Objective: To extrapolate the human equivalent dose (HED) for a Phase I/II clinical trial in adults to explore the safety, tolerability, and efficacy of striatally-administered recombinant adeno-associated virus serotype 5, microRNA huntingtin (rAAV5-miHTT; AMT-130) gene therapy to lower huntingtin protein (HTT) in the brains of early manifest Huntington’s disease (HD) patients.

Background: Background: Preclinical data in HD animal models supports that lowering aberrant mRNA and mutant (mut)HTT protein species by AMT-130 ameliorates the molecular, neuropathological, metabolic, and clinical phenotype in HD. GLP toxicology and safety studies in non-human primates, have shown excellent tolerability, and safety of a single administration of AMT-130 using intraparenchymal convection enhanced delivery to the striatum.

Method: The HED to lower mutHTT was extrapolated using a regression plot based on the brain biodistribution in small and large HD transgenic models. Volumetric MRI of the putamen and caudate nuclei for each HD patient were acquired. Real-time volume of distribution (Vd) and volume of infusion (Vi) data from non-human primates (NHPs) were used to estimate a scale-up factor for human delivery of AMT-130 gene therapy.

Results: Bioanalytical modeling showed that brain protein lowering was linearly related to the number of AMT-130 genome copies. The AMT-130 HED to achieve a 75% lowering of mutHTT in the striatum and 50% in the frontal cortex was 6 × 1013 gc/brain administered in a single dose. The mean volume of the early manifest HD patient putamen was calculated to be 3.11±0.54 cm³ (mean±SD). The volume of the entire caudate was 2.24 ±0.36 cm³. An infusion of 100 microliters with a Vd/Vi=2.0 filled two-thirds of the caudate and putamen in the NHPs. A factor of 5 achieved the same filling into human caudate head and putamen. Despite the generalized cortical and striatal atrophy evident in HD patients, simulated surgical planning showed the feasibility to deliver gene therapy safely to both the caudate and putamen.

Conclusion: We have determined the HED and injection volume to adequately cover the human putamen and caudate when treating early manifest HD patients. We designed a clinical study to detect changes in biomarkers and clinical parameters related to HD neuropathology. This clinical trial was cleared by the FDA for subject enrollment.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/translating-preclinical-data-to-a-human-equivalent-dose-for-amt-130-aav-gene-therapy-for-early-manifest-huntingtons-disease/