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AAV gene therapy for Tay-Sachs disease

Nature Medicine volume 28, pages 251–259 (2022)Cite this article

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Abstract

Tay-Sachs disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Here, we describe an adeno-associated virus (AAV) gene therapy expanded-access trial in two patients with infantile TSD (IND 18225) with safety as the primary endpoint and no secondary endpoints. Patient TSD-001 was treated at 30 months with an equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB administered intrathecally (i.t.), with 75% of the total dose (1 × 1014 vector genomes (vg)) in the cisterna magna and 25% at the thoracolumbar junction. Patient TSD-002 was treated at 7 months by combined bilateral thalamic (1.5 × 1012 vg per thalamus) and i.t. infusion (3.9 × 1013 vg). Both patients were immunosuppressed. Injection procedures were well tolerated, with no vector-related adverse events (AEs) to date. Cerebrospinal fluid (CSF) HexA activity increased from baseline and remained stable in both patients. TSD-002 showed disease stabilization by 3 months after injection with ongoing myelination, a temporary deviation from the natural history of infantile TSD, but disease progression was evident at 6 months after treatment. TSD-001 remains seizure-free at 5 years of age on the same anticonvulsant therapy as before therapy. TSD-002 developed anticonvulsant-responsive seizures at 2 years of age. This study provides early safety and proof-of-concept data in humans for treatment of patients with TSD by AAV gene therapy.

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Fig. 1: Longitudinal safety and immunological studies.
Fig. 2: Longitudinal biochemical and neurological function outcome measures.
Fig. 3: Anatomical MRI findings in patients with TSD who were treated with rAAVrh8.HEX/HEXB vectors.
Fig. 4: DTI in TSD patients treated with rAAVrh8.HEX/HEXB vectors.

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Data availability

Requests for data presented in this article should be addressed to the corresponding authors (miguel.esteves@umassmed.edu or terry.flotte@umassmed.edu) and will be reviewed individually. Requests will be answered within 30 days from the date they are received. The data available for sharing include the study protocol, raw data for ELISpot assays, GM2 ganglioside quantification in CSF, hexosaminidase activity levels in serum and CSF and MRI data. All shared data will be deidentified to protect patient privacy. A data transfer and use agreement may be required after evaluation by the UMass Chan Medical School Office of Technology Management. The MRI Atlas of Myelination (www.myelinationmriatlas.com) was the data source in 7- and 12-month-old healthy children shown in Extended Data Fig. 1. Source data are provided with this paper.

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Acknowledgements

This work was supported in part by the BlueGenes Foundation, which had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We are also grateful for the exceptional support from the National Tay-Sachs and Allied Diseases Association and the Cure Tay-Sachs Foundation during the preclinical development of this AAV gene therapy. We thank the families that provided MRI images from their deceased children with TSD or SD to support this study. We thank A. Singh for allowing us to use the MRI images from healthy children at 7 and 12 months of age for comparison purposes. We thank A. Zimmerman and B. Wong for their assistance during this study. We also thank N. Sanil and C. Dooley in the research pharmacy for their assistance in preparing the AAV doses for administration. We acknowledge the NEALS Biorepository for providing the biofluids from patient with amyotrophic lateral sclerosis used as non-TSD control samples in this study. M. Sena-Esteves was the sponsor of the clinical trial and was responsible for production of the AAVrh8 vectors in his laboratory as described in Methods. The hexosaminidase assays and western blots were also done in his laboratory. He had no role in the clinical aspects of the trial. During the manuscript review process, R.F. passed away in August 2021.

Author information

Authors and Affiliations

  1. Department of Pediatrics, UMass Chan Medical School, Worcester, MA, USA

    Terence R. Flotte, Oguz Cataltepe, Gwladys Gernoux, Meghan Blackwood, Christian Mueller, Scot Bateman, Allison M. Keeler & Laura Gibson

  2. Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research, UMass Chan Medical School, Worcester, MA, USA

    Terence R. Flotte, Ana Rita Batista, Gwladys Gernoux, Meghan Blackwood, Christian Mueller, Phillip W. L. Tai, Allison M. Keeler, Robert H. Brown Jr., Heather L. Gray-Edwards & Miguel Sena-Esteves

  3. Department of Neurosurgery, UMass Chan Medical School, Worcester, MA, USA

    Oguz Cataltepe & Richard Moser

  4. Department of Radiology, UMass Chan Medical School, Worcester, MA, USA

    Ajit Puri, Aly Abayazeed, Saurabh Rohatgi, Zeynep Vardar, Mohammed Salman Shazeeb, Matthew Gounis & Heather L. Gray-Edwards

