Objective: To describe the early screening experience and evidence-based adaptations to the inclusion criteria for HD-GeneTRX-1 (NCT04120493).

Background: AMT-130 is an AAV5-based gene therapy intended to modify the course of HD delivered via one-time MRI-guided intrastriatal neurosurgical administration. Selection of patients in the context of progressive striatal atrophy is particularly challenging and requires consideration of clinical symptoms (early manifest disease), remaining structure/connectivity to permit disease modification and sufficient cortical/striatal volume to allow for safe administration. As such, inclusion criteria for the first-in-human trial focused on a combination of volumetric MRI (vMRI), demographic, genetic and clinical parameters.

Method: HD-GeneTRX-1 is a Phase I/II randomized, multicenter, sequential ascending dose, double-blind, sham-controlled, first-in-human study. The original key inclusion criteria included adults (ages 25-65), motor onset (DCL=4) early manifest stage 1/2 (UHDRS TFC 7-13), fully penetrant mutation (CAG ≥44 then ≥40), and putamen/caudate volumes per side of ≥2.5cm³/2.0cm³ respectively. Regression analysis was performed for vMRI total (striatum, putamen, caudate) against screening parameters including age, CAG repeats, CAP score, Unified Huntington’s Disease Rating Scale [UDHRS] including Total Functional Capacity [TFC], Total Motor Score [TMS], Behavior, Independence, Function) and Symbol Digit Modalities Test (SDMT).

Results: Analysis was performed on 33 screening/re-screening vMRIs in 31 adults (ages 31-59) with motor manifest HD (DCL=4, TFC 6-13, TMS 11-55) and a fully penetrant mutation (CAG≥40). While TFC was associated with striatum/putamen volumes (r2= 0.164/0.163, p<0.05), the strongest association was with TMS (r2=0.368/0.298, p<0.001) and SDMT (r2=0.323/0.289, p<0.001). Number of CAG repeats and UHDRS Independence Scale were also significant predictors of striatal volume.

Conclusion: Initial screening showing closer correlation of vMRI with TMS than TFC, leading us to adapt inclusion to patients with fewer motor symptoms (eg. multidimensional manifest HD). This highlights the need for additional observational MRI data using current imaging pipelines further describing the progression of early manifest HD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/evolving-inclusion-criteria-in-early-manifest-huntingtons-disease-hd-to-address-striatal-atrophy-lessons-from-hd-genetrx-1-the-first-gene-therapy-trial/