Executive Summary
SPK-10001, a gene therapy candidate for Huntington’s disease, works by silencing the huntingtin gene, but only if it reaches the right brain tissue. This poster walks through the delivery testing behind that candidate in non-human primates, comparing intravenous, CSF, and direct parenchymal routes.
Direct injection into the caudate and putamen was the only route that meaningfully lowered HTT protein. CSF infusion did not extend coverage far enough to substitute for direct injection.
Early surgical attempts caused some mechanical and dose-related tissue damage. Refining the technique let the team raise doses while keeping inflammation low, a result that speaks directly to how the therapy might eventually be delivered in patients.
Abstract
Adeno-associated virus (AAV) is an effective platform for delivering genetic medicines to the brain via multiple routes, including direct brain infusion, cerebrospinal fluid (CSF) compartment infusion, or intravenous infusion.
SPK-10001 is a vectorized artificial microRNA targeting Huntington’s disease that induces a dose-dependent reduction of both Huntingtin (HTT) mRNA and protein levels.
Because SPK-10001’s proprietary capsid does not cross the blood-brain barrier via intravenous delivery, studies were conducted to determine the safest and most effective administration route. Results showed that only direct injection into the brain parenchyma significantly reduced HTT protein in the caudate and putamen. Intra-CSF injection did not improve target coverage and could not replace intraparenchymal injection.
While initial injection methods caused mechanical and AAV-dose-directed damage, optimization of the surgical technique improved efficacy and safety, enabling administration of higher doses with minimal inflammatory response. These findings highlight the importance of surgical refinement in developing effective brain-directed gene therapies for human patients.
Background
- HD is a rare neurodegenerative disorder, caused by an autosomal dominant repeat expansion (CAG) in the HTT gene, which leads to the production of mutant HTT protein (mHTT) on translation
- The toxic gain-of-function mechanism of mHTT drives nearly all cellular pathological mechanisms that underlie disease development (Bates et al., 20151)
- The striatum, and later the cerebral cortex, appears to be the brain region most susceptible to mHTT.
- Clinically, HD is characterized by progressive motor and cognitive impairment and behavioral dysfunction
- Reducing mHTT levels in the most affected brain regions could ameliorate all mHTT downstream pathogenic effects.
Experimental Approach
Results
Conclusion
- IPa delivery of AAV effectively reduces HTT protein in NHP caudate and putamen with minimal spread to the periphery and moderate increase of anti-AAV Nab titer compared to other routes (IT and ICV).
- Safety and efficacy of treatment depend on both AAV vector load and the surgical strategy that delivers them to the target brain structures
- The safest and most effective IPa strategy to deliver AAVs to caudate and putamen for Huntington’s disease treatment is a step-wise release of the infusion in small deposits at gradually ramping speed along the longitudinal axis of the target structures under the monitoring of intraoperative MRI.
