Gene Therapy for Phelan-McDermid Syndrome

Recruiting at 1 trial location

Overseen By Jaguar Gene Therapy

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Jaguar Gene Therapy, LLC

Must not be taking: Immunosuppressants, Gene therapy

Disqualifiers: Developmental regression, Prion disease, Epilepsy, others

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

Compensation: Varies

Number of Visits: Unknown

6 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase 1/2, first in human, open-label, dose-escalation study to evaluate the safety, tolerability, and clinical activity of a single dose of JAG201 administered via intracerebroventricular (ICV) injection in pediatric and adult participants with SHANK3 haploinsufficiency resulting from SHANK3 loss of function mutations and chromosomal deletions encompassing the SHANK3 gene. Clinical data will be evaluated for safety, tolerability, and preliminary clinical activity of JAG201 in pediatric and adult participants with SHANK3 haploinsufficiency. The pediatric cohorts will start enrolling first and the enrollment for adult cohorts may be initiated at a later timepoint in the study.

Will I have to stop taking my current medications?

The trial requires that participants be stable on their current medications for at least 3 months before starting the study treatment, so you will not need to stop taking them if they have been stable.

What safety data exists for gene therapy treatments similar to JAG201?

Gene therapy using adeno-associated virus (AAV) vectors, similar to JAG201, has been tested in various conditions and generally shows promise in terms of safety. For example, in a mouse model of CLN8-Batten Disease, AAV9 gene therapy was safe and well tolerated, with treated mice showing improved lifespan and reduced disease symptoms. Additionally, in a study on Pompe Disease, AAV9 gene therapy was used to promote immune tolerance, which is important for reducing potential immune reactions that could pose safety risks. ^{1 2 3 4 5}

Research Team

Dan Gallo, PhD

Principal Investigator

Jaguar Gene Therapy

Eligibility Criteria

This trial is for children and adults with SHANK3 haploinsufficiency, which can occur due to mutations or deletions of the SHANK3 gene. Participants must have a diagnosis of Phelan-McDermid Syndrome. Specific eligibility criteria are not provided, but typically include health status assessments and consent requirements.

Inclusion Criteria

Has an overall Phelan-McDermid Syndrome (PMS)-specific Clinical Global Impression-Severity (CGI-S) Score of 3 or greater at Screening

Has evidence of developmental/cognitive delay of at least 2 standard deviations (SD) below the mean (i.e., < 70) via either Intelligence Quotient (IQ) OR Developmental Quotient (DQ) assessment (as applicable)

I am between 2 and 9 years old.

Exclusion Criteria

Has known allergy or hypersensitivity to prednisolone or other glucocorticosteroids, or their excipients

Has medical illness or other concern that would cause the Investigator to conclude that the participant will not be able to perform the study procedures or assessments or would confound interpretation of data obtained during assessments

I have lost a skill I had for 3 months or more.

Timeline

Pre-Screening

Participants are evaluated for initial treatment eligibility

Up to 90 days

Screening

Participants are screened for eligibility to participate in the trial

Up to 90 days

Gene Therapy Administration and Perioperative Management

Participants receive a one-time ICV injection of JAG201 and are monitored closely in a hospital setting

1 day

Initial Follow-Up

Participants return at regularly scheduled intervals for safety and clinical activity assessments

Up to 2 years

Long-Term Follow-Up

Participants continue to be monitored for safety and tolerability

Up to 5 years

Treatment Details

Interventions

• JAG201

Trial Overview The study tests JAG201, a gene therapy given as a single dose through an injection into the brain's ventricles (ICV). It's in early stages (Phase 1/2) to see if it’s safe and tolerable, and also to check for any signs that it might be effective in treating symptoms related to SHANK3 haploinsufficiency.

Participant Groups

Group I: Pediatric Cohort 2 Experimental Treatment 1 Intervention

Escalated Dose

Group II: Pediatric Cohort 1 Experimental Treatment 1 Intervention

Starting Dose

Who Is Running the Clinical Trial?

Jaguar Gene Therapy, LLC

Lead Sponsor

Trials

1

Recruited

6+

Findings from Research

AAV-SPL 2.0 gene therapy significantly improved survival and health outcomes in newborn mice with sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS), extending their lifespan to over 5 months and maintaining normal neurodevelopment and weight gain.

The modified AAV-SPL 2.0 showed 30% higher enzyme expression and activity compared to the original AAV-SPL, indicating its potential as a more effective treatment, although further improvements in kidney targeting are needed for optimal results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV-SPL 2.0, a Modified Adeno-Associated Virus Gene Therapy Agent for the Treatment of Sphingosine Phosphate Lyase Insufficiency Syndrome. Khan, R., Oskouian, B., Lee, JY., et al.[2023]

The homology-mediated end joining (HMEJ)-based CRISPR/Cas9 system allows for efficient targeted integration of transgenes in vivo, particularly in mouse zygotes and liver cells, overcoming challenges associated with traditional methods.

This approach successfully corrected a specific genetic mutation related to liver failure in mice, demonstrating its potential for developing gene therapies and genetically modified animal models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CRISPR/Cas9-mediated Targeted Integration In Vivo Using a Homology-mediated End Joining-based Strategy. Yao, X., Wang, X., Liu, J., et al.[2021]

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is caused by mutations in the SGPL1 gene, leading to a deficiency in sphingosine-1-phosphate lyase, which results in various health issues including lymphopenia, nephrotic syndrome, and neurological defects.

Gene therapy using adeno-associated virus (AAV) to deliver the SGPL1 gene showed significant improvements in survival and kidney and neurological function in a mouse model of SPLIS, suggesting it could be a promising curative treatment for affected patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genotype/Phenotype Interactions and First Steps Toward Targeted Therapy for Sphingosine Phosphate Lyase Insufficiency Syndrome. Saba, JD., Keller, N., Wang, JY., et al.[2022]

AAV-mediated gene therapy using a human codon-optimized GAA gene can promote immune tolerance in a mouse model of Pompe disease, potentially improving treatment outcomes by reducing immune responses that limit efficacy.

The combination of AAV9 constructs targeting both liver and muscle tissues not only enhances enzyme expression but also expands regulatory T-cells, which can prevent allergic reactions to enzyme replacement therapy, suggesting a promising dual approach for treating Pompe disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease. Doerfler, PA., Todd, AG., Clément, N., et al.[2018]

In a mouse model of CLN8 disease, a single neonatal injection of a gene therapy vector (scAAV9) was found to be safe and well tolerated, leading to long-lasting expression of the human CLN8 gene and significant improvements in disease symptoms over a period of 24 months.

This gene therapy not only reduced the disease's behavioral and histopathological effects but also extended the lifespan of treated mice from 10 months to over 24 months, marking a major advancement in potential treatments for CLN8 disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV9 Gene Therapy Increases Lifespan and Treats Pathological and Behavioral Abnormalities in a Mouse Model of CLN8-Batten Disease. Johnson, TB., White, KA., Brudvig, JJ., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

AAV-SPL 2.0, a Modified Adeno-Associated Virus Gene Therapy Agent for the Treatment of Sphingosine Phosphate Lyase Insufficiency Syndrome. [2023]

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

CRISPR/Cas9-mediated Targeted Integration In Vivo Using a Homology-mediated End Joining-based Strategy. [2021]

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

Genotype/Phenotype Interactions and First Steps Toward Targeted Therapy for Sphingosine Phosphate Lyase Insufficiency Syndrome. [2022]

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

Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease. [2018]

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

AAV9 Gene Therapy Increases Lifespan and Treats Pathological and Behavioral Abnormalities in a Mouse Model of CLN8-Batten Disease. [2022]