Clinical Study of AAV1-gamma-sarcoglycan Gene Therapy for Limb Girdle Muscular Dystrophy Type 2C

Phase I Clinical Study of AAV1-gamma-sarcoglycan Gene Therapy for Limb Girdle Muscular Dystrophy Type 2C

The purpose of this trial is to study the evaluation of clinical safety and feasibility of gene therapy in patients with limb girdle muscular dystrophy type 2C (gamma-sarcoglycanopathy).

Study Overview

• Status: Completed
• Conditions: Limb Girdle Muscular Dystrophy Type 2C; Gamma-sarcoglycanopathy
• Intervention / Treatment: Biological: AAV1-gamma-sarcoglycan vector injection

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Paris, France, 75013
    • Hôpital Pitié-Salpêtrière

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Confirmed diagnosis of LGMD 2C including:

   • Molecular analysis proving del525T mutation on γ-sarcoglycan gene (chromosome 13) at homozygous state
   • Muscle biopsy with immunohistochemical and/or Western blot analyses showing marked decrease or absence of γ-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-enrollment period
2. Lower age limit of 15 years
3. Males and females may be equally enrolled

4. Adequate carpi radialis muscle bulk for muscle biopsy as assessed by examination. Subjects should be able to communicate with the investigation staff. They should be able to understand, to comply with and to perform all needed evaluations during the trial period, including muscle strength tests. Forearm muscle strength should be of at least 3+ as assessed through the British Medical Research Council (MRC) Manual Muscle Testing (MMT) scale.

   Subjects should also have already lost ambulation

5. Subjects should be able and willing to return for follow up
6. Subjects should be able and willing to give signed informed consent. For minor subjects, a signed informed consent will be given by legally authorized representative
7. 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:

   • Severe respiratory dysfunction such as subjects with tracheostomy or forced vital capacity (FVC) < 1000 ml and/or < 30%;
   • Uncompensated heart failure;
   • An ejection fraction (EF) < 30% as measured on either echocardiography or scintigraphy;
   • 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:

   • contraindications for injections and muscle biopsies
   • Platelet count < 100,000 / mm3
   • Total bilirubin > 10 mg/l (> 17 µmol/l)
   • Serum creatinin > 110 µmol/l
   • Lymphocytes CD4+ < 250/mm3 (< 15%)
   • History of diabetes mellitus
   • Current infectious diseases, including known positive HIV serology, hepatitis B and C
   • Abnormal profile on protein immunoelectrophoresis
   • Immunizations of any kind within the past month
   • receipt of another investigational agent within 4 weeks of study enrollment
   • History of or current steroid medication for indications other than muscular dystrophy, chemotherapy, radiotherapy or other immunosuppressive therapy. Steroid medication, if any, should be discontinued at least 3 months before entering the protocol and not received during the study
   • Pregnant or lactating women. 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
   • Pre-injection neutralizing anti-AAV1 antibodies titer (on pre-enrollment / D-30 visit) superior or equal to 1/800.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose level 1; AAV1-gamma-sarcoglycan vector dose level: 3x10e9 vg/100µl	Biological: AAV1-gamma-sarcoglycan vector injection; single intramuscular injection into carpi radialis muscle under open procedure; Other Names: in vivo gene therapy - Intramuscular route
Experimental: Dose level 2; AAV1-gamma-sarcoglycan vector dose level: 1.5x10e10 vg/100µl	Biological: AAV1-gamma-sarcoglycan vector injection; single intramuscular injection into carpi radialis muscle under open procedure; Other Names: in vivo gene therapy - Intramuscular route
Experimental: Dose level 3; AAV1-gamma-sarcoglycan vector dose level: 4.5x10e10 vg/300µl	Biological: AAV1-gamma-sarcoglycan vector injection; single intramuscular injection into carpi radialis muscle under open procedure; Other Names: in vivo gene therapy - Intramuscular route

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with adverse events or general or local signs as a measure of clinical safety	Standard general and local clinical examination as well as vital signs assessement, including pain, local inflammation, stiffness and fatigability.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with modified biological values (blood count, standard biochemistry, viral serology)	Assessment of biological tolerance: blood count; standard biochemistry; CPK viral serology (hepatitis B & C)	6 months
number of patients with changed or increased humoral immunity to AAV	assessment of anti-AAV antibodies titers	6 months
Number of patients with changed/increased humoral immunity to transgene	assessment of anti-gamma-sarcoglycan antibodies titers	6 months
Number of patients with changed/increased cellular immunity to AAV	assessment cellular immunity against AAV (ELispot assay)	6 months
Number of patients with changed/increased cellular immunity to transgene	assessment cellular immunity against gamma-sarcoglycan (ELispot assay)	6 months
number of patients with positively stained muscular fibers to gamma-sarcoglycan protein	Muscular biopsy immunohistaining for the detection of gamma-sarcoglycan	30 days
Number of patients with modified/decreased muscular force	functional testing of treated muscle through a specially designed ergometer	6 months

Collaborators and Investigators

• Sponsor: Genethon
• Investigators: Principal Investigator: Serge Herson, Prof, Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start: November 1, 2006
• Primary Completion (Actual): June 1, 2010
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: March 17, 2011
• First Submitted That Met QC Criteria: April 28, 2011
• First Posted (Estimate): April 29, 2011

Study Record Updates

• Last Update Posted (Estimate): April 29, 2011
• Last Update Submitted That Met QC Criteria: April 28, 2011
• Last Verified: April 1, 2011

More Information

Terms related to this study

• Keywords: gene therapy; neuromuscular disease; limb girdle muscular dystrophy type 2C; gamma-sarcoglycanopathy; AAV vector; orphan disease
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Nervous System Diseases; Respiratory Tract Diseases; Respiration Disorders; Genetic Diseases, Inborn; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Muscular Disorders, Atrophic; Cardiomyopathies; Muscular Dystrophies; Muscular Dystrophies, Limb-Girdle; Sarcoglycanopathies
• Other Study ID Numbers: GTG001.06