PMID- 35145305
OWN - NLM
STAT- MEDLINE
DCOM- 20220426
LR  - 20240113
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Print)
IS  - 1078-8956 (Linking)
VI  - 28
IP  - 2
DP  - 2022 Feb
TI  - AAV gene therapy for Tay-Sachs disease.
PG  - 251-259
LID - 10.1038/s41591-021-01664-4 [doi]
AB  - 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 x 
      10(14) 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 x 10(12) vg per thalamus) and i.t. infusion (3.9 x 10(13) 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.
CI  - (c) 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
FAU - Flotte, Terence R
AU  - Flotte TR
AUID- ORCID: 0000-0002-8255-0588
AD  - Department of Pediatrics, UMass Chan Medical School, Worcester, MA, USA. 
      Terry.Flotte@umassmed.edu.
AD  - Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research, 
      UMass Chan Medical School, Worcester, MA, USA. Terry.Flotte@umassmed.edu.
FAU - Cataltepe, Oguz
AU  - Cataltepe O
AD  - Department of Pediatrics, UMass Chan Medical School, Worcester, MA, USA.
AD  - Department of Neurosurgery, UMass Chan Medical School, Worcester, MA, USA.
FAU - Puri, Ajit
AU  - Puri A
AD  - Department of Radiology, UMass Chan Medical School, Worcester, MA, USA.
FAU - Batista, Ana Rita
AU  - Batista AR
AD  - Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research, 
      UMass Chan Medical School, Worcester, MA, USA.
AD  - Department of Neurology, UMass Chan Medical School, Worcester, MA, USA.
FAU - Moser, Richard
AU  - Moser R
AD  - Department of Neurosurgery, UMass Chan Medical School, Worcester, MA, USA.
FAU - McKenna-Yasek, Diane
AU  - McKenna-Yasek D
AD  - Department of Neurology, UMass Chan Medical School, Worcester, MA, USA.
FAU - Douthwright, Catherine
AU  - Douthwright C
AD  - Department of Neurology, UMass Chan Medical School, Worcester, MA, USA.
FAU - Gernoux, Gwladys
AU  - Gernoux G
AUID- ORCID: 0000-0002-1268-7001
AD  - Department of Pediatrics, UMass Chan Medical School, Worcester, MA, USA.
AD  - Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research, 
      UMass Chan Medical School, Worcester, MA, USA.
FAU - Blackwood, Meghan
AU  - Blackwood M
AD  - Department of Pediatrics, UMass Chan Medical School, Worcester, MA, USA.
AD  - Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research, 
      UMass Chan Medical School, Worcester, MA, USA.
FAU - Mueller, Christian
AU  - Mueller C
AD  - Department of Pediatrics, UMass Chan Medical School, Worcester, MA, USA.
AD  - Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research, 
      UMass Chan Medical School, Worcester, MA, USA.
FAU - Tai, Phillip W L
AU  - Tai PWL
AUID- ORCID: 0000-0001-7409-8344
AD  - Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research, 
      UMass Chan Medical School, Worcester, MA, USA.
FAU - Jiang, Xuntian
AU  - Jiang X
AUID- ORCID: 0000-0001-9048-7294
AD  - Department of Medicine and Cardiovascular Division, Washington University School 
      of Medicine, St. Louis, MO, USA.
FAU - Bateman, Scot
AU  - Bateman S
AD  - Department of Pediatrics, UMass Chan Medical School, Worcester, MA, USA.
FAU - Spanakis, Spiro G
AU  - Spanakis SG
AD  - Departments of Anesthesiology and Perioperative Medicine, UMass Chan Medical 
      School, Worcester, MA, USA.
FAU - Parzych, Julia
AU  - Parzych J
AD  - Departments of Anesthesiology and Perioperative Medicine, UMass Chan Medical 
      School, Worcester, MA, USA.
FAU - Keeler, Allison M
AU  - Keeler AM
AUID- ORCID: 0000-0002-5202-4616
AD  - Department of Pediatrics, UMass Chan Medical School, Worcester, MA, USA.
AD  - Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research, 
      UMass Chan Medical School, Worcester, MA, USA.
FAU - Abayazeed, Aly
AU  - Abayazeed A
AD  - Department of Radiology, UMass Chan Medical School, Worcester, MA, USA.
