Session Information
Date: Monday, September 23, 2019
Session Title: Huntington’s Disease
Session Time: 1:45pm-3:15pm
Location: Agora 3 West, Level 3
Objective: To assess the effects of intra-striatal administration of a huntingtin protein (HTT) lowering gene therapy in macaca fascicularis non-human primates (NHP).
Background: The aggregation of abnormal HTT in Huntington disease (HD) leads to striatal and cortical atrophy on MRI. Gene therapy delivered to the striatum using a recombinant adeno-associated virus serotype 5 (AAV5) expressing microHTT RNA (rAAV5-miHTT) holds promise to lower HTT in the brain and slow HD progression.
Method: The striatum of four equal groups of sex-matched NHP (n=24), including one control group (vehicle) and three groups treated with escalating doses AAV5-miHTT, were infused in parallel with 4×100 microliters of rAAV5-miHTT by convection enhanced delivery (CED) using micro step-cannulae and real-time MRI guidance. At three and six months after administration, a 1.5T MRI was used to assess brain structure. Neuropathological assessments were performed at six months.
Results: Cannulae were implanted in the striatum within 1.0 mm of the planned target in 97% of cases with an error of 0.5mm±0.03 (0.05-1.36 mm) [Mean±SEM (range)]. Neurological examinations did not show any sequelae related to the rAAV5-miHTT administration. MRIs were unremarkable in most NHPs (60%) at 6-months. T2-hyperintensities surrounding the narrow injection track lessened from 40% at three months to 28% by six months. Extension beyond the injection track was infrequent with no differences between control or treated groups. Necropsy showed granulomatous inflammation at the injection sites and adjacent areas in all groups, including controls. There was minimal perivascular cuffing and satellitosis adjacent to the injection sites in some NHPs administered rAAV5-miHTT.
Conclusion: Intra-striatal administration of rAAV5-miHTT is precise, well tolerated and safe in NHP. MRI and histopathological findings were mainly related to the neurosurgical procedure and not to rAAV5-miHTT administration.
To cite this abstract in AMA style:
J. Higgins, B. Blits, L. Spronck, A. Valles-Sanchez, M. Evers, S. van Deventer, P. Konstantinova, M. de Haan. MRI, Clinical, and Neuropathological Findings after Bilateral Intra-striatal Administration of rAAV5-miHTT in Non-human Primates [abstract]. Mov Disord. 2019; 34 (suppl 2). https://www.mdsabstracts.org/abstract/mri-clinical-and-neuropathological-findings-after-bilateral-intra-striatal-administration-of-raav5-mihtt-in-non-human-primates/. Accessed June 14, 2025.« Back to 2019 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/mri-clinical-and-neuropathological-findings-after-bilateral-intra-striatal-administration-of-raav5-mihtt-in-non-human-primates/