Gene Therapy for Canavan Disease

(CANaspire Trial)

Recruiting at 2 trial locations

Overseen By Mary Rohrer, RN, BSN

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Aspa Therapeutics

Must not be taking: Immunosuppressants, Anti-epileptics

Disqualifiers: Anti-AAV9 antibodies, Prior gene therapy, others

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

Compensation: Varies

Number of Visits: 2

26 Participants Needed

Trial Summary

What is the purpose of this trial?

The main objective of this trial is to evaluate the safety, tolerability, and pharmacodynamic activity of BBP-812, an investigational AAV9-based gene therapy, in pediatric participants with Canavan disease.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it excludes participants who are on high-dose immunosuppressants or have seizures that don't respond to three or more anti-epileptic medications.

What data supports the effectiveness of the treatment BBP-812 for Canavan Disease?

Research shows that gene therapy using a similar approach in mice with Canavan Disease extended their survival and improved symptoms. In a human trial, a patient showed increased brain myelination (protective covering of nerves) and improved motor function after receiving a similar gene therapy treatment. ^{1 2 3 4 5}

Is the gene therapy treatment BBP-812 safe for humans?

Research on gene therapy for Canavan disease, including treatments similar to BBP-812, shows that it can be safe in humans. In one study, a patient treated with a similar therapy showed improved motor function and no severe side effects over two years. Another study used a virus-based gene transfer in the brain, which was the first of its kind, and involved careful monitoring to ensure safety. ^{1 2 3 6 7}

How is the treatment BBP-812 for Canavan Disease different from other treatments?

BBP-812 is a gene therapy that uses a virus to deliver a healthy version of the aspartoacylase gene directly to the brain, which is unique because it targets the root cause of Canavan Disease by replacing the defective gene. Unlike other treatments, it can be administered intravenously and is designed to restrict its effects to the central nervous system, potentially reducing side effects. ^{1 2 3 4 7}

Eligibility Criteria

This trial is for children up to 30 months old with Canavan disease, a stable health condition, and no other serious diseases. They must have a genetic mutation in the ASPA gene and show signs of Canavan disease. Kids who've had previous gene therapy or certain immunosuppressants, or those with severe seizures uncontrolled by medication can't participate.

Inclusion Criteria

I have been diagnosed with Canavan disease through tests and symptoms.

I have a genetic mutation in the ASPA gene.

I'm sorry, but "Elevated urinary NAA" is not clear enough for me to simplify it for a fifth grader. Could you please provide more context or details about this criterion?

Exclusion Criteria

I exhibit involuntary, rigid body postures.

My Canavan disease has significantly worsened.

You have a positive result for antibodies against AAV9 when tested with a specific method called ELISA.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose-Finding Phase

Participants receive a single intravenous infusion of BBP-812 at either low or high dose on Day 0

1 day

1 visit (in-person)

Enrollment Expansion Phase

Participants receive a single IV infusion of BBP-812 at the selected dose from the dose-finding phase on Day 0

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• BBP-812

Trial Overview The study tests BBP-812, an experimental gene therapy using AAV9 to treat Canavan disease in young children. It aims to assess how safe it is, how well patients tolerate it, and its effect on the body's functions related to the disease.

Participant Groups

Group I: Enrollment Expansion Phase: BBP-812 Experimental Treatment 1 Intervention

Participants will receive a single IV infusion of BBP-812 at the selected dose from the dose-finding phase on Day 0 in expansion phase of the study.

Group II: Dose-Finding Phase: BBP-812 Dose Level 2 (Cohort 2) Experimental Treatment 1 Intervention

Participants will receive a single IV infusion of high-dose BBP-812 on Day 0 in the dose-finding phase of the study.

Group III: Dose-Finding Phase: BBP-812 Dose Level 1 (Cohort 1) Experimental Treatment 1 Intervention

Participants will receive a single intravenous (IV) infusion of low-dose BBP-812 on Day 0 in the dose-finding phase of the study.

Who Is Running the Clinical Trial?

