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Nat Med. 2018 Sep;24(9):1317-1323. doi: 10.1038/s41591-018-0106-7. Epub 2018 Jul 16.

Fetal gene therapy for neurodegenerative disease of infants.

Author information

1
UCL School of Pharmacy, University College London, London, UK.
2
Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
3
Department of Basic and Clinical Neuroscience, King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, UK.
4
UCL Great Ormond Street Institute of Child Health, University College London, London, UK.
5
UCL Institute for Women's Health, University College London, London, UK.
6
Institute for Reproductive and Developmental Biology, Imperial College London, London, UK.
7
Division of Molecular Medicine and Gene Therapy, Lund University, Lund, Sweden.
8
Paediatric Laboratory Medicine, Great Ormond Street Hospital and UCL Great Ormond Street Institute of Child Health, London, UK.
9
Department of Neurodegenerative Disease, UCL Institute of Neurology, University College London, London, UK.
10
Department of Pharmacology, University of Oxford, Oxford, UK.
11
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, David Geffen School of Medicine, University of California Los Angeles, Torrance, CA, USA.
12
Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
13
Department of Reproductive Medicine, KK Women's and Children's Hospital, Singapore, Singapore.
14
Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
15
Sanofi, Framingham, MA, USA.
16
UCL Institute for Women's Health, University College London, London, UK. s.waddington@ucl.ac.uk.
17
MRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of the Witswatersrand, Johannesburg, South Africa. s.waddington@ucl.ac.uk.

Abstract

For inherited genetic diseases, fetal gene therapy offers the potential of prophylaxis against early, irreversible and lethal pathological change. To explore this, we studied neuronopathic Gaucher disease (nGD), caused by mutations in GBA. In adult patients, the milder form presents with hepatomegaly, splenomegaly and occasional lung and bone disease; this is managed, symptomatically, by enzyme replacement therapy. The acute childhood lethal form of nGD is untreatable since enzyme cannot cross the blood-brain barrier. Patients with nGD exhibit signs consistent with hindbrain neurodegeneration, including neck hyperextension, strabismus and, often, fatal apnea1. We selected a mouse model of nGD carrying a loxP-flanked neomycin disruption of Gba plus Cre recombinase regulated by the keratinocyte-specific K14 promoter. Exclusive skin expression of Gba prevents fatal neonatal dehydration. Instead, mice develop fatal neurodegeneration within 15 days2. Using this model, fetal intracranial injection of adeno-associated virus (AAV) vector reconstituted neuronal glucocerebrosidase expression. Mice lived for up to at least 18 weeks, were fertile and fully mobile. Neurodegeneration was abolished and neuroinflammation ameliorated. Neonatal intervention also rescued mice but less effectively. As the next step to clinical translation, we also demonstrated the feasibility of ultrasound-guided global AAV gene transfer to fetal macaque brains.

PMID:
30013199
PMCID:
PMC6130799
DOI:
10.1038/s41591-018-0106-7
[Indexed for MEDLINE]
Free PMC Article

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