Studying the feasibility and safety of gene therapy to treat limb girdle muscular dystrophy (LGMD) type 2C

Completed

• Conditions: imb girdle muscular dystrophy (LGMD), type 2C (gamma-sarcoglycanopathy); Musculoskeletal Diseases; Limb girdle muscular dystrophy (LGMD), type 2C (gamma-sarcoglycanopathy)

• Registration Number: ISRCTN22225367
• Lead Sponsor: Genethon (France)

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2011-04-08
• Last Update Posted: 13 January 2015

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 9

Inclusion Criteria

1. Confirmed diagnosis of LGMD 2C including:
1.1. Molecular analysis proving del525T mutation on ?-sarcoglycan gene (chromosome 13) at homozygous state
1.2. Muscle biopsy with immunohistochemical and/or Western blot analysis showing marked decrease or absence of ?-sarcoglycan staining in muscle, as well as a fibrosis assessment should be available. If not, an initial muscular biopsy may be performed during the pre-enrolment period
2. Minimum age of 15 years
3. Males and females may be equally enrolled
4. Adequate carpi radialis muscle bulk for muscle biopsy as assessed by examination
5. Subjects should be able to communicate with the investigation staff
6. Subjects should be able to understand, to comply with and to perform all needed evaluations during the trial period including muscle strength tests
7. Forearm muscle strength should be of at least 3+ as assessed through the British Medical Research Council (MRC) Manual Muscle Testing (MMT) scale
8. Subjects should also have already lost ambulation
9. Subjects should be able and willing to return for follow up
10. Subjects should be able and willing to give signed informed consent
11. For minor subjects, a signed informed consent will be given by a legally authorised representative
12. Eligible subjects belonging to a multiplex family should not be enrolled in the same cohort

Exclusion Criteria

1. Severity of disease and presence of ill-prognosis complications:
1.1. Severe respiratory dysfunction such as subjects with tracheostomy or forced vital capacity (FVC) < 1000ml and/or < 30%
1.2. Uncompensated heart failure
1.3. An ejection fraction (EF) < 30% as measured on either echocardiography or scintigraphy
1.4. Severe rhythm disturbances and/or high degree conduction defect in the absence of a pacemaker insertion
2. Underlying conditions, diseases or active viral infections likely to increase risk of complications or to interfere with the investigational treatment:
2.1. Contraindications for injections and muscle biopsies
2.2. Platelet count < 100,000/mm3
2.3. Total bilirubin > 10 mg/l (> 17 µmol/l)
2.4. Serum creatinine > 110 µmol/l
2.5. Lymphocytes CD4+ < 250/mm3 (< 15%)
2.6. History of diabetes mellitus
2.7. Current infectious diseases, including known positive human immunodeficiency virus (HIV) serology, hepatitis B and C
2.8. Abnormal profile on protein immunoelectrophoresis
2.9. Immunisations of any kind within the past month
2.10. Receipt of another investigational agent within 4 weeks of study enrolment
2.11. History of or current steroid medication for indications other than muscular dystrophy, chemotherapy, radiotherapy or other immunosuppressive therapy
2.12. Steroid medication, if any, should be discontinued at least 3 months before entering the protocol and not received during the study
2.13. Pregnant or lactating women
2.14. Females or males of childbearing age must be willing to employ adequate contraception, that is to use condoms during the 3 months following the administration of the product
2.15. Pre-injection neutralising anti-AAV1 antibodies titer (on pre-enrolment / D-30 visit) superior or equal to 1/800

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Assessment of clinical tolerance by standard clinical examination

Secondary Outcome Measures

Name	Time	Method
1. Assessment of biological, immunological, histological and functional tolerance by laboratory monitoring, evaluation of humoral and cellular immune response to both transgene and vector as well as non-specific immune response, evaluation of histological changes on muscle biopsy and evaluation of changes in muscle function<br>2. Assessment of efficacy through studies of transduction efficiency, distribution, expression and fiber type specificity and muscle biopsy histological changes (based on immunohistochemistry and Western blot studies and analysis of sarcoglycan labelling)