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

Primary Purpose

Limb Girdle Muscular Dystrophy Type 2C, Gamma-sarcoglycanopathy

Status
Completed
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
AAV1-gamma-sarcoglycan vector injection
Sponsored by
Genethon
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Limb Girdle Muscular Dystrophy Type 2C focused on measuring limb girdle muscular dystrophy type 2C, gamma-sarcoglycanopathy, gene therapy, AAV vector, neuromuscular disease, orphan disease

Eligibility Criteria

15 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Hôpital Pitié-Salpêtrière

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Dose level 1

Dose level 2

Dose level 3

Arm Description

AAV1-gamma-sarcoglycan vector dose level: 3x10e9 vg/100µl

AAV1-gamma-sarcoglycan vector dose level: 1.5x10e10 vg/100µl

AAV1-gamma-sarcoglycan vector dose level: 4.5x10e10 vg/300µl

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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)
number of patients with changed or increased humoral immunity to AAV
assessment of anti-AAV antibodies titers
Number of patients with changed/increased humoral immunity to transgene
assessment of anti-gamma-sarcoglycan antibodies titers
Number of patients with changed/increased cellular immunity to AAV
assessment cellular immunity against AAV (ELispot assay)
Number of patients with changed/increased cellular immunity to transgene
assessment cellular immunity against gamma-sarcoglycan (ELispot assay)
number of patients with positively stained muscular fibers to gamma-sarcoglycan protein
Muscular biopsy immunohistaining for the detection of gamma-sarcoglycan
Number of patients with modified/decreased muscular force
functional testing of treated muscle through a specially designed ergometer

Full Information

First Posted
March 17, 2011
Last Updated
April 28, 2011
Sponsor
Genethon
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1. Study Identification

Unique Protocol Identification Number
NCT01344798
Brief Title
Clinical Study of AAV1-gamma-sarcoglycan Gene Therapy for Limb Girdle Muscular Dystrophy Type 2C
Official Title
Phase I Clinical Study of AAV1-gamma-sarcoglycan Gene Therapy for Limb Girdle Muscular Dystrophy Type 2C
Study Type
Interventional

2. Study Status

Record Verification Date
April 2011
Overall Recruitment Status
Completed
Study Start Date
November 2006 (undefined)
Primary Completion Date
June 2010 (Actual)
Study Completion Date
June 2010 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Genethon

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Limb Girdle Muscular Dystrophy Type 2C, Gamma-sarcoglycanopathy
Keywords
limb girdle muscular dystrophy type 2C, gamma-sarcoglycanopathy, gene therapy, AAV vector, neuromuscular disease, orphan disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
9 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dose level 1
Arm Type
Experimental
Arm Description
AAV1-gamma-sarcoglycan vector dose level: 3x10e9 vg/100µl
Arm Title
Dose level 2
Arm Type
Experimental
Arm Description
AAV1-gamma-sarcoglycan vector dose level: 1.5x10e10 vg/100µl
Arm Title
Dose level 3
Arm Type
Experimental
Arm Description
AAV1-gamma-sarcoglycan vector dose level: 4.5x10e10 vg/300µl
Intervention Type
Biological
Intervention Name(s)
AAV1-gamma-sarcoglycan vector injection
Other Intervention Name(s)
in vivo gene therapy - Intramuscular route
Intervention Description
single intramuscular injection into carpi radialis muscle under open procedure
Primary Outcome Measure Information:
Title
Number of patients with adverse events or general or local signs as a measure of clinical safety
Description
Standard general and local clinical examination as well as vital signs assessement, including pain, local inflammation, stiffness and fatigability.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Number of patients with modified biological values (blood count, standard biochemistry, viral serology)
Description
Assessment of biological tolerance: blood count standard biochemistry CPK viral serology (hepatitis B & C)
Time Frame
6 months
Title
number of patients with changed or increased humoral immunity to AAV
Description
assessment of anti-AAV antibodies titers
Time Frame
6 months
Title
Number of patients with changed/increased humoral immunity to transgene
Description
assessment of anti-gamma-sarcoglycan antibodies titers
Time Frame
6 months
Title
Number of patients with changed/increased cellular immunity to AAV
Description
assessment cellular immunity against AAV (ELispot assay)
Time Frame
6 months
Title
Number of patients with changed/increased cellular immunity to transgene
Description
assessment cellular immunity against gamma-sarcoglycan (ELispot assay)
Time Frame
6 months
Title
number of patients with positively stained muscular fibers to gamma-sarcoglycan protein
Description
Muscular biopsy immunohistaining for the detection of gamma-sarcoglycan
Time Frame
30 days
Title
Number of patients with modified/decreased muscular force
Description
functional testing of treated muscle through a specially designed ergometer
Time Frame
6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
15 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 Lower age limit of 15 years Males and females may be equally enrolled 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 Subjects should be able and willing to return for follow up 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 Eligible subjects belonging to a multiplex family should not be enrolled in the same cohort. Exclusion Criteria: 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. 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Serge Herson, Prof
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hôpital Pitié-Salpêtrière
City
Paris
ZIP/Postal Code
75013
Country
France

12. IPD Sharing Statement

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

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