I04 Aav5-mihtt gene therapy mediates sustained mutant huntingtin lowering in brain and cerebrospinal fluid of Huntington disease minipigs up to 4 years

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Background Huntingtin (HTT)-lowering gene therapies are being evaluated in clinical trials. We have previously shown that one-time intrastriatal administration of an adeno-associated viral vector serotype 5 encoding an engineered miRNA (AAV5-miHTT) targeting human mutant huntingtin (mHTT) protein leads to sustained CSF mHTT lowering in transgenic Huntington’s disease (tgHD) minipigs up to 2 years post-injection. Aims Here, we aimed to extend the observations on long-term safety and durability in tgHD minipigs up to 4 years post-injection. Furthermore, we aimed to delineate the extent to which CSF mHTT lowering reflects mHTT lowering in deep brain regions. Methods/Techniques rAAV5-miHTT (1.2E+13 gc/animal) was successfully administered into the striatum (bilaterally in caudate and putamen), using age-matched untreated animals as controls. CSF was collected periodically up to 48 months post-injection. In a second study, rAAV5-miHTT was administered in putamen (5.4E+12 gc/animal) or intrathecally (2.4E+14 gc/animal). CSF was collected periodically up to 12 months post-injection, when the animals were sacrificed. Results/Outcome CSF mHTT lowering was sustained up to at least 4 years post-injection. We did not observe an increase in NfL, GFAP, Tau or UCH-L1 in CSF, supporting the safety profile of AAV5-miHTT. Intrathecal injection led to more pronounced CSF mHTT lowering compared to low dose putamen injection, while mHTT lowering in the brain was generally similar between the two groups. Conclusions In this study, we confirm the safety and durability profile of AAV5-miHTT in a large animal model of HD. Furthermore, our data indicate that CSF mHTT lowering likely underestimates mHTT lowering in deep brain regions.

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