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

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.

griPASTA: A hacked kitchen scale-based system for quantification of grip strength in rodents

Assessment of neuromuscular function is critical for understanding pathophysiological changes related to motor system dysfunction in animal models of different diseases. Among a number of methods used for quantification of grip performance in rodents, gauge-based grip strength meters seem to provide the most reliable results, however such instruments are unaffordable by many laboratories. Here we demonstrate how to build a grip strength apparatus for rodents from scratch using a digital kitchen scale, an empty cage and a microcontroller, with both hardware and software being completely open-source to enable maximal modularity and flexibility of the instrument in concordance with the principles of open-source bioinstrumentation. Furthermore, we test the griPASTA system for assessment of increased muscular rigidity in the proof-of-concept experiment in the rat model of Parkinson’s disease induced by intrastriatal administration of 6-hydroxydopamine (6-OHDA). Finally, the importance of bioinstrumental customization is demonstrated by exploiting the ability of griPASTA to provide raw data and enable calculation of grip strength trial speed, a variable known to affect the grip strength measurements that is not standardly measured by the commercial grip strength meters.