FAU - Rohatgi, Saurabh
AU  - Rohatgi S
AD  - Department of Radiology, UMass Chan Medical School, Worcester, MA, USA.
FAU - Gibson, Laura
AU  - Gibson L
AD  - Department of Pediatrics, UMass Chan Medical School, Worcester, MA, USA.
AD  - Department of Internal Medicine, UMass Chan Medical School, Worcester, MA, USA.
FAU - Finberg, Robert
AU  - Finberg R
AD  - Department of Internal Medicine, UMass Chan Medical School, Worcester, MA, USA.
FAU - Barton, Bruce A
AU  - Barton BA
AD  - Population and Quantitative Health Sciences, UMass Chan Medical School, 
      Worcester, MA, USA.
FAU - Vardar, Zeynep
AU  - Vardar Z
AUID- ORCID: 0000-0002-7510-9524
AD  - Department of Radiology, UMass Chan Medical School, Worcester, MA, USA.
FAU - Shazeeb, Mohammed Salman
AU  - Shazeeb MS
AD  - Department of Radiology, UMass Chan Medical School, Worcester, MA, USA.
FAU - Gounis, Matthew
AU  - Gounis M
AUID- ORCID: 0000-0002-8034-2785
AD  - Department of Radiology, UMass Chan Medical School, Worcester, MA, USA.
FAU - Tifft, Cynthia J
AU  - Tifft CJ
AD  - National Human Genome Research Institute, National Institutes of Health, 
      Bethesda, MD, USA.
FAU - Eichler, Florian S
AU  - Eichler FS
AD  - Department of Neurology, Massachusetts General Hospital and Harvard Medical 
      School, Boston, MA, USA.
FAU - Brown, Robert H Jr
AU  - Brown RH Jr
AUID- ORCID: 0000-0001-6062-1528
AD  - Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research, 
      UMass Chan Medical School, Worcester, MA, USA.
AD  - Department of Neurology, UMass Chan Medical School, Worcester, MA, USA.
FAU - Martin, Douglas R
AU  - Martin DR
AUID- ORCID: 0000-0002-3444-8407
AD  - Scott-Ritchey Research Center, Department of Anatomy, Physiology and 
      Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, USA.
FAU - Gray-Edwards, Heather L
AU  - Gray-Edwards HL
AD  - Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research, 
      UMass Chan Medical School, Worcester, MA, USA.
AD  - Department of Radiology, UMass Chan Medical School, Worcester, MA, USA.
FAU - Sena-Esteves, Miguel
AU  - Sena-Esteves M
AUID- ORCID: 0000-0003-0854-0143
AD  - Horae Gene Therapy Center and The Li Weibo Institute for Rare Diseases Research, 
      UMass Chan Medical School, Worcester, MA, USA. Miguel.esteves@umassmed.edu.
AD  - Department of Neurology, UMass Chan Medical School, Worcester, MA, USA. 
      Miguel.esteves@umassmed.edu.
LA  - eng
GR  - P30 DK020579/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220210
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Anticonvulsants)
SB  - IM
CIN - Nat Med. 2022 Feb;28(2):236-237. PMID: 35145310
CIN - Nat Rev Genet. 2022 Apr;23(4):197. PMID: 35194181
MH  - Anticonvulsants
MH  - Dependovirus/genetics
MH  - Genetic Therapy
MH  - Humans
MH  - *Tay-Sachs Disease/genetics/therapy
PMC - PMC10786171
MID - NIHMS1954705
COIS- 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.
EDAT- 2022/02/12 06:00
MHDA- 2022/04/27 06:00
PMCR- 2024/01/12
CRDT- 2022/02/11 05:36
PHST- 2021/01/31 00:00 [received]
PHST- 2021/12/17 00:00 [accepted]
PHST- 2022/02/12 06:00 [pubmed]
PHST- 2022/04/27 06:00 [medline]
PHST- 2022/02/11 05:36 [entrez]
PHST- 2024/01/12 00:00 [pmc-release]
AID - 10.1038/s41591-021-01664-4 [pii]
AID - 10.1038/s41591-021-01664-4 [doi]
PST - ppublish
SO  - Nat Med. 2022 Feb;28(2):251-259. doi: 10.1038/s41591-021-01664-4. Epub 2022 Feb 
      10.