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Abstract Details

Evolving inclusion criteria in early manifest Huntington’s disease (HD) to address striatal atrophy: Lessons from HD-GeneTRX-1, the first gene therapy trial
Movement Disorders
Movement Disorders Posters (7:00 AM-5:00 PM)
146
To describe the early screening experience and evidence-based adaptations to the inclusion criteria for HD-GeneTRX-1 ().
AMT-130 is an AAV5-based gene therapy intended to modify the course of HD, delivered via single MRI-guided intrastriatal neurosurgical administration. Selection of patients in the context of progressive atrophy is particularly challenging and requires consideration of clinical symptoms (early manifest disease), remaining structure/connectivity to permit disease modification, and sufficient 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.

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].


 
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.
 

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.
Authors/Disclosures
Erin Furr-Stimming, MD, FÂ鶹´«Ã½Ó³»­ (University of Texas Health Science Center-Houston)
PRESENTER 		Dr. Furr-Stimming has received personal compensation for serving as an employee of Help4HD International. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medscape. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MedPage. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PTC Therapeutics. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Wave Life Sciences. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Latus Bio. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Atalanta Therapeutics. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Furr-Stimming has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for SkyHawk Therapeutics. The institution of Dr. Furr-Stimming has received research support from Roche/Genetech. The institution of Dr. Furr-Stimming has received research support from Uniqure. The institution of Dr. Furr-Stimming has received research support from CHDI. The institution of Dr. Furr-Stimming has received research support from Huntington Study Group/Neurocrine Bioscienes. The institution of Dr. Furr-Stimming has received research support from NIH/University of Iowa. The institution of Dr. Furr-Stimming has received research support from HDSA. Dr. Furr-Stimming has received publishing royalties from a publication relating to health care. Dr. Furr-Stimming has received publishing royalties from a publication relating to health care. Dr. Furr-Stimming has a non-compensated relationship as a Committee member with Â鶹´«Ã½Ó³»­ UES Committee that is relevant to Â鶹´«Ã½Ó³»­ interests or activities.
Claudia Testa, MD, PhD (University of North Carolina at Chapel Hill) Dr. Testa has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neurocrine. Dr. Testa has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for uniQure. Dr. Testa has received personal compensation in the range of $5,000-$9,999 for serving as an officer or member of the Board of Directors for Tremor Research Group.
Paul Larson No disclosure on file
Christopher Ross, MD, PhD (JHU) Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for uniqure. Christopher Ross, MD, PhD has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Teva. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Spark. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitoconix. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sage. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Annexon. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuCell. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuCell. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NeuBase. Christopher Ross, MD, PhD has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Huntington Study Group. Christopher Ross, MD, PhD has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Spark. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for uniQure. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Mitoconix. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sage. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Annexon. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NeuCell. Christopher Ross, MD, PhD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NeuBase. Christopher Ross, MD, PhD has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Christopher Ross, MD, PhD has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Huntington Study Group. Christopher Ross, MD, PhD has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Mintz. Christopher Ross, MD, PhD has received intellectual property interests from a discovery or technology relating to health care. Christopher Ross, MD, PhD has a non-compensated relationship as a consultant with Huntington Study Group that is relevant to Â鶹´«Ã½Ó³»­ interests or activities.
No disclosure on file
Ali Samii, MD, FRCP (University of Washington and Seattle VA) Dr. Samii has nothing to disclose.
No disclosure on file
Sarah H. Ying, MD (MEEI) Dr. Ying has nothing to disclose.
No disclosure on file
Eileen Sawyer, PhD (SwanBio Therapeutics Ltd.) Eileen Sawyer has received personal compensation for serving as an employee of uniQure Inc. Eileen Sawyer has received stock or an ownership interest from uniQure Inc.
Ralf Reilmann, MD, FÂ鶹´«Ã½Ó³»­ (George-Huntington-Institute) The institution of Dr. Reilmann has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Hoffmann-La Roche. The institution of Dr. Reilmann has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for uniQure. The institution of Dr. Reilmann has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for WAVE. Dr. Reilmann has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for WAVE. The institution of Dr. Reilmann has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for IOS-Press. The institution of Dr. Reilmann has received research support from European Union. Dr. Reilmann has a non-compensated relationship as a Executive Committee Member with Huntington Study Group that is relevant to Â鶹´«Ã½Ó³»­ interests or activities. Dr. Reilmann has a non-compensated relationship as a Member of Executive Committee with European Huntington Disease Network that is relevant to Â鶹´«Ã½Ó³»­ interests or activities. Dr. Reilmann has a non-compensated relationship as a Co-Chair Task Force on Huntington Disease with Movement Disorders Socitey that is relevant to Â鶹´«Ã½Ó³»­ interests or activities.