Abstract
This open-label phase 1/2 clinical study uses a novel recombinant vector, rAAV-Olig001, with selective tropism for oligodendrocytes, to deliver gene therapy for Canavan disease (CD), a rare leukodystrophy characterized by defective aspartoacylase and elevated N-acetyl-aspartic acid (NAA) concentrations. A total of 8 participants received intracranial doses of 3.7 × 1013 vector genomes (vg) of rAAV-Olig001-ASPA (MYR-101), with an interim analysis at 12 months. The primary objective was to assess the safety of intracranial dosing of MYR-101 in children with typical CD. Efficacy measures included Mullen Scales of Early Learning (MSEL), Gross Motor Function Measure (GMFM) and analysis of NAA, myelination, white matter and extracellular water content in the brain. The participants were White; 5 (62.5%) were male. Of the participants, 7 (87.5%) experienced ≥1 serious adverse event, none of which were considered MYR-101 related. All participants experienced ≥1 adverse event. All adverse events and serious adverse events resolved fully. Treatment reduced NAA concentrations in cerebrospinal fluid (P = 0.0008), increased myelination (P = 0.0137) and improved MSEL developmental outcomes (P = 0.0171). Thus, interim results suggest that gene therapy with MYR-101 is well tolerated and shows early effects in CD. While these findings are preliminary, reductions in NAA concentrations indicate ASPA expression and increases in myelination and imply successful targeting of oligodendrocytes. These results may support the development of similar gene therapy strategies for other demyelinating and metabolic brain disorders. ClinicalTrials.gov registration: NCT04833907.
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Data availability
At the outset of the trial, we omitted a data-sharing provision from the consent documents signed by participants. As a result, in accordance with our Ethics Committee policies, we are not authorized to release the raw data to the public. Furthermore, the study is still in progress. De-identified patient characteristics, safety and preliminary efficacy data from raw datasets generated in this study are included in the paper. Requests for more information about the raw data are subject to a confidentiality agreement with Myrtelle and must comply with applicable legal and regulatory requirements. Qualified researchers may request access to the trial information by contacting corresponding author O.F. The requests will be addressed within 120 days, and data transfer agreement may be required.
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Acknowledgements
We thank the patients and families who generously contributed their time, courage and commitment to this research that made this study possible. We also wish to thank all of the Canavan Disease Patient Advocacy Groups worldwide for their commitment to research and patient care in this community, and the entire team at Dayton Children's Hospital for their support and collaboration. We sincerely thank S. Hesterlee, now interim president and CEO of the Muscular Dystrophy Association, for her exceptional guidance and support during the early development of this program in her former role as program director of the Canavan Disease Program. We also thank L. E. Kratz and the Kennedy Krieger Institute Biochemical Genetics Lab for analyzing the CSF NAA samples. We thank A. Pace for statistical support on this project, particularly with MSEL statistical analysis. We also wish to acknowledge the important scientific contributions of J. R. Samulski and S. Gray, whose expertise has been instrumental during the first phase of this program. We gratefully acknowledge the members of the Independent Data Monitoring Committee for their expert guidance, oversight and commitment to ensuring the integrity of the trial. Their independent review and thoughtful recommendations have been invaluable in guiding the conduct of this study. We thank the FDA for their supportive guidance and for recognizing the urgent, unmet needs of patients and families affected by this devastating disease and their commitment to accelerating the progress of this program. This study is funded by Myrtelle, Inc. Paper preparation support, provided by J. G. Jacobson, InSeption Group, was also funded by Myrtelle, Inc.
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P.L. contributed to study design, data interpretation, revision of the paper and approval of the paper for submission. R.M.L. contributed to data interpretation, revision of the paper and approval of the paper for submission. J.F. contributed to data interpretation, revision of the paper and approval of the paper for submission. O.F. contributed to data interpretation, writing and revision of the paper and approval of the paper for submission. C.G.J. contributed to data analysis and interpretation, writing and revision of the paper, approval of the paper for submission. D.S. contributed to statistical analyses, revision of the paper and approval of the paper for submission. K.M.C. contributed to data interpretation, revision of the paper and approval of the paper for submission.
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P.L. is a shareholder of and paid consultant for Myrtelle, Inc. R.M.L. and J.F. report no conflicts of interest. C.G.J., D.S. and K.M.C. are paid consultants for Myrtelle, Inc. O.F. is co-chief medical officer and a shareholder of Myrtelle, Inc.
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Extended data
Extended Data Fig. 1 Change in N-acetyl-aspartic acid (NAA) concentrations in the brain, measured by magnetic resonance spectroscopy after MYR-101 treatment.
Panel a. Mean change in NAA across the occipital region for individual participants (average of right and left occipital voxels), measured by MRS. Population fit (i.e., mean line for the entire population) is shown in red. For reference, normal age-matched NAA concentrations in the occipital lobe range from 4-7 mM. Panel b. individual NAA values for each participant, including participant for whom pre-treatment values were available; in those participants, NAA slope was positive leading up to gene therapy and negative afterwards, as previously described2.
Extended Data Fig. 2 Participant-level changes in myelin as a function of time from treatment.
Myelin volume is shown in mLs. Participants are identified by their age at time of treatment.
Extended Data Fig. 3 Change in Gross Motor Function Measure (GMFM-88) raw scores in treated participants by chronological age.
Panel a: Change in individual participants on the Lying and Rolling domain of the Gross Motor Function Measure. Population fit (mean line for the entire population) is shown in red. Panel b: Change in individual participants on the Sitting domain of the Gross Motor Function Measure. Population fit is shown in red.
Supplementary information
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Supplementary methods.
Supplementary Video 1
A child with typical Canavan disease before treatment.
Supplementary Video 2
Video 1 of the same child after treatment.
Supplementary Video 3
Video 2 of the same child after treatment.
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Leone, P., Lober, R.M., Francis, J. et al. Oligodendrocyte-targeted adeno-associated virus gene therapy for Canavan disease in children: a phase 1/2 trial. Nat Med (2025). https://doi.org/10.1038/s41591-025-03919-w
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DOI: https://doi.org/10.1038/s41591-025-03919-w