Aspa Therapeutics

Lead Sponsor

Trials

2

Recruited

100+

Findings from Research

Gene therapy using recombinant adeno-associated viruses (rAAVs) significantly improved survival and alleviated symptoms in a mouse model of Canavan's disease, extending the lifespan of treated mice to up to 2 years when administered as late as postnatal day 20.

The study successfully employed microRNA-mediated detargeting to limit the expression of therapeutic genes to the central nervous system, reducing the risk of harmful effects from overexpression in other tissues, while still enhancing CNS myelination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in Canavan mice. Ahmed, SS., Li, H., Cao, C., et al.[2022]

This clinical protocol outlines a groundbreaking approach using virus-based gene transfer to treat Canavan disease, a severe childhood disorder caused by a defective gene for the enzyme aspartoacylase, affecting brain myelination.

The study involves administering approximately 900 billion genomic particles of a recombinant adeno-associated virus (AAV) containing the functional ASPA gene directly into the brains of 21 patients, marking the first use of AAV for gene therapy in humans and potentially offering a new treatment avenue for neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Janson, C., McPhee, S., Bilaniuk, L., et al.[2012]

In a trial for Canavan disease involving a single patient, dual administration of gene therapy (intravenous and intracerebroventricular) led to significant improvements in white matter myelination and motor function over two years, while preventing severe epilepsy.

Prophylactic immunomodulation was effective in preventing immune responses to the therapy, allowing for repeat dosing and indicating that this approach may enhance the safety and efficacy of gene replacement therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adeno-associated virus-mediated gene therapy in a patient with Canavan disease using dual routes of administration and immune modulation. Corti, M., Byrne, BJ., Gessler, DJ., et al.[2023]

A new knock-out mouse model for Canavan disease has been successfully created, which displays neurological impairments and elevated N-acetylaspartic acid (NAA) levels, mimicking the human condition.

This model will aid in the development of gene therapy vectors for Canavan disease and enhance understanding of its pathophysiology, potentially benefiting research on other neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Knock-out mouse for Canavan disease: a model for gene transfer to the central nervous system. Matalon, R., Rady, PL., Platt, KA., et al.[2012]

The study involved ten subjects receiving a gene therapy for Canavan disease using a viral vector (rAAV2) delivered directly to the brain, which showed promising safety with minimal immune response and inflammation.

Most subjects (7 out of 10) did not develop neutralizing antibodies against the AAV2 vector, indicating that the treatment is well tolerated and suggesting a relatively safe profile for further clinical development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune responses to AAV in a phase I study for Canavan disease. McPhee, SW., Janson, CG., Li, C., et al.[2012]

Canavan disease is a rare genetic disorder caused by mutations in the ASPA gene, leading to severe neurological symptoms that typically appear between 3 to 5 months of age.

Cranial ultrasound findings in a patient with Canavan disease suggest a characteristic pattern that may help in early diagnosis, as observed through comparisons with other documented cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain ultrasound in Canavan disease. Drera, B., Poggiani, C.[2021]

A novel dual-function gene therapy approach combining ASPA gene replacement and suppression of the NAT8L enzyme showed promising results in reversing symptoms of Canavan disease in a mouse model, significantly reducing brain vacuoles and other pathological features.

This late-stage gene therapy not only improved neurological function but also suggests the potential for a permanent treatment option for Canavan disease, expanding the possibilities for future therapies in adult patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual-function AAV gene therapy reverses late-stage Canavan disease pathology in mice. Fröhlich, D., Kalotay, E., von Jonquieres, G., et al.[2023]

References

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

A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in Canavan mice. [2022]

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

Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. [2012]

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

Adeno-associated virus-mediated gene therapy in a patient with Canavan disease using dual routes of administration and immune modulation. [2023]

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

Knock-out mouse for Canavan disease: a model for gene transfer to the central nervous system. [2012]

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

Immune responses to AAV in a phase I study for Canavan disease. [2012]

6. Italy pubmed.ncbi.nlm.nih.gov

Brain ultrasound in Canavan disease. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Dual-function AAV gene therapy reverses late-stage Canavan disease pathology in mice. [2023]