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Adeno-Associated Virus Serotype 8 Expressing The Human Gamma-Sarcoglycan Gene

This article discusses a clinical trial investigating the use of ATA-200, a gene therapy drug, for treating limb-girdle muscular dystrophy type R5 (LGMDR5). The trial aims to evaluate the safety and effectiveness of this innovative treatment approach in pediatric patients. ATA-200 uses a modified virus to deliver a healthy copy of the gamma-sarcoglycan gene, potentially addressing the underlying cause of LGMDR5.

Table of Contents

What is ATA-200?

ATA-200 is a new gene therapy medication being developed to treat limb-girdle muscular dystrophy type R5 (LGMDR5), also previously known as LGMD2C[1]. It is classified as a genetically modified recombinant viral vector, which means it uses a modified virus to deliver genetic material into cells[1].

The full name of this therapy is “adeno-associated virus serotype 8 expressing the human gamma-sarcoglycan gene.” Let’s break this down:

  • Adeno-associated virus (AAV): A small virus that can infect humans but doesn’t cause disease. It’s often used in gene therapy because it can deliver genetic material to cells.
  • Serotype 8: A specific variant of the AAV that is particularly good at targeting muscle cells.
  • Human gamma-sarcoglycan gene: The healthy gene that ATA-200 delivers to cells to replace the faulty gene in LGMDR5 patients.

ATA-200 is also known by its sponsor product code “ATA-200” and is being developed by ATAMYO THERAPEUTICS[1].

Target Condition: LGMDR5

Limb-girdle muscular dystrophy type R5 (LGMDR5) is a rare genetic disorder that causes progressive muscle weakness, primarily affecting the shoulders, upper arms, pelvic area, and thighs[1]. It’s caused by mutations in the SGCG gene, which provides instructions for making a protein called gamma-sarcoglycan. This protein is important for maintaining the structure and function of muscle cells.

How ATA-200 Works

ATA-200 works by delivering a healthy copy of the human Sarcoglycan Gamma (SGCG) gene to muscle cells[1]. Here’s how it does this:

  1. The therapy is given through an intravenous infusion (a drip into a vein)[1].
  2. The AAV8 virus, carrying the healthy SGCG gene, travels through the bloodstream and enters muscle cells.
  3. Once inside the cells, the healthy gene is released.
  4. The cells can then use this healthy gene to produce the gamma-sarcoglycan protein that they were previously lacking.

This approach is known as in vivo gene therapy, meaning the genetic modification happens inside the patient’s body[1].

Clinical Trial Overview

ATA-200 is currently being studied in a Phase I/II clinical trial[1]. This trial is designed to test the safety of the therapy and gather initial data on how well it works. The study is divided into two parts:

  1. Part 1: Dose Escalation Phase (28 weeks)
    • Cohort C1: 3 patients receive a dose of 1.0E+14 vg/Kg
    • Cohort C2: 3 patients receive a higher dose of 3.0E+14 vg/Kg
  2. Part 2: Long-Term Follow-up (4.5 years)
    • All patients who received the treatment will be monitored for an additional 4.5 years

Eligibility Criteria

To participate in this study, patients must meet certain criteria. Some key inclusion criteria are[1]:

  • Ambulant (able to walk) male or female patients aged 6 to 11 years
  • Confirmed LGMDR5 diagnosis before age 10
  • Able to perform certain physical tests, like walking 10 meters in 15 seconds or less
  • Seronegative for neutralizing antibodies against AAV8 (meaning their immune system hasn’t previously encountered this virus type)

There are also several exclusion criteria, such as previous participation in gene therapy trials, certain medical conditions, or inability to undergo MRI scans[1].

Study Objectives and Endpoints

The main goal of this study is to assess the safety and tolerability of ATA-200 in children with LGMDR5[1]. Researchers will be looking at:

  • Incidence of adverse events (side effects)
  • Changes in vital signs
  • Physical examination findings
  • Muscle pain (myalgia)
  • Heart function
  • Laboratory test results

The study will also collect preliminary data on how well the treatment works. This includes measures of[1]:

  • Muscle function (e.g., ability to walk, climb stairs)
  • Muscle strength
  • Muscle composition (using MRI scans)
  • Lung function
  • Quality of life

Potential Benefits and Risks

While ATA-200 shows promise, it’s important to remember that this is an experimental therapy still in early stages of testing. Potential benefits could include improved muscle function and strength, but these are not guaranteed.

As with any medical treatment, there are potential risks. These may include immune reactions to the virus used to deliver the gene, or unexpected effects of the new gene in the body. The study includes careful monitoring to watch for any side effects[1].

