Breakthrough Clinical Results
Myrtelle Inc. announced encouraging interim results from its Phase 1/2 clinical trial of rAAV-Olig001-ASPA (MYR-101), an investigational gene therapy for Canavan disease. The study, published in Nature Medicine, showed a favorable safety profile, significant reductions in N-acetylaspartate (NAA) levels, increases in brain myelin volume, and measurable developmental progress in participants. rAAV-Olig001-ASPA (MYR-101) has received several designations from regulatory agencies, including FDA's START pilot program, RMAT designation, and Orphan Drug, Rare Pediatric Disease, and Fast Track designations.
Key Highlights
- MYR-101 demonstrated a favorable safety profile with no serious adverse events related to treatment.
- Significant reductions in N-acetylaspartate (NAA) levels in cerebrospinal fluid (CSF), consistent with restoration of ASPA enzyme function.
- Increases in brain myelin volume measured by Synthetic MRI (SyMRI) confirm remyelination consistent with therapeutic benefit.
- Participants demonstrated measurable developmental progress compared with historical controls, reflecting broad functional gains.
Incidence and Prevalence
Latest Estimates of Incidence and Prevalence of Canavan Disease Globally
Prevalence in Jewish Populations
The most recent data from a 2022 study indicates that Canavan disease affects one in 6,400 to 13,500 people in the Jewish population. This disease has a higher prevalence among children of Jewish extraction, particularly those of Ashkenazi Jewish descent.
In the Ashkenazi Jewish population, the carrier frequency among healthy Jews is 1:37-58. Three specific mutations account for 98.8% of the Canavan chromosomes of Ashkenazi Jewish origin, with the glu285→ala mutation being predominant (82.9%). This high prevalence makes the Ashkenazi Jewish population at increased risk for Canavan disease, alongside several other recessively inherited disorders.
A study of 5,685 Ashkenazi Jewish exomes documented that Canavan disease (ASPA, p.Glu285Ala) shows 12-fold enrichment in Ashkenazi Jewish populations compared to non-AJ populations.
Prevalence in Other Populations
While Canavan disease is most commonly associated with Ashkenazi Jewish descent, it has been diagnosed in many diverse ethnic groups. The disease is an autosomal recessive leukodystrophy caused by the deficiency of aspartoacylase (ASPA).
In India, a 2022 study reported 12 children diagnosed with Canavan disease, with 83.3% (10 children) born out of consanguineous parentage, suggesting potential higher risk in populations with consanguineous marriages. However, the prevalence and presentation of the disease in India and many other regions is largely unknown.
In Saudi Arabia, researchers have identified one novel and one known large deletion and two previously known mutations (IVS4 + 1G>T and G27R) associated with Canavan disease.
Genetic Variations
The genetic profile of Canavan disease varies significantly between Jewish and non-Jewish populations. Two mutations comprise the majority of mutant alleles in Jewish patients, while mutations in the ASPA gene among non-Jewish patients are different and more diverse. In a study of 22 unrelated non-Jewish patients with Canavan disease, 24 different mutations were found, of which 14 were novel.
Global Prevalence
Recent advances in understanding the biochemical defect have led to increased awareness and diagnosis, revealing that the disease is not as rare as initially thought. However, the global prevalence outside specific ethnic groups remains poorly documented in the available literature.
It's worth noting that Canavan disease occurs more frequently outside Ashkenazi Jewish communities than previously reported, though specific global incidence rates beyond the Jewish population statistics are not well established.
Key Unmet Needs for Canavan Disease
Current Treatment Landscape
Canavan disease, a fatal white matter disorder, has historically been considered untreatable. While the field is shifting from "therapeutic nihilism to cautious optimism," there are currently no effective treatments available for patients. Previous experimental gene therapy trials have failed to provide sufficient amelioration of symptoms.
