Abstract
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.
Highlights
To determine the safety of intrastriatal administration and biodistribution of AAV5miHTT in NHP, Cynomolgus monkeys were randomized to a single bilateral intrastriatal administration of vehicle control or AAV5-miHTT at 2 × 1012, 7 × 1012 or 2 × 1013 genome copies/animal
Every animal was injected bilaterally in the caudate nucleus and putamen under magnetic resonance imaging (MRI) guidance by convection enhanced delivery (CED) and animals were followed for 6 months
Biodistribution of the vector and the miHTT transgene was assessed for both species, a full list of toxicology parameters was evaluated, and histopathology was performed on all major organs, including the brain as target organ
Summary
There are currently no disease-modifying treatments for HD, strategies targeting HTT hold great promise [6]. These include antisense oligonucleotides (ASO), small molecules and gene therapy approaches [7,8]. In this regard, results of a phase 1–2a study of an antisense oligonucleotide (ASO) targeting the HTT protein have been published recently, which are suggestive of target engagement [9,10]. The intrastriatal administration of gene therapy with a recombinant adeno-associated virus serotype 5 expressing a microRNA (miRNA) targeting HTT (AAV5-miHTT) holds promise for lowering mRNA and HTT protein in the brain and slowing HD progression [6,7]
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