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Fetal gene therapy for neurodegenerative disease of infants

Massaro, Giulia; Mattar, Citra N.Z.; Wong, Andrew M.S.; Sirka, Ernestas; Buckley, Suzanne M.K.; Herbert, Bronwen R.; Karlsson, Stefan LU ; Perocheau, Dany P.; Burke, Derek and Heales, Simon, et al. (2018) In Nature Medicine 24(9). p.1317-1323
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... (More)

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.

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Nature Medicine
volume
24
issue
9
pages
1317 - 1323
publisher
Nature Publishing Group
external identifiers
  • scopus:85049956315
ISSN
1078-8956
DOI
10.1038/s41591-018-0106-7
language
English
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yes
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9aed14ae-16c5-4324-9db4-84abca2428c6
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2018-08-01 13:44:43
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2019-08-25 05:05:37
@article{9aed14ae-16c5-4324-9db4-84abca2428c6,
  abstract     = {<p>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 apnea<sup>1</sup>. 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 days<sup>2</sup>. 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.</p>},
  author       = {Massaro, Giulia and Mattar, Citra N.Z. and Wong, Andrew M.S. and Sirka, Ernestas and Buckley, Suzanne M.K. and Herbert, Bronwen R. and Karlsson, Stefan and Perocheau, Dany P. and Burke, Derek and Heales, Simon and Richard-Londt, Angela and Brandner, Sebastian and Huebecker, Mylene and Priestman, David A. and Platt, Frances M. and Mills, Kevin and Biswas, Arijit and Cooper, Jonathan D. and Chan, Jerry K.Y. and Cheng, Seng H. and Waddington, Simon N. and Rahim, Ahad A.},
  issn         = {1078-8956},
  language     = {eng},
  number       = {9},
  pages        = {1317--1323},
  publisher    = {Nature Publishing Group},
  series       = {Nature Medicine},
  title        = {Fetal gene therapy for neurodegenerative disease of infants},
  url          = {http://dx.doi.org/10.1038/s41591-018-0106-7},
  volume       = {24},
  year         = {2018},
}