Capsida Biotherapeutics' CAP-003, an intravenously delivered gene therapy, is showing promise as a potential treatment for Parkinson's disease associated with GBA mutations (PD-GBA). Preclinical data presented at the Society for Neuroscience annual meeting demonstrated that CAP-003 achieved brainwide RNA expression in nonhuman primates (NHPs) more than 200-fold greater than IV administered adeno-associated virus serotype 9 (AAV9). This correlated with substantial increases in GCase protein and enzyme activity compared to untreated NHPs.
Enhanced GCase Activity and Target Engagement
The data indicated that all CAP-003 doses surpassed the 30% efficacy threshold anticipated for normalizing GCase activity in human patients. Notably, GCase activity in the NHPs, including within the substantia nigra, was 2-8 times higher than this threshold. At a dose of 5.5x10^13 vg/kg, CAP-003 led to a 488% increase in GCase brain protein level, which was 8 to 24 times higher than that achieved by ICM AAV9 in a previous NHP study. A lower dose of 2.2x10^13 vg/kg still produced a 335% increase in GCase protein.
Furthermore, the analysis revealed that levels of glucosylsphingosine (GluSph) were reduced in the terminal plasma of NHPs treated with CAP-003. The 2.2x10^13 vg/kg dose reduced GluSph levels by 59%, while the 5.5x10^13 vg/kg dose reduced GluSph levels by 79%. These reductions suggest effective lysosomal activity and target engagement.
Correlation with CSF Biomarkers
The average GCase activity in the brain of treated NHPs showed a significant positive correlation with GCase protein levels in the cerebrospinal fluid (CSF) and a trend of positive correlation with GCase activity in the CSF. In the CSF of NHPs that received CAP-003 at a dose of 5.5x10^13 vg/kg, a 1068% increase in GCase protein was observed along with a 103% increase in GCase activity, bolstering confidence in the use of CSF GCase biomarkers in clinical settings.
Safety Profile
NHPs treated with CAP-003 also exhibited significantly lessened DNA and RNA biodistribution to the liver and dorsal root ganglia (DRGs) compared to historical IV-delivered AAV9. Specifically, a 19-fold lower liver biodistribution and a 17-fold lower expression in DRGs were reported, with no adverse histopathology observed.
Clinical Significance
Approximately 5-15% of patients with Parkinson's disease have mutations in the GBA gene, making it the most significant genetic risk factor for the disease. Mutations in GBA can lead to loss of GCase activity and lysosomal dysfunction, impairing alpha-synuclein metabolism. Peter Anastasiou, MBA, CEO of Capsida, stated that CAP-003 offers the potential to normalize GCase activity with a single IV infusion, potentially enabling long-term disease modification and slowing disease progression. Capsida anticipates entering clinical trials with CAP-003 in the first half of 2025.
