Gene Therapy for Sanfilippo Syndrome

Recruiting at 1 trial location

Overseen By HCPs Contact: Medical Information

Age: Any Age

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Ultragenyx Pharmaceutical Inc

Must not be taking: Prednisolone, Strong CYP3A4 inhibitors

Disqualifiers: HIV, Hepatitis, Cardiomyopathy, Seizure, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 1 day

36 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it does mention avoiding certain substances like grapefruit juice and specific drugs that interact with sirolimus. It's best to discuss your current medications with the trial team to ensure safety and compliance.

What data supports the effectiveness of the treatment ABO-102, scAAV9.U1a.hSGSH for Sanfilippo Syndrome?

The research does not provide direct evidence for the effectiveness of ABO-102, scAAV9.U1a.hSGSH, but it mentions ongoing clinical trials for gene therapy in Sanfilippo Syndrome, suggesting that similar approaches are being explored for their potential benefits. ^{1 2 3 4 5}

Is gene therapy for Sanfilippo Syndrome safe?

Gene therapy for Sanfilippo Syndrome has shown a good safety profile in clinical trials, with most adverse events being mild and not leading to study discontinuation. In one study, severe adverse events were reported, but no serious drug reactions occurred, indicating the treatment is generally well tolerated. ^{1 2 3 6 7}

How is the gene therapy treatment ABO-102 for Sanfilippo Syndrome different from other treatments?

ABO-102 is a gene therapy that uses a viral vector to deliver a healthy copy of the SGSH gene directly to cells, aiming to correct the underlying genetic defect in Sanfilippo Syndrome. This approach is unique because it targets the root cause of the disease at the genetic level, unlike other treatments that may only address symptoms or provide enzyme replacement. ^{1 3 8 9 10}

What is the purpose of this trial?

The main objective of this study is to evaluate the efficacy and safety of UX111 for the treatment of MPS IIIA.

Research Team

Medical Director

Principal Investigator

Ultragenyx Pharmaceutical Inc

Eligibility Criteria

This trial is for children diagnosed with MPS IIIA, a genetic disorder. Eligible participants are from birth to 2 years old or older than 2 with a cognitive score of at least 60. They must have confirmed mutations in the SGSH gene and reduced enzyme activity. Children can't join if they have uncontrolled seizures, heart issues, previous gene therapy, or conditions that interfere with testing.

Inclusion Criteria

I am under 2 years old or older with a cognitive score above 60.

I have been diagnosed with MPS IIIA through specific genetic and enzyme tests.

Exclusion Criteria

I am not pregnant nor have I tested positive for pregnancy.

You have a high level of antibodies against AAV9 in your blood.

I have a condition that makes spinal taps unsafe for me.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single intravenous dose of UX111 (scAAV9.U1a.hSGSH) with optional prophylactic immunomodulatory therapy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness, including CSF Heparan Sulfate and Ganglioside exposure, up to 24 months

24 months

Regular visits (in-person)

Treatment Details

Interventions

• ABO-102
• scAAV9.U1a.hSGSH

Trial Overview The study tests ABO-102's effectiveness and safety in treating MPS IIIA alongside adjuvant immunosuppression therapy. It aims to see how well this gene transfer approach works by delivering a functional copy of the SGSH gene into patients.

Participant Groups

Group I: Cohort 4 High Dose (Spain Only) Experimental Treatment 3 Interventions

Dose of 3 X 10\^13 vg/kg

Group II: Cohort 3 High Dose Experimental Treatment 3 Interventions

Dose of 3 X 10\^13 vg/kg

Group III: Cohort 2 Mid Dose Experimental Treatment 3 Interventions

Dose of 1 X 10\^13 vg/kg

Group IV: Cohort 1 Low Dose Experimental Treatment 3 Interventions

Dose of 0.5 X 10\^13 vg/kg

Who Is Running the Clinical Trial?

Ultragenyx Pharmaceutical Inc

Lead Sponsor

Trials

94

Recruited

104,000+

Dr. Emil D. Kakkis

Ultragenyx Pharmaceutical Inc

Chief Executive Officer since 2010

MD/PhD in Biological Chemistry from UCLA

Dr. Eric Crombez

Ultragenyx Pharmaceutical Inc

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Abeona Therapeutics, Inc

Industry Sponsor

Trials

12

Recruited

1,100+

Findings from Research

A phase 1/2 study involving four young children with Mucopolysaccharidosis type IIIB showed that intracerebral gene therapy using rAAV2/5 was well tolerated, with no unexpected serious adverse reactions, and resulted in improved neurocognitive progression compared to the natural history of the disease.

The therapy led to sustained production of the NAGLU enzyme in the brain, and the youngest patient showed cognitive function close to that of healthy children, suggesting that early intervention may be crucial for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial. Tardieu, M., Zérah, M., Gougeon, ML., et al.[2022]

In a study involving 21 patients with Sanfilippo syndrome type A, treatment with intrathecal recombinant human heparan-N-sulfatase (rhHNS) was generally well tolerated, with mostly mild adverse events and no treatment-related deaths over a period of up to 96 weeks.

