Gene Therapy for Phelan-McDermid Syndrome

Recruiting at 3 trial locations

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new gene therapy, JAG201, to determine its safety and effectiveness for individuals with Phelan-McDermid Syndrome, a condition associated with developmental and cognitive delays. The study will initially focus on children aged 2 to 9 with specific genetic mutations affecting the SHANK3 gene. Suitable participants should have significant developmental delays and stable treatment plans and therapies. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, providing participants the opportunity to be among the first to receive this new therapy.

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.

Is there any evidence suggesting that JAG201 is likely to be safe for humans?

In earlier studies, JAG201 was tested in animals and successfully delivered the SHANK3 gene throughout the brain without causing obvious harm. However, since this is the first trial in humans, limited information exists about its safety in people. This trial is in the early stages (Phase 1/2), so researchers are closely monitoring participants' reactions. This phase mainly focuses on identifying any side effects and understanding the treatment's safety. Since the study includes both children and adults, researchers will also examine any safety differences between these groups. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about JAG201 for Phelan-McDermid Syndrome because it represents a novel approach to treatment through gene therapy. Unlike current options that primarily focus on managing symptoms, JAG201 aims to address the root cause of the condition by correcting genetic anomalies. This gene therapy could potentially offer a more lasting solution, providing hope for improved cognitive and developmental outcomes. Additionally, with its two dosage levels being tested, there is potential to fine-tune effectiveness and safety for pediatric patients.

What evidence suggests that JAG201 might be an effective treatment for Phelan-McDermid Syndrome?

Research shows that JAG201 is designed to address the main cause of Phelan-McDermid Syndrome by correcting a malfunction in the SHANK3 gene, where one copy does not function properly. In early animal studies, JAG201, which uses a virus to deliver a working SHANK3 gene, restored the gene's function. This trial will test JAG201 in two separate pediatric cohorts: one receiving a starting dose and another receiving an escalated dose. The gene therapy aims for a long-lasting effect by addressing the genetic issue at its source. Although direct evidence in humans remains limited, the approach is grounded in strong genetic science. Initial findings suggest this could significantly improve symptoms related to this genetic disorder. ^{1 2 4 6 7}

Who Is on the Research Team?

Dan Gallo, PhD

Principal Investigator

Jaguar Gene Therapy

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. jaguargenetherapy.com jaguargenetherapy.com/wp-content/uploads/Community-Letter-and-FAQ_10.29.24.pdf

JAG201 Clinical Study Record Available o A: Our goal with JAG201 is to treat the root cause of PMS. Gene therapy could offer the opportunity to have a lasting impact on the disease including, ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT06662188

JAG201 Gene Therapy Study in Children & Adults ... Clinical data will be evaluated for safety, tolerability, and preliminary clinical activity of JAG201 in pediatric and adult participants with SHANK3 ...

3. jaguargenetherapy.com jaguargenetherapy.com/wp-content/uploads/ASGCT-2024-JAG201-POC-Final.pdf

Preclinical Assessment of JAG201, a Clinical Stage ... JAG201 is as an investigational AAV9-based gene therapy designed to be a one-time treatment for SHANK3 haploinsufficiency including Phelan-McDermid syndrome ( ...

4. checkrare.com checkrare.com/phelan-mcdermid-syndrome-and-the-jag201-study/

Phelan-McDermid Syndrome and the JAG201 Study Phelan-McDermid syndrome is a rare, genetic form of autism spectrum disorder. It is caused by a variant in the SHANK3 gene on chromosome 22.

5. pmsf.org pmsf.org/clinical-trials/

Clinical Trials in Phelan-McDermid Syndrome Phelan-McDermid syndrome is a rare genetic disorder that can affect many critical functions in a person's body. See its causes, symptoms and treatments.

6. scge.mcw.edu scge.mcw.edu/platform/data/clinicalTrials/report/NCT06662188

Gene Therapy Trial Report Clinical data will be evaluated for safety ... JAG201 in a Genetic Form of Autism Spectrum Disorder and Phelan-McDermid Syndrome ...

7. jaguargenetherapy.com jaguargenetherapy.com/wp-content/uploads/Community-Letter-and-FAQ_3.4.25-FINAL.pdf

Members of the Phelan-McDermid Syndrome Community ... Additionally, JAG201 treatment resulted in widespread and persistent delivery of SHANK3 throughout the brains of treated animals, suggesting ...