Executive Summary
This poster reports the long-term safety and durability data for SPK-10001 in cynomolgus macaques. Using bilateral, MRI-guided infusion into the brain parenchyma, the study tracked HTT protein reduction across a range of doses for twelve months.
Higher doses produced longer-lasting knockdown, and the therapy’s genetic material stayed detectable in cerebrospinal fluid, a marker the team used as a stand-in for durability. Imaging showed surgery-related injuries resolved within two months, and CSF protein levels along with tissue analysis pointed to minimal lasting neuronal damage.
Together, the safety and durability picture supports moving SPK-10001 forward in Huntington’s disease development.
Abstract
SPK-10001, an AAV-based gene therapy for Huntington’s disease (HD), targets Huntingtin protein (HTT) accumulation in the brain’s basal ganglia. Administered via bilateral intraparenchymal (IP) infusion using MRIguided ClearPoint SmartFlow cannula, SPK-10001 aims for a durable, dose-dependent reduction of HTT protein while minimizing brain tissue disruption and ensuring neuronal tolerance.
In cynomolgus macaques, increasing doses of SPK-10001 demonstrated lasting HTT reduction and safety over 12 months, with detectable transgene in the cerebrospinal fluid (CSF) serving as a durability biomarker. MRI scans showed resolution of surgery-related injuries within two months post-injection, while CSF protein analysis and histopathology confirmed minimal neuronal damage. Overall, SPK-10001’s preclinical data support its further development for Huntington’s disease.
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) up on translation
- The striatum, and later the cerebral cortex, appear to be the brain regions most susceptible to mHTT, clinically translating to progressive motor and cognitive impairment and behavioral dysfunction
- Reduction of mHTT levels in these brain regions could ameliorate mHTT downstream pathogenic effects and halt or slow down disease progression
- SPK-10001 is an artificial microRNA vectorized in an AAV (adeno-associated virus) and its designed to reduce HTT mRNA and protein
- An effective, safe, and less invasive surgical procedure was developed and optimized to deliver SPK-10001 to the caudate and putamen nuclei
Experimental Approach
Results
Conclusion
- SPK-10001 reduction of HTT protein is POTENT and durable throughout the brain up to 12 months post injection
- SPK-10001 delivery and presence in the brain is SAFE at every tested dose up to 365- days post-injection (green dots, left)
- SPK-10001 transgene durability can be measured in CSF and it’s a potentially valuable biomarker for further development
- SPK-10001 vector genome and transgene expression are DURABLE up to 12 months post injection
- Overall, these data support the further development of SPK-10001 for Huntington’s disease
