Expression of human beta-hexosaminidase alpha-subunit gene (the gene defect of Tay-Sachs disease) in mouse brains upon engraftment of transduced progenitor cells

Nature Medicine
H D LacorazzaM Jendoubi

Abstract

In humans, beta-hexosaminidase alpha-subunit deficiency prevents the formation of a functional beta-hexosaminidase A heterodimer resulting in the severe neurodegenerative disorder, Tay-Sachs disease. To explore the feasibility of using ex vivo gene transfer in this lysosomal storage disease, we produced ecotropic retroviruses encoding the human beta-hexosaminidase alpha-subunit cDNA and transduced multipotent neural cell lines. Transduced progenitors stably expressed and secreted high levels of biologically active beta-hexosaminidase A in vitro and cross-corrected the metabolic defect in a human Tay-Sachs fibroblasts cell line in vitro. These genetically engineered CNS progenitors were transplanted into the brains of both normal fetal and newborn mice. Engrafted brains, analyzed at various ages after transplant, produced substantial amounts of human beta-hexosaminidase alpha-subunit transcript and protein, which was enzymatically active throughout the brain at a level reported to be therapeutic in Tay-Sachs disease. These results have implications for treating neurologic diseases characterized by inherited single gene mutations.

References

Nov 15, 1985·The Biochemical Journal·T WilemanP Stahl
Jun 1, 1994·Experimental Neurology·R AntonR H Edwards
Apr 24, 1995·Biochimica Et Biophysica Acta·V Gieselmann
Oct 11, 1994·Proceedings of the National Academy of Sciences of the United States of America·S YamanakaR L Proia
Nov 1, 1993·Archives of Neurology·S T Suhr, F H Gage

❮ Previous
Next ❯

Citations

Mar 16, 2011·Archives of Neurology·Steven A Goldman
Feb 1, 1996·Molecular Neurobiology·S R Whittemore, E Y Snyder
Aug 2, 2007·Journal of Applied Genetics·Iram AhmadRobert P Erickson
Mar 9, 2007·Neuroradiology·Letterio S Politi
Feb 18, 2010·Journal of Inherited Metabolic Disease·Raphael Schiffmann
May 18, 2011·Journal of Inherited Metabolic Disease·Kim M Hemsley, John J Hopwood
Sep 10, 2011·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Lamya S Shihabuddin, Seng H Cheng
Nov 5, 2003·Brain Research. Molecular Brain Research·Stephanos KyrkanidesHoward J Federoff
May 24, 2005·Brain Research. Molecular Brain Research·Ines RichardUdo Bartsch
Oct 9, 2007·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Jaime Imitola
Apr 9, 2002·Lancet·Dennis A Steindler, David W Pincus
Apr 12, 2002·Brain Research. Developmental Brain Research·Laura ColombaioniMercedes Garcia-Gil
Nov 19, 1997·Trends in Neurosciences·A Martínez-Serrano, A Björklund
Aug 16, 2000·Advanced Drug Delivery Reviews·P A TrescoM D Noble
Dec 29, 2000·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·C Caillaud, L Poenaru
May 8, 1998·Molecular Medicine Today·C Chavany, M Jendoubi
May 18, 1999·Molecular Medicine Today·M C Senut, F H Gage
Mar 29, 2012·Molecular Therapy : the Journal of the American Society of Gene Therapy·M Begoña Cachón-GonzálezTimothy M Cox
Jul 29, 2005·Nature Reviews. Neuroscience·Mylvaganam JeyakumarFrances M Platt
Jun 9, 1999·Proceedings of the National Academy of Sciences of the United States of America·B D YandavaE Y Snyder
Mar 28, 2002·Human Gene Therapy·Gary HsichXandra O Breakefield
Feb 24, 2004·Journal of Hematotherapy & Stem Cell Research·Stanley E Lazic, Roger A Barker
Jul 18, 2008·Human Molecular Genetics·Steven A GoldmanMartha S Windrem
Sep 4, 2003·The Cancer Journal·Stephen YipEvan Y Snyder
Jun 14, 2003·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Volkmar GieselmannKlaus Harzer
Aug 31, 2006·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Steven A Goldman, Martha S Windrem
Dec 21, 2012·Science Translational Medicine·Yang D TengEvan Y Snyder
Nov 15, 2006·Annual Review of Medicine·Ilyas SingecEvan Y Snyder
May 27, 2004·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Timothy P Harrower, Roger A Barker
May 12, 2010·Regenerative Medicine·Kevin KempAlastair Wilkins
Mar 18, 2008·Neurosurgical Focus·Gregory M Enns, Stephen L Huhn
Jul 10, 2003·Lancet Neurology·Mark H Tuszynski
May 27, 2014·Brain Research·Donald G Phinney, Iryna A Isakova
Aug 28, 2014·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Casey A MaguireXandra O Breakefield
Oct 23, 1997·Proceedings of the National Academy of Sciences of the United States of America·E Y SnyderJ D Macklis

❮ Previous
Next ❯

Related Concepts

Related Feeds

Adult Stem Cells

Adult stem cells reside in unique niches that provide vital cues for their survival, self-renewal, and differentiation. They hold great promise for use in tissue repair and regeneration as a novel therapeutic strategies. Here is the latest research.

CREs: Gene & Cell Therapy

Gene and cell therapy advances have shown promising outcomes for several diseases. The role of cis-regulatory elements (CREs) is crucial in the design of gene therapy vectors. Here is the latest research on CREs in gene and cell therapy.