Combined gene/cell therapies provide long-term and pervasive rescue of multiple pathological symptoms in a murine model of globoid cell leukodystrophy

Human Molecular Genetics
Alessandra RiccaAngela Gritti

Abstract

Globoid cell leukodystrophy (GLD) is a lysosomal storage disease caused by deficient activity of β-galactocerebrosidase (GALC). The infantile forms manifest with rapid and progressive central and peripheral demyelination, which represent a major hurdle for any treatment approach. We demonstrate here that neonatal lentiviral vector-mediated intracerebral gene therapy (IC GT) or transplantation of GALC-overexpressing neural stem cells (NSC) synergize with bone marrow transplant (BMT) providing dramatic extension of lifespan and global clinical-pathological rescue in a relevant GLD murine model. We show that timely and long-lasting delivery of functional GALC in affected tissues ensured by the exclusive complementary mode of action of the treatments underlies the outstanding benefit. In particular, the contribution of neural stem cell transplantation and IC GT during the early asymptomatic stage of the disease is instrumental to enhance long-term advantage upon BMT. We clarify the input of central nervous system, peripheral nervous system and periphery to the disease, and the relative contribution of treatments to the final therapeutic outcome, with important implications for treatment strategies to be tried in human patients. Thi...Continue Reading

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Citations

Nov 26, 2015·Human Molecular Genetics·Alessandra Biffi
Mar 24, 2016·Journal of Inherited Metabolic Disease·Stephanie DoovesVivi M Heine
Oct 29, 2015·Molecular Therapy. Methods & Clinical Development·Silvia UngariAlessandra Biffi
Sep 4, 2015·Molecular Therapy : the Journal of the American Society of Gene Therapy·Mohammad A RafiDavid A Wenger
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Sep 18, 2016·Journal of Neuroscience Research·David A WengerPaola Luzi
Feb 9, 2017·Nature Communications·Pietro Giuseppe MazzaraVania Broccoli
May 1, 2020·Frontiers in Molecular Biosciences·Jacob M FavretDaesung Shin
Jul 16, 2016·Human Gene Therapy·Faez Siddiqi, John H Wolfe
Sep 18, 2016·Journal of Neuroscience Research·Alessandra Ricca, Angela Gritti
Nov 8, 2018·International Journal of Molecular Sciences·Chiara ArgentatiSabata Martino
Nov 14, 2019·International Journal of Molecular Sciences·Chiara ArgentatiSabata Martino
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Jan 4, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Yedda LiMark S Sands
Jan 29, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Gregory J HellerErnesto R Bongarzone
Feb 27, 2021·Frontiers in Cellular Neuroscience·Stefanie PerrierGeneviève Bernard
Aug 28, 2021·International Journal of Neonatal Screening·David A WengerMohammad A Rafi
Dec 1, 2016·Neurology. Clinical Practice·Marjo S van der KnaapVivi M Heine

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Methods Mentioned

BETA
transgenic
fluorescence-activated cell sorting
FACS
confocal microscopy
PCR

Software Mentioned

LaserSharp
ACT
Graph Pad Prism
Adobe Photoshop
ImageJ

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