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- W4295261190 abstract "<h3>Background</h3> 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. <h3>Aims</h3> 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. <h3>Methods/Techniques</h3> 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. <h3>Results/Outcome</h3> 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. <h3>Conclusions</h3> 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." @default.
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- W4295261190 date "2022-09-01" @default.
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- W4295261190 title "I04 Aav5-mihtt gene therapy mediates sustained mutant huntingtin lowering in brain and cerebrospinal fluid of Huntington disease minipigs up to 4 years" @default.
- W4295261190 doi "https://doi.org/10.1136/jnnp-2022-ehdn.230" @default.
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