  5. Department of Neurology, UMass Chan Medical School, Worcester, MA, USA

    Ana Rita Batista, Diane McKenna-Yasek, Catherine Douthwright, Robert H. Brown Jr. & Miguel Sena-Esteves

  6. Department of Medicine and Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, USA

    Xuntian Jiang

  7. Departments of Anesthesiology and Perioperative Medicine, UMass Chan Medical School, Worcester, MA, USA

    Spiro G. Spanakis & Julia Parzych

  8. Department of Internal Medicine, UMass Chan Medical School, Worcester, MA, USA

    Laura Gibson & Robert Finberg

  9. Population and Quantitative Health Sciences, UMass Chan Medical School, Worcester, MA, USA

    Bruce A. Barton

  10. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Cynthia J. Tifft

  11. Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Florian S. Eichler

  12. Scott-Ritchey Research Center, Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA

    Douglas R. Martin

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  1. Terence R. Flotte
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Contributions

T.R.F., R.H.B., O.C., R.M., A.P., S.B., S.G.S., J.P., A.A., L.G., C.J.T., R.F. and F.S.E. were part of the medical team. D.M.-Y., C.D. and A.M.K. were part of the clinical trial coordination team, data collection and analysis. P.W.L.T. analyzed the NGS data for the plasmids used in vector production. A.R.B. and M.S.-E. produced the AAVrh8 vectors. G.W., M.B. and C.M. performed all immunological assays and respective data interpretation. A.R.B. performed all enzyme assays and western blots, as well as respective data analysis and interpretation. B.A.B. performed the statistical analyses. A.A., S.R., Z.V., M.S.S. and M.G. were responsible for analysis and interpretation of MRI data. T.R.F., R.H.B., D.R.M., H.L.G.-E. and M.S.-E. wrote the manuscript.

Corresponding authors

Correspondence to Terence R. Flotte or Miguel Sena-Esteves.

Ethics declarations

Competing interests

The University of Massachusetts Chan Medical School licensed the AAV vectors to Axovant Gene Therapies (now Sio Gene Therapies) in December 2018. Licensing revenue is shared with Auburn University and M.S.-E., D.R.M. and H.G.-E. receive part of the licensing revenue according to institutional policies. The schedule of licensing payments is governed by accomplishment of milestones related to an ongoing phase 1/2 clinical trial where the investigators named above have no role. The remaining authors declare no competing interests.

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Peer review information

Nature Medicine thanks Timothy Yu, Steven Gray and Guilherme Baldo for their contribution to the peer review of this work. Anna Maria Ranzoni was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Structural brain MRI in healthy children during development and an infantile TSD patient.

T2 brain MRIs at 7 and 12 months of age in healthy children are from the MRI Atlas of Normal Myelination (www.myelinationmriatlas.com) with permission from Dr. Achint Singh. The T2 brain MRI of an 11-month-old infantile Tay-Sachs disease child was kindly provided by a family of a deceased child through the National Tay-Sachs and Allied Disease Association with permission to publish it here.

Extended Data Fig. 2 Volumetric calculations of lateral ventricular size and size of the lentiform nucleus.

TSD-001 has larger ventricles consistent with cortical atrophy whereas the relevance of TSD-002 ventricular size remains unclear and could be associated with normal brain development.

Extended Data Fig. 3 DTI of normal brain development.

Tractography of the normal developing brain from Hermoye et al, 2006. The color scheme of the tractography pathways is based on a standard red-green-blue (RGB) color code that shows the spatial locations of terminal regions of each pathway (right-left: red; dorsal-ventral: blue; and, anterior-posterior: green.

Extended Data Fig. 4 DTI results.

a, Mean diffusivity (MD) maps of TSD-002 brain indicating regions of interest (ROI) for calculation of DTI parameters. MD quantifications over time are displayed below the images for various ROIs in the brain for both TSD-001 and TSD-002. b, Axial diffusivity (AD) and c, radial diffusivity (RD) measurements are also shown for the same brain ROIs over time for both patients. Data is represented as mean ± SD of pixel intensity in the ROI. In TSD-002 both optic radiations show stable FA values and increased average diffusivity values. AD values remain stable even when FA decreases, as shown in the anterior corpus callosum for TSD-001.

Supplementary information

Supplementary Information

Supplementary Methods, Tables 1 and 2, Redacted certificates of analysis of AAV vector lots used in clinical trial

Reporting Summary

Source data

Source Data Fig. 1

Unprocessed western blots.

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Flotte, T.R., Cataltepe, O., Puri, A. et al. AAV gene therapy for Tay-Sachs disease. Nat Med 28, 251–259 (2022). https://doi.org/10.1038/s41591-021-01664-4

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