Gene Transfer Clinical Trial for LGMD2D (Alpha-sarcoglycan Deficiency) Using scAAVrh74.tMCK.hSGCA

• Safety with fewer than 2 grade 3 adverse events [ Time Frame: 1 year from start ] [ Designated as safety issue: Yes ]
  Safety with fewer than 2 grade 3 adverse events
  
  

• Efficacy outcome measure 6MWT [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  6 minute walk test (6MWT)-(primary variable to measure efficacy) Efficacy would be a significant improvement in distance walked in the 6 minute walk test.
  
  

The proposed clinical trial is a dose escalation study of self-complementary scAAVrh74.tMCK.hSGCA to LGMD2D (alpha-SG deficient) subjects delivered via a major lower limb artery of each leg sequentially by modified isolated limb perfusion and isolated limb infusion (ILP/ILI);1 henceforth designated as isolated limb recirculation for gene therapy (ILR-GT). Two cohorts will undergo gene transfer in a standard three-six dose escalation scheme to establish maximum tolerated dose (MTD) using toxicity. A minimum of three subjects will be enrolled into each cohort. The first cohort will receive a total dose of 2 x 1012 vg/kg split between the 2 lower extremities (1 x 1012 vg/kg per limb). The vector will be infused into an indwelling catheter in the femoral artery. This will be a one-time vector infusion that will recirculate over a period of 30 minutes in a closed circuit that includes: arterial delivery to an isolated limb (proximal tourniquet), return via the femoral vein and redelivered to the artery via extracorporeal pump. The second cohort will receive 6 x 1012 vg/kg total dose - split between the 2 lower extremities (3 x 1012 vg/kg per limb) delivered to the whole limb according to the same protocol. The total vector genome dose for each subject will be adjusted by rounding down to the closest 10 kg.

The primary objective of this study is the assessment of the safety of intravascular administration of scAAVrh.74.tMCK.hSGCA delivered via the femoral artery to both lower extremities LGMD2D (alpha-SG deficient) subjects. Safety monitoring during recirculation will include: activated clotting times, limb gases, real time monitoring of arterial and venous access pressures, and perfusate temperature. Safety endpoints will be assessed by changes in hematology, serum chemistry, urinalysis, immunologic response to rAAVrh74 and hSGCA, and reported history and observations of symptoms. The six minute walk test will be used as secondary outcome for these disorders. Other exploratory measure will include direct muscle testing for strength (MVICT) of lower limb muscles. These quantitative measures will be done at baseline, day 30, 60, 90, 180, and at the end of 1st and 2nd years. Subjects will be evaluated at baseline, infusion visit (days 0-2), and return for follow up visits on days 7, 14, 30, 60, 90, and 180. On Day 180, subjects will undergo a muscle biopsy on the injected muscles in one leg to compare with the pre-treatment biopsy done at baseline screening in the opposite leg to establish the size of muscle fibers and any potential toxicity from gene transfer.