Aspect Details
Trial Name ATA-200 gene therapy trial in patients with LGMDR5
Trial Phase Phase I/II
Main Objective Assess safety and tolerability of intravenous ATA-200 in pediatric ambulant LGMDR5 patients
Secondary Objective Collect preliminary efficacy data
Participant Age Range 6 to 12 years old
Treatment ATA-200 (rAAV8-hSGCG) administered intravenously
Dosage Levels Two cohorts: 1.0E+14 vg/Kg and 3.0E+14 vg/Kg
Trial Duration 28 weeks (Part 1) + 4.5 years follow-up (Part 2)
Key Assessments Safety monitoring, muscle function tests, imaging, respiratory assessments, muscle biopsies, quality of life measures

FAQ

  • What is ATA-200 and how does it work? ATA-200 is a gene therapy drug that uses a modified adeno-associated virus (AAV8) to deliver a healthy copy of the gamma-sarcoglycan gene to muscle cells. This approach aims to address the underlying genetic cause of limb-girdle muscular dystrophy type R5 by providing a functional version of the gene that is mutated in patients with this condition.
  • Who is eligible to participate in this clinical trial? The trial is open to ambulant male or female patients between 6 and 12 years of age with a confirmed LGMDR5 diagnosis. Participants must be able to perform specific physical tasks, such as the 10-meter walk test, and meet other criteria, including being seronegative for neutralizing antibodies against AAV8.
  • What are the main objectives of this clinical trial? The primary objective of this trial is to assess the safety and tolerability of intravenous administration of ATA-200 in pediatric ambulant patients with LGMDR5 at two different dosage levels. Additionally, the trial aims to select the recommended dose for future studies and collect preliminary efficacy data.
  • How long does the clinical trial last? The trial consists of two parts. Part 1 is the dose escalation phase, which lasts 28 weeks. Part 2 is a long-term follow-up period that continues for an additional 4.5 years after the completion of Part 1. In total, participants will be monitored for about 5 years.
  • What types of assessments will be performed during the trial? The trial includes various assessments to evaluate safety and efficacy. These include monitoring for adverse events, physical examinations, muscle function tests, timed function tests, muscle strength tests, imaging assessments (MRI), respiratory function tests, muscle biopsies, and quality of life questionnaires. Blood and urine samples will also be collected for biomarker analysis.

Ongoing Clinical Trials on Adeno-Associated Virus Serotype 8 Expressing The Human Gamma-Sarcoglycan Gene

  • Study on the Safety of ATA-200 Gene Therapy for Patients with Limb-Girdle Muscular Dystrophy Type R5

    Not yet recruiting

    2 1 1 1
    Investigated diseases:
    Investigated drugs:
    France Italy

Glossary

  • Limb-girdle muscular dystrophy type R5 (LGMDR5): A genetic disorder that causes progressive muscle weakness and wasting, primarily affecting the muscles around the shoulders and hips. It is caused by mutations in the SGCG gene, which provides instructions for making the gamma-sarcoglycan protein.
  • Gene therapy: A treatment approach that involves introducing genetic material into a person's cells to compensate for abnormal genes or to make a beneficial protein. In this trial, gene therapy is used to deliver a healthy copy of the gamma-sarcoglycan gene.
  • Adeno-associated virus (AAV): A small virus that infects humans but is not known to cause disease. Modified versions of AAV are often used in gene therapy to deliver genetic material to cells.
  • Gamma-sarcoglycan: A protein that is part of a complex of proteins in muscle cells. It helps stabilize and protect muscle fibers. Mutations in the gene that produces this protein can lead to LGMDR5.
  • Vector: In gene therapy, a vector is a vehicle used to deliver genetic material into cells. In this trial, a modified AAV8 serves as the vector to carry the gamma-sarcoglycan gene.
  • Intravenous administration: A method of delivering medication directly into a vein, allowing it to circulate throughout the body quickly.
  • Ambulant: Able to walk and move around independently, without the need for a wheelchair or other mobility aids.
  • Efficacy: The ability of a treatment to produce the desired beneficial effect under ideal circumstances.
  • Biomarker: A measurable indicator of a biological state or condition. In this trial, biomarkers are used to assess the effects of the treatment on the body.
  • Muscle biopsy: A medical procedure in which a small sample of muscle tissue is removed and examined to diagnose or monitor muscle conditions.

References

  1. http://clinicaltrials.eu/trial/study-on-the-safety-of-ata-200-gene-therapy-for-patients-with-limb-girdle-muscular-dystrophy-type-r5/