Emerging Therapeutic Approaches
Recent research shows promising developments:
- Gene replacement therapy has become a viable option with ongoing trials
- Lowering NAT8L expression (the enzyme synthesizing N-acetyl-L-aspartate)
- Combined vector dual-function approach that has shown long-term reversal of pathological hallmarks in post-symptomatic mice
Critical Unmet Needs
Despite these advances, significant challenges remain:
- Early Diagnosis: New gene therapies will require presymptomatic diagnosis to be fully effective, highlighting the need for newborn screening programs
- Limited Natural History Data: The ultrarare nature of Canavan disease has resulted in insufficient understanding of disease progression
- Treatment Accessibility: High treatment costs and barriers to accessibility prevent patients from receiving innovative therapies
- Diagnostic Capabilities: While a new LC-MS/MS-based screening test has been developed, it requires further evaluation in population-based studies
Pathophysiological Understanding
Research indicates incomplete understanding of disease mechanisms:
- The precise involvement of elevated NAA in pathogenesis remains an ongoing debate
- The disease involves both disrupted NAA metabolism and excessive NAA-related signaling processes in oligodendrocytes
- There are still mechanisms of the disease that have not been fully determined
Future Directions
To address these unmet needs, the field is focusing on:
- Implementing newborn screening to enhance early diagnosis
- Fostering close international collaboration to refine treatment timing
- Making efforts to expand access to innovative therapies
- Further research to understand the complete pathophysiology of Canavan disease
- Evaluating the new screening test once promising treatments become available
The combination of improved diagnostic capabilities and emerging gene therapy approaches offers hope, but requires addressing these substantial unmet needs to translate scientific progress into effective patient care.
Recent Studies
Recent Studies for Canavan Disease
2024 LC-MS/MS Screening Test Study
Intervention: Development of a fast and highly sensitive liquid chromatography mass spectrometry (LC-MS/MS)-based method for quantification of N-acetylaspartate in dried blood spots. Efficacy Outcomes: Successfully distinguished Canavan patients from controls with clear separation - patients showed levels of 5.7; 1.6-13.6 μmol/L compared to controls at 0.44; 0.24-0.99 μmol/L. The test meets general requirements of newborn screening and can be multiplexed with other screening approaches.
2023 Dual-Function Vector Combination Therapy
Intervention: Gene therapy combining ASPA gene replacement with lowering NAT8L expression using intracranial adeno-associated virus-mediated gene delivery. Efficacy Outcomes: Demonstrated significant knockdown of neuronal Nat8l paired with robust ectopic aspartoacylase expression. Treatment decreased brain vacuoles and reversed pathological hallmarks including loss of body weight, locomotor impairments, elevated N-acetyl-L-aspartate levels, astrogliosis, and demyelination. Shows potential to permanently alleviate Canavan disease symptoms and expand the therapeutic window for adult subjects.
Open-Label Expanded-Access Trial
Intervention: Simultaneous intravenous (i.v.) and intracerebroventricular (i.c.v.) administration of rAAV9-CB6-ASPA with prophylactic immunomodulation. Safety Outcomes: Immunomodulation successfully prevented anti-transgene immune response and enabled repeat dosing. Efficacy Outcomes: Two years post-treatment, the patient showed increased white matter myelination, improved motor function, and remained free of typical severe epilepsy. N-acetylaspartate (NAA) level was reduced at 3 months and remained stable up to 4 years post-treatment.
2015 Dietary Intervention Study
Intervention: Triheptanoin dietary treatment in the nur7 mouse model. Efficacy Outcomes: Treatment reduced oxidative stress, promoted long-term oligodendrocyte survival, increased myelin in the brain, achieved highly significant reduction in spongiform degeneration, and improved motor function. Results indicated a window of therapeutic intervention that corresponds with developmental myelination.
2014 Intravenous rAAV Gene Therapy Study
Intervention: Single intravenous (IV) injections of primate-derived recombinant adeno-associated viruses (rAAVs) with microRNA (miRNA)-mediated post-transcriptional detargeting. Efficacy Outcomes: Treatment completely rescued early lethality in mice when administered as late as postnatal day 20. Extended survival in P0-injected rAAV9 and rAAVrh8 groups to as long as 2 years. Treatment globally improved CNS myelination, although some abnormalities persisted.
2011 Enzyme Replacement Therapy Study
Intervention: PEGylated aspartoacylase enzyme replacement therapy. Efficacy Outcomes: Demonstrated statistically significant increases in brain enzyme activity levels in a mouse model and decreases in elevated substrate levels that mimic those found in Canavan disease patients. The modified enzyme gained access to the brain and functioned to correct the metabolic defect.