uniQure announced two publications of preclinical data from its gene therapy candidate AMT-130 in Huntington's disease, in the journals Nucleic Acids Research and Molecular Therapy - Methods & Clinical Development. The first publication in Nucleic Acids Research examines the tolerability and efficacy of non-selective huntingtin protein lowering using an AAV5 encoded micro-RNA targeting human HTT in the humanized Hu128/21 mouse model of Huntington's disease. The Hu128/21 model represents a genetically accurate model of Huntington's disease, as it expresses both the mutant and wild type full-length human HTT transgene. The animals received bilateral intrastriatal infusions by convection-enhanced delivery of either the control dose, or three ascending doses at the onset of the disease and were evaluated for 7 months, when sacrifice occurred. A dose-dependent suppression of full length HTT (both wild-type and mutant) was observed 7 months after a single injection of AAV5-miHTT, with reductions of 92% in the striatum and 64% in the frontal cortex. AAV5 also showed broad distribution at all time points evaluated and was clearly observed in the striatum, the hippocampus and the cortex. These data are consistent with prior studies and further demonstrate that AAV5 undergoes anterograde and retrograde axonal transport following infusion, resulting in broad transduction of the structures affected by Huntington's disease. AAV5-miHTT resulted in both cognitive and psychiatric improvements, as well as the prevention of neuronal degeneration, indicating the potential therapeutic benefit of non-selective HTT lowering. The authors concluded that the Hu128/21 model is not ideal for evaluating therapeutic changes in motor performance as a result of inherently increasing obesity in the mice that likely contributed to progressive motor deficits. The authors did cite improved motor coordination in an R6/2 mouse model that better demonstrates the characteristic weight loss associated with Huntington's disease. Tolerability was evaluated using measures of gliosis, brain morphology, body weight and survival. Results demonstrated that non-selective knock down of HTT was safe and well tolerated in the humanized mouse model, even in the absence of background mouse wild-type HTT. Additionally, there were no lateral ventricle size changes observed at any dose tested. These findings were further supported by a recently published study in Molecular Therapy - Methods & Clinical Development, on neuronal and astrocytic cell cultures derived from induced pluripotent stem cells from two Huntington's disease patients with different CAG-repeat lengths. Results from this study demonstrated significant non-selective reduction of up to 68% of human HTT in Huntington's disease patient-derived iPSC neurons and astrocytes, with no observed toxicity or off-target effects in gene expression and regulation.
