Clinical trial NCT04833907: rAAV-Olig001-ASPA Gene Therapy for Treatment of Children With Typical Canavan Disease
Official title: Phase 1/2, Open Label, Sequential Cohort Study of a Single Intracranial Dose of AVASPA Gene Therapy for Treatment of Children With Typical Canavan Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Canavan Disease
Keywords: Canavan Disease
Gene Therapy
Aspartoacylase
N-Acetyl-Aspartate
Oligodendrocyte
Leukodystrophy
Adeno-Associated Virus Vector
Autosomal Recessive Disorder
Neurodegenerative
White Matter Disorder
Lead sponsor: Myrtelle Inc.
Sponsor class: INDUSTRY
First posted: 2021-04-06
Enrollment: 24
Sex: ALL
Minimum age (years): 3
Maximum age (years): 60
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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 PatientAdvocacy@myrtellegtx.com.

Detailed description: rAAV-Olig001-ASPA is the first gene therapy designed to target the oligodendrocytes, which are critical for myelination and brain development.

This study is a Phase 1/2 First-In-Human protocol designed to obtain safety, pharmacodynamics, and efficacy data following neurosurgical administration of a single dose of rAAV-Olig001-ASPA delivered intracerebroventricularly in up to 24 children with Canavan Disease.

Patients with a diagnosis of typical Canavan Disease who meet all eligibility criteria may be enrolled in this open-label, sequential cohort study of a single dose of rAAV-Olig001-ASPA.

Eligibility criteria: Inclusion Criteria:

* Definitive diagnosis of typical CD by a board certified neurologist.
* Written informed consent from parent(s)/guardian(s). Consent to enroll into the study will include a written agreement to comply with all the conditions of the study, including attendance at follow-up visits.
* For cohort 1: age more than 36 months and up to 60 months.
* For cohort 2: age between 15 months and 36 months.
* For cohort 3: age less than 15 months.

Exclusion Criteria:

* At the discretion of the PI, any significant chronic medical condition, including, but not limited to neurological, cardiac, hepatic, renal, hematological, gastrointestinal, endocrine, pulmonary, or infectious disease, which would put the subject at increased risk during surgery or which would interfere with participation in the study, interpretation of safety monitoring, or the integrity of the study data.
* History of severe allergic reaction or anaphylaxis.
* Past participation in gene therapy trials or receipt of any other investigational product within 6 months prior to enrollment.
* Prior intracranial surgery.
* Any absolute contraindication to immunosuppression.
* Any absolute contraindication to MRI.
* Any vaccination less than 1 month prior to gene therapy.
* Anticipated life expectancy of less than 12 months for any reason.
* GMFM-88 total raw score \>35%.
* Clinically significant out-of-range lab values, at the discretion of clinical PI.

Primary outcomes:
measure: Safety evaluation
timeFrame: 12 Months Post Dose
Secondary outcomes:
measure: Myelination
timeFrame: 12 Months Post Dose
measure: N-Acetyl-Aspartate (NAA) concentrations in the Brain
timeFrame: 12 Months Post Dose
measure: Neurological Evaluation - Motor Function
timeFrame: 12 Months Post Dose
measure: Neurological Evaluation - Neurocognitive Function
timeFrame: 12 Months Post Dose
measure: Neurological Evaluation - Spasticity
timeFrame: 12 Months Post Dose
measure: Seizure Assessment
timeFrame: 12 Months Post Dose
measure: NAA concentration measured in Cerebrospinal Fluid (CSF)
timeFrame: 6 months
Other outcomes:
Locations:
city: Dayton
country: United States
facility: Dayton Children's Hospital
state: Ohio
Study officials:
affiliation: Dayton Children's Hospital
name: Robert Lober, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Francis JS, Markov V, Wojtas ID, Gray S, McCown T, Samulski RJ, Figueroa M, Leone P. Preclinical biodistribution, tropism, and efficacy of oligotropic AAV/Olig001 in a mouse model of congenital white matter disease. Mol Ther Methods Clin Dev. 2021 Jan 21;20:520-534. doi: 10.1016/j.omtm.2021.01.009. eCollection 2021 Mar 12.
citation: Francis JS, Wojtas I, Markov V, Gray SJ, McCown TJ, Samulski RJ, Bilaniuk LT, Wang DJ, De Vivo DC, Janson CG, Leone P. N-acetylaspartate supports the energetic demands of developmental myelination via oligodendroglial aspartoacylase. Neurobiol Dis. 2016 Dec;96:323-334. doi: 10.1016/j.nbd.2016.10.001. Epub 2016 Oct 4.