Gene Therapy for Spinal Muscular Atrophy

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Megan Waldrop

Must not be taking: Immune modulatory therapy

Disqualifiers: HIV, Hepatitis B/C, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

10 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial uses a harmless virus to deliver a healthy gene directly into the spinal fluid of patients with diseases caused by IGHMBP2 gene defects. The virus helps correct the genetic issues by bringing the healthy gene to the affected cells. This approach has been shown to improve conditions in similar diseases in animals.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it mentions that if you require chronic drug treatment that poses unnecessary risks for gene transfer, you may be excluded. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment for spinal muscular atrophy?

Research shows that the gene therapy onasemnogene abeparvovec improves survival and motor skills in infants with spinal muscular atrophy type 1. This therapy delivers a functional gene to help produce a necessary protein, leading to better outcomes when given early. ^{1 2 3 4 5}

Is gene therapy for spinal muscular atrophy safe for humans?

Gene therapy for spinal muscular atrophy, specifically onasemnogene abeparvovec, has been generally considered safe, but there have been reports of temporary liver issues in some patients. It's important to follow medical guidelines and discuss any concerns with healthcare providers. ^{5 6 7 8 9}

How is gene therapy different from other treatments for spinal muscular atrophy?

Gene therapy for spinal muscular atrophy is unique because it involves a one-time delivery of a functional gene to restore the production of a crucial protein, SMN, which is missing due to a genetic mutation. This approach contrasts with other treatments that focus on modifying gene splicing or using drugs to enhance protein levels, and it has shown significant improvements in survival and motor skills, especially when given before symptoms appear. ^{1 3 10 11 12}

Research Team

Megan Waldrop, MD

Principal Investigator

Nationwide Children's Hospital

Eligibility Criteria

This trial is for individuals with genetic confirmation of IGHMBP2-related diseases, such as Spinal Muscular Atrophy or Charcot-Marie-Tooth Disease. Participants can be pre-ambulant, ambulant, or non-ambulant and must be able to perform functional assessments. They cannot have had recent immunizations, infections like HIV/Hepatitis B/C, abnormal blood counts or liver function tests, high AAV9 antibody levels, other systemic illnesses that increase gene transfer risks or require chronic drug treatment.

Inclusion Criteria

I have two confirmed genetic mutations in the IGHMBP2 gene.

I can follow through with tests as my doctor sees fit.

I can walk more than, less than, or exactly 10 meters without help.

Exclusion Criteria

I cannot safely stop my immune therapy for a washout period.

Serological evidence of HIV infection, or Hepatitis B or C infection

My liver isn't working properly, shown by high GGT or bilirubin levels, or abnormal PT/INR.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single intrathecal injection of AAV9 vector carrying the IGHMBP2 gene

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• Gene Therapy

Trial Overview The study involves a one-time intrathecal injection (into the spinal canal) of an AAV9 vector carrying the IGHMBP2 gene. It's an open-label trial meaning everyone knows what treatment is being given. The goal is to see if this gene therapy can help with conditions related to IGHMBP2 mutations.

Participant Groups

Group I: Single Intrathecal Delivery Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Megan Waldrop

Lead Sponsor

Trials

2

Recruited

10+

Alcyone Therapeutics

Collaborator

Trials

1

Recruited

10+

Findings from Research

In a phase 3 trial involving 22 infants with spinal muscular atrophy type 1, 59% achieved independent sitting for 30 seconds or longer by 18 months, compared to 0% in an untreated cohort, demonstrating significant efficacy of the gene therapy onasemnogene abeparvovec.

91% of treated patients survived without the need for permanent ventilation by 14 months, highlighting the therapy's potential to improve survival outcomes compared to only 26% in the untreated group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Day, JW., Finkel, RS., Chiriboga, CA., et al.[2021]

Onasemnogene abeparvovec, the first approved gene-replacement therapy for spinal muscular atrophy, has been shown to have manageable safety risks, with 101 out of 102 patients experiencing at least one treatment-emergent adverse event (AE) during clinical trials.

Key safety concerns include hepatotoxicity, which resolved with treatment, and transient decreases in platelet counts, while thrombotic microangiopathy (TMA) was noted in postmarketing data, indicating the need for monitoring and potential medical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. Day, JW., Mendell, JR., Mercuri, E., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Spinal Muscular Atrophy: A (Now) Treatable Neurodegenerative Disease. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Outcome measures in a cohort of ambulatory adults with spinal muscular atrophy. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Onasemnogene abeparvovec for the treatment of spinal muscular atrophy. [2022]

4. England pubmed.ncbi.nlm.nih.gov

How far away is spinal muscular atrophy gene therapy? [2018]

5. England pubmed.ncbi.nlm.nih.gov

Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. [2021]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy. [2022]

7. England pubmed.ncbi.nlm.nih.gov

New treatments in spinal muscular atrophy: an overview of currently available data. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Subacute Liver Failure Following Gene Replacement Therapy for Spinal Muscular Atrophy Type 1. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Newborn screening and gene therapy in SMA: Challenges related to vaccinations. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Update on gene and stem cell therapy approaches for spinal muscular atrophy. [2018]

11. Romania pubmed.ncbi.nlm.nih.gov

Spinal muscular atrophy disease: a literature review for therapeutic strategies. [2021]

12. United States pubmed.ncbi.nlm.nih.gov

Timing is everything: Clinical evidence supports pre-symptomatic treatment for spinal muscular atrophy. [2022]