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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 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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Fig. 1: Brain disease at birth in nGD mice.
Fig. 2: Fetal gene therapy of nGD mice.
Fig. 3: Intracerebroventricular and intravenous gene therapy in neonatal nGD mice.
Fig. 4: In utero gene delivery to the macaque brain via ultrasound-guided intracerebroventricular injection of vector.

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S.N.W., A.A.R. and J.D.C. received funding from UK Medical Research Council grant G1000709. S.N.W. received funding from MR/N019075/1 and MR/P026494/1 and SPARKS (17UCL01). A.A.R. and S.N.W. received funding from MRC grants MR/R015325/1 and MR/N026101/1 and NC3Rs grant NC/L001780/1. G.M., A.A.R. and S.N.W. received funding from the UK Gauchers Association. A.A.R. received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 666918 (BATCure), Action Medical Research (GN2485), MRC grant MR/M00676X/1, Asociación Niemann Pick de Fuenlabrada, Niemann-Pick UK, Niemann Pick Research Foundation and the NBIA Disorders Association. S.M.K.B. and S.N.W. received funding from ERC grant ‘Somabio’ 260862. C.N.Z.M. received salary support from the Singapore Ministry of Health’s National Medical Research Council NMRC/TA/0003/2012 and NMRC/CSA-INV/0012/2016. M.H. is supported by Parkinson’s UK grant H-1501. F.M.P. is a Royal Society Wolfson Research Merit Award holder and a Wellcome Trust Investigator in Science. F.M.P. and D.A.P. were supported by the Mizutani Foundation for Glycoscience. J.K.Y.C. is funded by Singapore’s Ministry of Health’s National Medical Research Council NMRC CSA/043/2012, CSA(SI)/008/2016 and CIRG/1459/2016. J.D.C. received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 666918 (BATCure), the Batten Disease Support and Research Association (US) and Batten Disease Family Association (UK). K.M. received funding from the Peto Foundation. S.B. was supported by the National Institute of Health Research (NIHR) UCLH/UCL Biomedical Research Centre. We thank R. Baker, M. Choolani, N. Johana, N. Wen, B. Warburton, S. Richards, T. O’Mahoney, G. Sturges O. Woolmer, E.-H. Davies, T. Collin-Histed, A. Mehta and D. Hughes. Most of all, for guidance, mentorship and inspiration, we thank C. Coutelle.

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Authors and Affiliations



G.M. contributed murine analysis, immunohistochemistry and manuscript drafting. C.N.Z.M. contributed NHP work and manuscript drafting. A.M.S.W. contributed immunohistochemistry. E.S. contributed mass spectrometry. S.M.K.B. contributed murine analysis. B.R.H. contributed murine analysis. S.K. contributed manuscript drafting. D.P.P. contributed murine analysis. D.B. and S.H. contributed blood spots. A.R.-L. contributed immunohistochemistry. S.B. contributed immunohistochemistry and manuscript drafting. M.H. and D.A.P. contributed immunohistochemistry. F.M.P. contributed immunohistochemistry and manuscript drafting. K.M. contributed mass spectrometry and manuscript drafting. A.B. contributed NHP work. J.D.C. contributed immunohistochemistry and manuscript drafting. J.K.Y.C. contributed NHP work and manuscript drafting. S.H.C. contributed vector generation. S.N.W. contributed murine analysis and manuscript drafting. A.A.R. contributed murine analysis, immunohistochemistry and manuscript drafting.

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Correspondence to Simon N. Waddington.

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S.H.C. is an employee at Sanofi, a biopharmaceutical company.

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Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 1–4

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Supplementary Video 1

Treated knockout mouse with two knockout pups

Supplementary Video 2

Behavior of treated knockouts versus age-matched controls

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Massaro, G., Mattar, C.N.Z., Wong, A.M.S. et al. Fetal gene therapy for neurodegenerative disease of infants. Nat Med 24, 1317–1323 (2018).

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