Objective: We have developed AAV5-miHTT, a recombinant AAV-based gene therapy expressing an engineered microRNA that specifically binds to HTT exon1, resulting in lowering of both full-length and exon1 HTT mRNA expression.

Background: Huntingtin (HTT)-lowering therapies hold great promise to slow-down or halt neurodegeneration in Huntington’s disease (HD). From the different approaches under development, gene therapies using adeno-associated viral vectors (AAVs) are typically administered locally into the brain region of interest, after which they expand to interconnected regions though different mechanisms. A single administration should be sufficient to ensure long-term persistence of the therapeutic transgene (i.e. lowering agent), especially in non-dividing cells such as neurons.

Method: Adequate translational measures to evaluate the safety, efficacy and durability of HTT lowering mediated by AAV5-miHTT in patients are much needed. To this end, we assessed the response of candidate biofluid and imaging biomarkers in preclinical models (from rodents to minipigs and non-human primates) to AAV5-miHTT administration. In cerebrospinal fluid (CSF), assessments included pharmacokinetic (miHTT expression) and pharmacodynamic (HTT protein, NFL) measures. Imaging biomarkers included volumetric magnetic resonance imaging (vMRI) and magnetic resonance spectroscopy (MRS). Data supporting this customized selection will be presented, in light of the known mechanism of action of AAV5-miHTT.

Results: Now on its way to clinical development, AAV5-miHTT has demonstrated safety and efficacy in small and large animal studies, with remarkable brain-wide spread and long-term persistence, through retrograde and anterograde transport of the AAV followed by extracellular spread of the therapeutic miRNA, and without off-target effects. These observations in brain tissue can be correlated to some of the candidate biomarkers assessed.

Conclusion: Many of these measures have the potential to follow-up safety and efficacy of HTT-lowering therapies in general. However, because of the unique properties of gene therapy approaches in contrast to other HTT-lowering therapies, a tailored biomarker panel for HTT-lowering gene therapies in HD patients may be needed. (Partial data presented at CHDI HD Therapeutics Conference Palm Springs, February 27, 2020)

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MDS Abstracts - https://www.mdsabstracts.org/abstract/translatable-biomarkers-in-gene-therapy-for-huntingtons-disease-learnings-from-pre-clinical-studies/