The proposed study represents a systematic approach to recruit subjects and develop outcome measuresnecessary to reach a phase I gene transfer trial in Duchenne muscular dystrophy (DMD) and in two forms oflimb girdle muscular dystrophy [LGMD 2D or alpha-sarcoglycan (SG) deficiency, and LGMD 2E or beta-SGdeficiency]. The prepatory stage will be carried out in years one through three of the proposal. In years fourand five, Phase 1 clinical transfer trials will be done in these three forms of muscular dystrophy.
The specificaims define the approach to reach the stated goals:
Specific Aim 1 : Identify a cohort of DMD subjects with small gene mutations to participate in Phase 1 genetransfer studiesSpecific Aim 2: Establish the most appropriate muscle(s) for gene transfer in a population of DMD subjectsusing magnetic resonance imaging (Aim 2A) and quantitative muscle strength testing (maximum voluntaryisometric contraction testing or MVICT) (Aim 2B)Specific Aim 3: Identify a population of LGMD 2D (alpha-SG) and LGMD 2E (beta-SG) subjects forparticipation in Phase 1 gene transfer studiesSpecific Aim 4: Establish the most appropriate muscle(s) for gene transfer in a population of LGMD 2D andLGMD 2E subjects using magnetic resonance imaging (Aim 4A) and quantitative muscle strength testing(MVICT) (Aim 4B)Specific Aim 5: Establish appropriate delivery methods for gene transfer of adeno-associated virus (AAV)considering volume, rate, and spread of vector from the site of injectionSpecific Aim 6: Perform Phase 1 gene transfer trials in DMD and two forms of LGMD (2D alpha-SG) and (2Ebeta-SG)
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