to a GBA mutation -- may lead to build-up of alpha-synuclein. The company is testing an inhibitor of glucosylceramide, which they believe may prevent alpha-synuclein clumping and protect brain cells.

Laboratory tests showed pre-clinical PD models with a GBA mutation treated with a similar compound had fewer alpha-synuclein clumps and did better on memory tests than similar models not given the drug.

Recruiting Participants with Parkinson's and Known GBA Mutation
The Phase II trial recently began enrolling people with PD and a GBA mutation and aims to enroll 230 people across 50 international sites. The company expects to complete the trial by 2022. While currently one must know if they carry the mutation to enter the study, Sanofi Genzyme plans to offer genetic testing for individuals who meet other screening criteria in the future.

Who carries GBA mutations? These variants are more common in people of Ashkenazi Jewish descent and in people with Gaucher disease or a relative with Gaucher. This disorder, where fatty substances build up and cause enlarged organs, is also caused by a GBA mutation. It's important to note while GBA mutations are common, their chance of leading to Parkinson's disease is low.

In studies such as the MJFF-led Parkinson's Progression Markers Initiative (PPMI), researchers are observing people with GBA mutations (with and without PD) to understand more about what may lead some to develop the disease while others do not. [Sanofi Genzyme is one of 19 PPMI industry partners.]

PPMI is recruiting people of Ashkenazi Jewish descent with PD, Gaucher or a relative with either disease for genetic screening and counseling to see if they're eligible to participate in the study, a large-scale effort to learn more about PD variability and progression. Take a screening survey to see if you're eligible.

Have questions about where else to access genetic testing and counseling? Discuss your options with your movement disorder specialist.

Broadening the Reach of This Therapy beyond PD and GBA
What if you don't have the GBA mutation? While this specific trial doesn't apply to you, the knowledge we gain from it, and other studies, may. Studying genetic connections in PD gives a greater understanding of disease mechanisms and leads toward therapies that could potentially be applicable to the broader Parkinson's community, regardless of genetic status.

GZ/SAR402671 is currently in Phase II trials for Gaucher disease type 3 and Fabry disease, and other companies are also working on drugs to correct the dysfunction seen in PD and associated with GBA mutations.

The Sanofi trial is just starting, so not many sites are activated yet. Register with our online tool Fox Trial Finder to be matched with recruiting studies looking for volunteers like you and monitor the trial's page for updates. We'll share more on our blog and social channels as this study continues.

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