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

Study Description

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Brief Summary:

Dose escalation study of self-complementary (sc) AAVrh74.tMCK.hSGCA delivered to single leg (low dose n=2) and bilaterally (n=6) via a major lower limb artery to the whole lower limb of limb girdle muscular dystrophy type 2D (LGMD2D; alpha-sarcoglycan deficient) patients.

Condition or disease	Intervention/treatment	Phase
Limb Girdle Muscular Dystrophy Type 2D (LGMD2D)	Drug: scAAVrh74.tMCK.hSGCA	Phase 1; Phase 2

Detailed Description:

The proposed clinical trial is a dose escalation study of self-complementary scAAVrh74.tMCK.hSGCA to LGMD2D (alpha-sarcoglycan deficient) subjects delivered via a major lower limb artery of each leg sequentially by isolated limb perfusion (ILP). Three cohorts (Cohorts 1A, 1B, and 2) will undergo gene transfer in a dose escalation scheme to establish maximum tolerated dose (MTD) using toxicity. Two (n=2) adult wheelchair-dependent patients will be enrolled in Cohort 1A and three (n =3) ambulatory subjects will be enrolled in Cohort 1B. Three (n =3) ambulatory subjects will be enrolled in Cohort 2. The first cohort (1A) will receive a dose of 1E12 vg/kg in a single limb with delivery to the whole limb. This same dose will be delivered to both limbs in Cohort 1B. Cohort 2 will receive a total dose escalation of 3E12vg/kg per limb delivered to both extremities. The vector will be infused into an indwelling catheter in the femoral artery. This will be a one-time vector infusion to an isolated limb with a 10-minute dwell time. The total vector genome dose for each subject will be adjusted by rounding down to the closest 10 kg.

Safety monitoring during infusion 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. Efficacy will be measured by the six minute walk test as well as 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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	6 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase I/IIa Gene Transfer Clinical Trial for LGMD2D (Alpha-sarcoglycan Deficiency) Using scAAVrh74.tMCK.hSGCA
Study Start Date :	February 2015
Estimated Primary Completion Date :	February 2019
Estimated Study Completion Date :	February 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Cohort 1A; Two (n=2) adult LGMD2D wheelchair-dependent subjects will receive self-complementary scAAVrh74.tMCK.hSGCA via single-limb perfusion at the low dose. Subjects will receive a dose of 1 x 10 12th vg/kg in a single limb with delivery to the whole limb.	Drug: scAAVrh74.tMCK.hSGCA
Experimental: Cohort 1B; Three (n=3) LGMD2D subjects will receive self-complementary scAAVrh74.tMCK.hSGCA via bilateral whole limb perfusion at low dose of 1 x 10 12th vg/kg.	Drug: scAAVrh74.tMCK.hSGCA
Experimental: Cohort 2; Three (n=3) LGMD2D subjects will receive self-complementary scAAVrh74.tMCK.hSGCA bilateral whole limb perfusion at high dose.Subjects will receive a total dose of 3 x 10 12th vg/kg per limb delivered to both extremities	Drug: scAAVrh74.tMCK.hSGCA

Outcome Measures

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Primary Outcome Measures :

1. Safety with fewer than one grade 3 adverse events or fewer than two grade 2 adverse events [ Time Frame: 2 years ]
   Safety will be measured based on fewer than one grade 3 adverse event or fewer than two grade 2 adverse events

Secondary Outcome Measures :

1. Change in Six-Minute-Walk-Test (6MWT) distance from baseline over two years [ Time Frame: 2 years ]
   Efficacy would be a significant improvement in distance walked in the 6 minute walk test.

Eligibility Criteria

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Ages Eligible for Study:	7 Years and older (Child, Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria

• Subjects age 7 or older; cohort 1A must be adult and wheelchair-dependent
• Proven alpha-sarcoglycan deficiency by muscle biopsy or DNA testing.
• Onset of weakness by 5 years age based on history of difficulty running, jumping and climbing stairs.
• Subject enrolled in Cohort 1A must be adult and wheelchair dependent
• Subjects enrolled in Cohorts 1B or 2 must be able to walk independently, but must exhibit signs of lower extremity weakness (i.e. a Gowers' sign, use a handrail for climbing stairs) and walk ≤ 80% of predicted distance on the 6MWT based on normative data.
• Males and females of any ethnic group will be eligible
• Ability to cooperate with muscle testing.
• Willingness of sexually active subjects with reproductive capacity to practice reliable method of contraception (If appropriate), during the first six months after gene therapy (females) or until two negative sperm samples are obtained post gene transfer (males).

Exclusion Criteria

• Active viral infection based on clinical observations.
• The presence of SGCA mutations without weakness or loss of function

• Symptoms or signs of cardiomyopathy, including:

  • Dyspnea on exertion, pedal edema, shortness of breath upon lying flat, or rales at the base of the lungs
  • Echocardiogram with ejection fraction below 40%
• Serological evidence of HIV infection, or Hepatitis A, B or C infection
• Diagnosis of (or ongoing treatment for) an autoimmune disease
• Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin ≥ 3.0 mg/dL , creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 15,000 per cmm)
• Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer
• Pregnancy
• Subjects with AAVrh74 or AAV8 binding antibody titers ≥ 1:50 as determined by ELISA immunoassay

Contacts and Locations

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Locations

United States, Ohio
Nationwide Children's Hospital
Columbus, Ohio, United States, 43205

Sponsors and Collaborators

Jerry R. Mendell

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital 

Gene Therapy Clinical Trials at Nationwide Children's Hospital 

Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center at Nationwide Children's Hospital 

Publications:

Mendell JR, Rodino-Klapac LR, Rosales XQ, Coley BD, Galloway G, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Taylor LE, Flanigan KM, Gastier-Foster JM, Astbury C, Kota J, Sahenk Z, Walker CM, Clark KR. Sustained alpha-sarcoglycan gene expression after gene transfer in limb-girdle muscular dystrophy, type 2D. Ann Neurol. 2010 Nov;68(5):629-38. doi: 10.1002/ana.22251.

Mendell JR, Rodino-Klapac LR, Rosales-Quintero X, Kota J, Coley BD, Galloway G, Craenen JM, Lewis S, Malik V, Shilling C, Byrne BJ, Conlon T, Campbell KJ, Bremer WG, Viollet L, Walker CM, Sahenk Z, Clark KR. Limb-girdle muscular dystrophy type 2D gene therapy restores alpha-sarcoglycan and associated proteins. Ann Neurol. 2009 Sep;66(3):290-7. doi: 10.1002/ana.21732.

Responsible Party:	Jerry R. Mendell, Director, Center for Gene Therapy, Nationwide Children's Hospital
ClinicalTrials.gov Identifier:	NCT01976091 History of Changes
Other Study ID Numbers:	5U01AR060911 ( U.S. NIH Grant/Contract )
First Posted:	November 5, 2013
Last Update Posted:	November 24, 2017
Last Verified:	November 2017

Keywords provided by Jerry R. Mendell, Nationwide Children's Hospital:

limb girdle muscular dystrophy; LGMD2D; alpha-sarcoglycan; gene transfer; adeno-associated virus

Additional relevant MeSH terms:

Muscular Dystrophies, Limb-Girdle; Muscular Dystrophies; Sarcoglycanopathies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases	Nervous System Diseases; Genetic Diseases, Inborn; Respiration Disorders; Respiratory Tract Diseases; Cardiomyopathies; Heart Diseases; Cardiovascular Diseases