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Intrastriatal Administration of AAV5-miHTT in Non-Human Primates and Rats Is Well Tolerated and Results in miHTT Transgene Expression in Key Areas of Huntington Disease Pathology

1
uniQure biopharma B.V., 1105 BP Amsterdam, The Netherlands
2
Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
3
Madeha Management & Consultancy, 1222 LM Nederhorst den Berg, The Netherlands
*
Author to whom correspondence should be addressed.
Brain Sci. 2021, 11(2), 129; https://doi.org/10.3390/brainsci11020129
Received: 27 November 2020 / Revised: 10 January 2021 / Accepted: 17 January 2021 / Published: 20 January 2021
Huntington disease (HD) is a fatal, neurodegenerative genetic disorder with aggregation of mutant Huntingtin protein (mutHTT) in the brain as a key pathological mechanism. There are currently no disease modifying therapies for HD; however, HTT-lowering therapies hold promise. Recombinant adeno-associated virus serotype 5 expressing a microRNA that targets HTT mRNA (AAV5-miHTT) is in development for the treatment of HD with promising results in rodent and minipig HD models. To support a clinical trial, toxicity studies were performed in non-human primates (NHP, Macaca fascicularis) and Sprague-Dawley rats to evaluate the safety of AAV5-miHTT, the neurosurgical administration procedure, vector delivery and expression of the miHTT transgene during a 6-month observation period. For accurate delivery of AAV5-miHTT to the striatum, real-time magnetic resonance imaging (MRI) with convection-enhanced delivery (CED) was used in NHP. Catheters were successfully implanted in 24 NHP, without neurological symptoms, and resulted in tracer signal in the target areas. Widespread vector DNA and miHTT transgene distribution in the brain was found, particularly in areas associated with HD pathology. Intrastriatal administration of AAV5-miHTT was well tolerated with no clinically relevant changes in either species. These studies demonstrate the excellent safety profile of AAV5-miHTT, the reproducibility and tolerability of intrastriatal administration, and the delivery of AAV5-miHTT to the brain, which support the transition of AAV5-miHTT into clinical studies. View Full-Text
Keywords: AAV5; Huntington disease; miRNA; gene therapy AAV5; Huntington disease; miRNA; gene therapy
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MDPI and ACS Style

Spronck, E.A.; Vallès, A.; Lampen, M.H.; Montenegro-Miranda, P.S.; Keskin, S.; Heijink, L.; Evers, M.M.; Petry, H.; Deventer, S.J.v.; Konstantinova, P.; Haan, M.d. Intrastriatal Administration of AAV5-miHTT in Non-Human Primates and Rats Is Well Tolerated and Results in miHTT Transgene Expression in Key Areas of Huntington Disease Pathology. Brain Sci. 2021, 11, 129. https://doi.org/10.3390/brainsci11020129

AMA Style

Spronck EA, Vallès A, Lampen MH, Montenegro-Miranda PS, Keskin S, Heijink L, Evers MM, Petry H, Deventer SJv, Konstantinova P, Haan Md. Intrastriatal Administration of AAV5-miHTT in Non-Human Primates and Rats Is Well Tolerated and Results in miHTT Transgene Expression in Key Areas of Huntington Disease Pathology. Brain Sciences. 2021; 11(2):129. https://doi.org/10.3390/brainsci11020129

Chicago/Turabian Style

Spronck, Elisabeth A., Astrid Vallès, Margit H. Lampen, Paula S. Montenegro-Miranda, Sonay Keskin, Liesbeth Heijink, Melvin M. Evers, Harald Petry, Sander J.v. Deventer, Pavlina Konstantinova, and Martin d. Haan. 2021. "Intrastriatal Administration of AAV5-miHTT in Non-Human Primates and Rats Is Well Tolerated and Results in miHTT Transgene Expression in Key Areas of Huntington Disease Pathology" Brain Sciences 11, no. 2: 129. https://doi.org/10.3390/brainsci11020129

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