The Genetic Link Between Gaucher Disease And Parkinson's: How GBA1 Could Play A Role In The Next Generation Of Gene Therapy
By Henning Stennicke, Chief Scientific Officer at Spur Therapeutics
At first glance, Gaucher disease – a rare, debilitating, chronic lysosomal storage disorder – appears to have little in common with Parkinson’s disease. But the diseases share a common thread: mutations in a gene called GBA1. GBA1 encodes the enzyme glucocerebrosidase (GCase), which is responsible for clearing the toxic buildup of the lipids glucosylceramide (Gb-1) and glucosylsphingosine (lyso-Gb1) in cells. GBA1 mutations dramatically increase one’s likelihood of developing Gaucher disease and are the most common genetic risk factor for Parkinson’s disease.
In Gaucher disease, the accumulation of these lipids affects multiple organs, including the liver, spleen, bone, and lungs, leading to enlarged organs, low blood counts, abdominal pain, bone pain and fractures, severe fatigue, and lung dysfunction.
In Parkinson’s, the toxic lipid build-up in brain cells, facilitating a cascade of events that result in the death of dopaminergic neurons, which leads to the progressive worsening of symptoms, including tremors, muscle rigidity, impaired balance, and cognitive decline.
Standard-of-care therapies for Gaucher and some treatments in development for Parkinson’s are designed to deliver a recombinant version of the naturally occurring GCase enzyme. Because this enzyme, known as wild-type GCase, is notoriously unstable, many Gaucher patients receiving the standard of care continue to have unaddressed symptoms. As part of our work to advance a gene therapy for the treatment of Gaucher disease, Spur Therapeutics has developed GCase85, a rationally engineered form of GCase with significantly improved stability.
Preclinical data for both Gaucher and Parkinson’s show that compared to wild-type GCase, GCase85 has a much longer half-life in plasma, greater exposure in target cells, and enhanced cross-correction in the brain when delivered via AAV gene therapy. These data indicate that a gene therapy leveraging GCase85 could improve the standard of care for Gaucher disease and potentially change the course of disease for patients with GBA1-linked Parkinson’s disease (GBA1-PD).
Discovery of the GBA1 Link
While the rarer forms of Gaucher – types 2 and 3 – can cause severe neurological abnormalities, Gaucher disease type 1, which affects ~95% of Gaucher patients, has little neurological impact on patients. The link between Parkinson’s disease and GBA1 mutations was first made when researchers observed that people with Gaucher disease type 1, and even asymptomatic carriers of the GBA1 mutation, were developing Parkinson's disease at a higher rate than the general population. By 2004, scientists confirmed that GBA1 mutations not only increased the risk of developing Parkinson’s disease but also led to earlier onset and more severe disease. Genome-wide associated studies, starting with Sidransky et al. in The Lancet Neurology in 2009, further documented this connection. It is estimated that 5-15% of people with Parkinson’s disease have a GBA1 mutation, and those in this group generally have a more severe form of the disease.
It is now well established that GBA1 mutations reduce GCase activity, promoting α-synuclein polymer formation in the brain – a hallmark of Parkinson’s disease. As α-synuclein aggregates in the brain, it reduces mitophagy and ultimately increases death of dopaminergic neurons.
Because both conditions are linked to a mutation in the GBA1 gene, we are building on our work in Gaucher disease to develop what we believe could be a transformative gene therapy delivering GCase85 for the treatment of GBA1-PD.
A New Standard
There are currently no disease-modifying therapies available for Parkinson’s disease, and patients are largely limited to supportive care and symptomatic treatments, the effects of which wane over time. While people with Gaucher disease have therapeutic options to address the underlying cause of disease, there have been no major advancements in treatment for decades. The current standard of care is biweekly infusions of GCase enzyme replacement therapy (ERT). Unfortunately, unmet needs persist, in part due to the use of wild-type GCase, which doesn’t last long enough in the bloodstream to reach deeper tissues, and doesn’t last long enough in cells to provide consistent enzyme coverage in between infusions. As a result, some patients only have partial relief from the disease, and even after a decade or more of ERT, up to 60% of patients still experience symptoms.
Due to its enhanced stability, GCase85 lasts substantially longer than wild-type GCase in the body, giving rise to both higher plasma levels and better tissue coverage. Spur’s AAV gene therapy candidate for Gaucher disease, FLT201, is designed to deliver the transgene for GCase85 directly to liver cells, subsequently enabling the liver to continuously produce GCase85. The enzyme is then distributed through the bloodstream and taken up by cells to accumulate in the lysosomes and clear the Gb1 and Lyso-Gb1. If approved, this therapy could, with a single infusion, halt the progression of Gaucher disease, reduce or eliminate symptoms, and allow patients to come off their current lifelong treatments.
Results from the Phase 1/2 GALILEO-1 clinical trial of FLT201 are encouraging. Patient data show a dramatic reduction in a key biomarker indicative of disease severity and treatment response. We have seen durable improvements in areas where patients weren’t well-controlled, and maintenance where they were, after withdrawal of prior treatments.
In addition, FLT201 had favorable safety and tolerability in all patients – potentially attributable to the fact that FLT201 delivers a remarkably low therapeutic dose. Many gene therapies require higher viral loads, which are associated with greater safety risks, to deliver efficacious levels of therapeutic protein, but GCase85’s extended half-life contributes to FLT201’s ability to deliver benefit at a much lower dose.
Phase 1/2 data support advancement into a Phase 3 clinical trial set to initiate in 2025, bringing forward what we believe will be a first- and best-in-class gene therapy for Gaucher disease.
These promising data, along with preclinical data from direct-to-brain administration in mouse models, indicate that GCase85 could potentially also be used to treat GBA1-PD. While FLT201 is designed to deliver GCase85 exclusively to the liver, Spur Therapeutics has developed a new gene therapy candidate for GBA1-PD, SPR301, to deliver GCase85 to regions of the brain affected by Parkinson’s disease. For SPR301, GCase85 has been further optimized to more effectively express in neuronal cells, where preclinical data have shown it can clear toxic lipid build-up, while minimizing the activation of astrocytes and microglia, which promote inflammation in the brain.
By tailoring every component of our gene therapy candidates and minimizing the required AAV doses for potentially improved safety profiles, we are aiming to redefine gene therapies and the kinds of diseases they can treat. We’re moving beyond rare diseases into more prevalent conditions like Parkinson’s disease and envision a future in which gene therapies could be used to treat many chronic diseases that result from deficient or missing proteins in the body’s cells – not just those that are linked to genetic mutations.
About the Author
Henning Stennicke has more than 25 years of experience in scientific research and leadership. Henning holds a PhD in protein chemistry from University of Copenhagen, Denmark, an eMBA from Technical University of Denmark, and conducted his postdoctoral work at the Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA. Prior to joining Spur in March 2022, he held leadership positions at Novo Nordisk, including shepherding new treatments for several rare diseases through clinical development and regulatory approval.