While most patients experienced cognitive decline, a small number showed improvements in specific developmental areas, suggesting that earlier intervention may enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A multicenter open-label extension study of intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A. Wijburg, FA., Whitley, CB., Muenzer, J., et al.[2022]

In a phase IIb trial involving 21 patients with Sanfilippo syndrome type A, intrathecal administration of recombinant human heparan-N-sulfatase (rhHNS) successfully reduced levels of heparan sulfate and glycosaminoglycans in the cerebrospinal fluid and urine, indicating a biochemical response to treatment.

Although the primary goal of preventing neurocognitive decline was not achieved, the treatment was generally safe with mostly mild adverse events, and no serious complications or deaths occurred, suggesting that rhHNS IT may be a tolerable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial. Wijburg, FA., Whitley, CB., Muenzer, J., et al.[2019]

In a study of 19 patients with Sanfilippo syndrome type B, cognitive abilities, adaptive behavior, and brain volume declined over 12 months, particularly in younger patients diagnosed before age 6, indicating significant disease progression.

While urine GAG and cerebrospinal fluid heparan sulfate levels remained stable, younger patients had higher levels, suggesting these biomarkers may have prognostic value but need further investigation to confirm their sensitivity to disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Observational Prospective Natural History of Patients with Sanfilippo Syndrome Type B. Whitley, CB., Cleary, M., Eugen Mengel, K., et al.[2019]

Sanfilippo syndrome (MPS III) is a neurodegenerative disorder caused by enzyme deficiencies that lead to heparan sulfate accumulation, resulting in severe neurological symptoms starting in childhood, but currently, there is no effective therapy available.

Research using animal models has advanced the understanding of MPS III and is paving the way for potential treatments, including planned clinical trials for enzyme replacement and gene therapy specifically targeting MPS IIIA and MPS IIIB.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sanfilippo syndrome: causes, consequences, and treatments. Fedele, AO.[2022]

The novel intracerebral gene therapy for Sanfilippo B demonstrated a good safety profile over 5.5 years, with no serious drug reactions reported despite 30 treatment-emergent adverse events, three of which were severe.

Sustained enzyme production was observed in the cerebrospinal fluid, and while one younger patient showed cognitive improvement, the older patients did not exhibit significant cognitive benefits, suggesting that earlier intervention may be crucial for better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracerebral Gene Therapy in Four Children with Sanfilippo B Syndrome: 5.5-Year Follow-Up Results. Deiva, K., Ausseil, J., de Bournonville, S., et al.[2022]

Hematopoietic stem cell gene therapy (HSCGT) using a lentiviral vector for the SGSH gene shows promise for treating Mucopolysaccharidosis type IIIA (MPSIIIA), with pre-clinical studies indicating effective gene transfer and safety in humanized mouse models.

The therapy demonstrated effective engraftment and biodistribution without vector shedding or germline transmission, and showed low genotoxicity, suggesting it is a safe and viable option for clinical trials in treating this neurological disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated Ex Vivo Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIA. Ellison, SM., Liao, A., Wood, S., et al.[2020]

Gene therapy for Sanfilippo A syndrome is feasible, as demonstrated by the successful use of a retroviral vector to deliver the sulfamidase gene, resulting in complete correction of the enzymatic defect in fibroblasts.

The study achieved phenotypic correction even at low levels of viral transduction, indicating that effective gene therapy may not require high viral loads, but careful selection of target cells is crucial for optimal outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correction of Sanfilippo A skin fibroblasts by retroviral vector-mediated gene transfer. Bielicki, J., Hopwood, JJ., Anson, DS.[2008]

Sanfilippo disease, a type of mucopolysaccharidosis (MPS III), is caused by genetic defects leading to the accumulation of heparan sulfate, resulting in severe neurodegenerative changes and cognitive disabilities.

While there are currently no approved therapies for Sanfilippo disease, recent advancements in clinical trials are exploring enzyme replacement therapy, gene therapy, and substrate reduction therapy as potential treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

How close are we to therapies for Sanfilippo disease? Gaffke, L., Pierzynowska, K., Piotrowska, E., et al.[2019]

Sanfilippo A syndrome (MPS-IIIA) is caused by a deficiency in the enzyme sulphamidase, which is essential for breaking down heparan sulphate, leading to lysosomal storage issues.

The sulphamidase gene, located on chromosome 17, consists of 8 exons and spans about 11 kilobases, with detailed analysis of its structure and sequence providing insights into the genetic basis of the disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structure and sequence of the human sulphamidase gene. Karageorgos, LE., Guo, XH., Blanch, L., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Intracerebral gene therapy in children with mucopolysaccharidosis type IIIB syndrome: an uncontrolled phase 1/2 clinical trial. [2022]

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

A multicenter open-label extension study of intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A. [2022]

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

Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial. [2019]

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

Observational Prospective Natural History of Patients with Sanfilippo Syndrome Type B. [2019]

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

Sanfilippo syndrome: causes, consequences, and treatments. [2022]

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

Intracerebral Gene Therapy in Four Children with Sanfilippo B Syndrome: 5.5-Year Follow-Up Results. [2022]

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

Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated Ex Vivo Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIA. [2020]

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

Correction of Sanfilippo A skin fibroblasts by retroviral vector-mediated gene transfer. [2008]

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

How close are we to therapies for Sanfilippo disease? [2019]

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

Structure and sequence of the human sulphamidase gene. [2022]