CAP-003 may restore GCase activity above effective levels

09 Oct 2024, 12:00 by Margarida Maia, PhD · Parkinson's News Today

A single dose of CAP-003, a gene therapy being developed by Capsida Biotherapeutic, significantly increased the levels of GCase enzyme in the brains of non-human primates. The enzyme levels reached up to eight times the amount considered necessary to restore normal enzyme activity in individuals with Parkinson’s disease linked to GBA gene mutations.

Given as an intravenous (into-the-vein) infusion into the bloodstream, CAP-003 allows for widespread delivery of a working version of the GBA gene to the brain without targeting other parts of the body like the liver, which may help avoid common side effects of gene therapy.

“Capsida’s wholly owned novel gene therapy offers the potential to normalize GCase activity in patients with a single [intravenous] infusion safely, enabling the potential for long-term disease modification and substantial slowing of disease progression,” Peter Anastasiou, Capsida’s CEO, said in a company press release.

With these data in hand, Capsida plans to file an investigational new drug application for approval to advance CAP-003 to clinical testing. “These data give us confidence that we are on track to enter the clinic with CAP-003 in the first half of 2025,” Anastasiou said.

The data were presented as a poster titled, “Systemic AAV gene therapy with CNS-targeted engineered capsids achieves significant GCase activity increases in the primate brain to support the potential treatment of PD-GBA,” at Neuroscience 2024, the annual meeting of the Society for Neuroscience, held Oct. 5–9 in Chicago.

Most common genetic risk

Mutations in GBA, the gene that provides instructions for producing the GCase enzyme, is the most common genetic risk for Parkinson’s, affecting up to 15% of people with the disease.

Mutations in this gene result in decreased GCase activity, leading to the accumulation of toxic clumps of misfolded alpha-synuclein proteins that build up within nerve cells in the brain, causing Parkinson’s motor symptoms.

CAP-003 is designed to deliver a working version of the GBA gene specifically to nerve cells in the brain. The working gene is packed in a delivery vehicle called capsid that’s been engineered from an adeno-associated virus (AAV). This virus doesn’t cause disease in humans.

When infused into the bloodstream, CAP-003 travels to the brain, where the working gene is unpacked from the capsid. Nerve cells can then use this gene to produce GCase. This is expected to increase GCase activity and slow disease progression.

The primate study found a single infusion of a low or moderate dose of CAP-003 outperformed infusion with AAV9, a commonly used delivery vehicle for gene therapy. The delivered gene was active brain-wide at levels more than 200 times higher with CAP-003 compared with AAV9.

CAP-003 delivered its genetic cargo at “particularly high levels in [disease-relevant] brain regions such as the substantia nigra and putamen,” the researchers wrote. Both the substantia nigra and putamen are important for motor control.

As a result, the levels of GCase also increased in the brain, reaching up to six times the normal levels seen in untreated animals. GCase activity was increased by about 250%. Since just a 30% increase is needed to normalize GCase activity in patients, these data suggest CAP-003 could offer benefits in Parkinson’s linked to mutations in the GBA gene.

CAP-003 didn’t reach other parts of the body as much as AAV9. The delivered gene’s activity was reduced by 19 times in the liver with CAP-003 compared with AAV9, and by 17 times in the dorsal root ganglia, clusters of nerve cells in the spinal cord that relay sensory information.

In a mouse model with reduced GCase activity, CAP-003 led to increased GCase activity. GCase can break down fatty molecules called glycolipids. As GCase activity increased, fewer glycolipids built up in the brain. This is expected to prevent misfolded alpha-synuclein from building up.

“Taken together, CAP-003 is being advanced with the ultimate goal of achieving [disease-modifying] clinical benefit for patients with PD-GBA through a convenient [single-dose intravenous],” the researchers wrote.