Category: Huntington's Disease
Objective: Our objective is to assess long-term safety of and durability of an adeno-associated viral vector serotype 5 encoding an engineered miRNA (AAV5-miHTT) targeting human mutant huntingtin (mHTT), up to 5 years after AAV5-miHTT administration. Furthermore, we aim to delineate the extent to which CSF mHTT lowering reflects mHTT lowering in different brain regions.
Background: Huntingtin (HTT)-lowering gene therapies are being evaluated in clinical trials. We have previously shown that one-time intrastriatal administration of AAV5-miHTT leads to sustained cerebrospinal fluid (CSF) mHTT protein lowering in Libechov transgenic Huntington’s disease (tgHD) minipigs up to 4 years post-injection.
Method: AAV5-miHTT (1.2E+13 gc/animal) was successfully administered into the striatum (bilaterally into the caudate and putamen), using age-matched untreated animals as controls. CSF was collected periodically up to 60 months post-injection, with CSF mHTT analyzed up to 60 months and NfL, GFAP, Tau and UCH-L1 analyzed up to 48 months. In a second study, AAV5-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: CSF mHTT lowering was sustained up to at least 5 years post-injection. We did not observe an increase in NfL, GFAP, Tau or UCH-L1 in CSF up to at least 4 years post injection. Analysis of the latest timepoints is ongoing. In the second study, intrathecal injection led to more pronounced CSF mHTT lowering compared to lower dose putamen injection, while mHTT lowering in the brain was generally similar between the two groups.
Conclusion: In this study, we confirm the durability and safety profile of AAV5-miHTT in a large animal model of HD up to 5 years post injection. Furthermore, our data indicate that CSF mHTT lowering does not always reflect the magnitude of mHTT lowering in different brain regions.
To cite this abstract in AMA style:
L. Van_der Bent, C. Brouwers, A. Stam, L. Spronck, J. Klíma, J. Juhásová, B. Levinská, S. Juhás, J. Motlík, M. Evers, Z. Ellederova, A. Valles. AAV5-miHTT gene therapy mediates sustained mutant huntingtin lowering in brain and cerebrospinal fluid of Huntington’s disease minipigs up to 5 years [abstract]. Mov Disord. 2023; 38 (suppl 1). https://www.mdsabstracts.org/abstract/aav5-mihtt-gene-therapy-mediates-sustained-mutant-huntingtin-lowering-in-brain-and-cerebrospinal-fluid-of-huntingtons-disease-minipigs-up-to-5-years/. Accessed May 18, 2025.« Back to 2023 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/aav5-mihtt-gene-therapy-mediates-sustained-mutant-huntingtin-lowering-in-brain-and-cerebrospinal-fluid-of-huntingtons-disease-minipigs-up-to-5-years/