Fetal gene therapy for neurodegenerative disease of infants

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 hepatomegal...

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Main Authors: Massaro, G, Mattar, C, Wong, A, Huebecker, M, Priestman, D, Platt, F, al., E
Format: Journal article
Published: Springer Nature 2018
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author Massaro, G
Mattar, C
Wong, A
Huebecker, M
Priestman, D
Platt, F
al., E
author_facet Massaro, G
Mattar, C
Wong, A
Huebecker, M
Priestman, D
Platt, F
al., E
author_sort Massaro, G
collection OXFORD
description 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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spelling oxford-uuid:805c653c-1d26-42b1-bdc3-91113741f06f2022-03-26T21:22:47ZFetal gene therapy for neurodegenerative disease of infantsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:805c653c-1d26-42b1-bdc3-91113741f06fSymplectic Elements at OxfordSpringer Nature2018Massaro, GMattar, CWong, AHuebecker, MPriestman, DPlatt, Fal., EFor 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.
spellingShingle Massaro, G
Mattar, C
Wong, A
Huebecker, M
Priestman, D
Platt, F
al., E
Fetal gene therapy for neurodegenerative disease of infants
title Fetal gene therapy for neurodegenerative disease of infants
title_full Fetal gene therapy for neurodegenerative disease of infants
title_fullStr Fetal gene therapy for neurodegenerative disease of infants
title_full_unstemmed Fetal gene therapy for neurodegenerative disease of infants
title_short Fetal gene therapy for neurodegenerative disease of infants
title_sort fetal gene therapy for neurodegenerative disease of infants
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