Gene Therapy for Canavan Disease

(CAN-GT Trial)

Overseen By Jordana Holovach

Age: < 18

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Myrtelle LLC

Disqualifiers: Chronic medical conditions, Allergic reactions, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

Canavan Disease is a congenital white matter disorder caused by mutations to the gene encoding for aspartoacylase (ASPA). Expression of ASPA is restricted to oligodendrocytes, the sole white matter producing lineage in the brain. ASPA supports myelination in the capacity of its sole known function, namely, the catabolism of N-acetylaspartate (NAA). Inherited mutations that result in loss of ASPA catabolic activity result in a typically severe phenotype of Canavan Disease, characterized by chronically elevated brain NAA, gross motor abnormalities, hypomyelination, progressive spongiform degeneration of the brain, epilepsy, blindness, and a short life expectancy. Disease severity is correlated with residual levels of enzyme activity. Reconstitution of ASPA function in oligodendrocytes of the brains of Canavan patients is expected to rescue NAA metabolism in its natural cellular compartment and support myelination/remyelination by resident white matter producing cells. This protocol directly targets oligodendrocytes in the brain, which are intimately involved with disease initiation and progression. Targeting oligodendrocytes offers the safest and most direct therapy for affected individuals. The latest generation AAV viral vector (rAAV-Olig001-ASPA) will be administered to patients using neurosurgical procedure which involves direct administration of gene therapy to affected regions of the brain. Outcome measures for the open label clinical trial include longitudinal clinical assessments and brain imaging. Currently, there is no effective treatment for Canavan Disease. The purpose of this study is to validate a new technology targeted to the cells most affected by Canavan Disease in the safest way possible. The study investigators are committed to supporting the Rare Disease \& Canavan Disease Communities. For more information, please contact Jordana Holovach, Head of Communications and Community at [e-mail].

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

How is the rAAV-Olig001-ASPA treatment different from other treatments for Canavan disease?

The rAAV-Olig001-ASPA treatment is unique because it uses a viral vector to deliver a healthy version of the ASPA gene directly to the brain, aiming to restore enzyme function and reduce harmful substances in the brain. This gene therapy is novel as it targets the central nervous system and is administered through a specific route to reach affected brain areas, offering hope for a condition with no current standard treatment. ^{1 2 3 4 5}

Who Is on the Research Team?

Robert Lober, MD, PhD

Principal Investigator

Dayton Children's Hospital

Are You a Good Fit for This Trial?

This trial is for children with typical Canavan Disease, a brain disorder. Eligible participants are aged 3-60 months and diagnosed by a neurologist. They can't have had gene therapy or intracranial surgery before, severe allergies, MRI contraindications, immune system issues, or other serious health problems.

Inclusion Criteria

You have been diagnosed with typical CD by a neurologist who is certified by the board.

Written informed consent from parent(s)/guardian(s) including a written agreement to comply with all the conditions of the study

My child is younger than 15 months.

Exclusion Criteria

You are expected to live for less than 12 months for any reason.

Your lab test results are not within the normal range and the doctor in charge decides they are important.

Your GMFM-88 score is higher than 35%.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Neurosurgical administration of a single dose of rAAV-Olig001-ASPA delivered intracerebroventricularly

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including neurological evaluations and imaging

12 months

Multiple visits (in-person and virtual)

Long-term follow-up

Extended monitoring of participants for long-term safety and efficacy outcomes

Additional 12 months

What Are the Treatments Tested in This Trial?

Interventions

• rAAV-Olig001-ASPA

Trial Overview The trial tests rAAV-Olig001-ASPA gene therapy delivered directly to the brain to treat Canavan Disease. It aims to restore enzyme function in cells responsible for producing white matter. The study includes clinical assessments and brain imaging over time.

How Is the Trial Designed?

Group I: 3.7 x 10^13 v.g. rAAV-Olig001-ASPA Experimental Treatment 3 Interventions

3.7 x 10\^13 v.g. of rAAV-Olig001-ASPA administered as a single dose neurosurgically to the brain via 2 pre-defined intracerebroventricular sites

rAAV-Olig001-ASPA is already approved in United States, European Union for the following indications:

Approved in United States as rAAV-Olig001-ASPA Gene Therapy for:

• Orphan Drug, Fast-Track and Rare Pediatric Disease Designations for the treatment of Canavan disease

Approved in European Union as rAAV-Olig001-ASPA Gene Therapy for:

• Orphan Drug Designation for the treatment of Canavan disease

Who Is Running the Clinical Trial?

Myrtelle LLC

Lead Sponsor

Trials

1

Recruited

20+

Myrtelle Inc.

Lead Sponsor

Trials

2

Recruited

12,000+

Published Research Related to This Trial

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]

In a study of 28 patients with Canavan disease, gene therapy using the AAV2-ASPA vector showed long-term safety with no significant adverse events over a minimum 5-year follow-up period.

The treatment led to a decrease in elevated N-acetyl-aspartate (NAA) levels in the brain, slowed brain atrophy progression, and showed some improvement in seizure frequency and overall clinical stability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term follow-up after gene therapy for canavan disease. Leone, P., Shera, D., McPhee, SW., et al.[2022]

The novel AAV capsid variant AAV/Olig001 demonstrated over 70% oligotropism in key brain regions for Canavan disease treatment, effectively targeting oligodendrocytes without needing specific expression elements.

Using intracerebroventricular infusion to deliver AAV/Olig001 led to a dose-dependent improvement in enzyme activity and motor function in Canavan mice, showing significant advantages over the AAV9 vector, which supports its potential for clinical use in white matter diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical biodistribution, tropism, and efficacy of oligotropic AAV/Olig001 in a mouse model of congenital white matter disease. Francis, JS., Markov, V., Wojtas, ID., et al.[2021]

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]

The non-viral lipid-entrapped delivery system (LPD) for gene therapy demonstrated effective and safe gene transfer in both animal models and preliminary studies in 2 children with Canavan disease, showing no significant adverse effects.

In animal studies, the gene delivery system resulted in widespread gene expression for over 10 months, and in the children, it was associated with positive biochemical and clinical changes, indicating potential efficacy for treating neurological disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. Leone, P., Janson, CG., Bilaniuk, L., et al.[2019]

Citations

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

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

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

Long-term follow-up after gene therapy for canavan disease. [2022]

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

Preclinical biodistribution, tropism, and efficacy of oligotropic AAV/Olig001 in a mouse model of congenital white matter disease. [2021]

4. 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]

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

Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implications for Canavan disease. [2019]