title: Direct muscle delivery of GDNF with human mesenchymal stem cells improves motor neuron survival and function in a rat model of familial ALS.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which there is a progressive loss of motor neurons and their connections to muscle, leading to paralysis. In order to maintain muscle connections in a rat model of familial ALS (FALS), we performed intramuscular transplantation with human mesenchymal stem cells (hMSCs) used as "Trojan horses" to deliver growth factors to the terminals of motor neurons and to the skeletal muscles. hMSCs engineered to secrete glial cell line-derived neurotrophic factor (hMSC-GDNF) were transplanted bilaterally into three muscle groups. The cells survived within the muscle, released GDNF, and significantly increased the number of neuromuscular connections and motor neuron cell bodies in the spinal cord at mid-stages of the disease. Further, intramuscular transplantation with hMSC-GDNF was found to ameliorate motor neuron loss within the spinal cord where it connects with the limb muscles receiving transplants. While disease onset was similar in all the animals, hMSC-GDNF significantly delayed disease progression, increasing overall lifespan by up to 28 days, which is one of the largest effects on survival noted for this rat model of FALS. This preclinical data provides a novel and practical approach toward ex vivo gene therapy for ALS.
authors.affiliation: The Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin 53705-2280, USA. suzuki@waisman.wisc.edu
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Suzuki
authors.forename: Jacalyn
authors.initials: J
authors.lastname: McHugh
authors.forename: Craig
authors.initials: C
authors.lastname: Tork
authors.forename: Brandon
authors.initials: B
authors.lastname: Shelley
authors.forename: Antonio
authors.initials: A
authors.lastname: Hayes
authors.forename: Ilaria
authors.initials: I
authors.lastname: Bellantuono
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
authors.forename: Clive N
authors.initials: CN
authors.lastname: Svendsen
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D000818:Animals; D002470:Cell Survival; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009046:Motor Neurons / Q000166:cytology* / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009457:Neuroglia / Q000378:metabolism; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D015996:Survival Rate
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; C000606290:SOD1 protein, human; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
references.citation: N Engl J Med. 2001 May 31;344(22):1688-700
references.pmid: 11386269
references.citation: Cell. 2001 Feb 23;104(4):581-91
references.pmid: 11239414
references.citation: J Clin Invest. 2000 Jun;105(12):1669-74
references.pmid: 10862780
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1604-9
references.pmid: 11818550
references.citation: Science. 2003 Aug 8;301(5634):839-42
references.pmid: 12907804
references.citation: J Neurosci. 1996 Apr 1;16(7):2335-41
references.pmid: 8601813
references.citation: J Biol Chem. 2002 Mar 22;277(12):10614-25
references.pmid: 11790765
references.citation: Nat Med. 2003 Dec;9(12):1528-32
references.pmid: 14625543
references.citation: Neuroscience. 2004;128(3):497-509
references.pmid: 15381279
references.citation: J Neurosci. 1999 Nov 1;19(21):9322-31
references.pmid: 10531437
references.citation: Blood. 2004 Nov 1;104(9):2643-5
references.pmid: 15251986
references.citation: Mol Neurobiol. 2001 Aug-Dec;24(1-3):1-28
references.pmid: 11831547
references.citation: Sci Am. 2007 Nov;297(5):86-93
references.pmid: 17990828
references.citation: Expert Opin Biol Ther. 2007 Jul;7(7):965-73
references.pmid: 17665987
references.citation: Hum Gene Ther. 1999 Jul 20;10(11):1853-66
references.pmid: 10446925
references.citation: PLoS One. 2007 Aug 01;2(8):e689
references.pmid: 17668067
references.citation: J Cell Biol. 2003 Mar 17;160(6):909-18
references.pmid: 12629053
references.citation: Science. 1997 Apr 4;276(5309):71-4
references.pmid: 9082988
references.citation: Science. 1994 Jun 17;264(5166):1772-5
references.pmid: 8209258
references.citation: Nature. 1993 Mar 4;362(6415):59-62
references.pmid: 8446170
references.citation: Exp Hematol. 2000 Aug;28(8):875-84
references.pmid: 10989188
references.citation: J Neurosci. 2008 Jan 23;28(4):963-75
references.pmid: 18216204
references.citation: Amyotroph Lateral Scler Other Motor Neuron Disord. 2003 Jun;4(2):62-73
references.pmid: 14506936
references.citation: J Anat. 2003 Jul;203(1):89-99
references.pmid: 12892408
references.citation: J Neurosci. 2006 Aug 23;26(34):8774-86
references.pmid: 16928866
references.citation: J Neurosci. 2001 Aug 15;21(16):6136-46
references.pmid: 11487637
references.citation: Cell. 2002 Nov 15;111(4):589-601
references.pmid: 12437931
references.citation: Cell. 1995 Mar 10;80(5):687-92
references.pmid: 7889564
references.citation: Exp Neurol. 2004 Feb;185(2):232-40
references.pmid: 14736504
references.citation: Stem Cells. 2004;22(5):675-82
references.pmid: 15342932
references.citation: Hum Gene Ther. 2002 Jun 10;13(9):1047-59
references.pmid: 12067438
references.citation: J Histochem Cytochem. 2002 May;50(5):589-610
references.pmid: 11967271
references.citation: Exp Neurol. 2007 Feb;203(2):457-71
references.pmid: 17034790
references.citation: J Neurol Sci. 1986 Apr;73(2):205-17
references.pmid: 3701376
references.citation: Prog Neurobiol. 2008 May;85(1):94-134
references.pmid: 18282652
references.citation: Science. 1999 Apr 2;284(5411):143-7
references.pmid: 10102814
references.citation: Nat Rev Neurosci. 2001 Nov;2(11):806-19
references.pmid: 11715057
references.citation: Dev Biol. 2005 Mar 15;279(2):336-44
references.pmid: 15733662
references.citation: BJOG. 2002 Aug;109(8):952-4
references.pmid: 12197378
references.citation: J Comp Neurol. 2001 Aug 6;436(4):399-410
references.pmid: 11447585
references.citation: Science. 1994 Nov 11;266(5187):1062-4
references.pmid: 7973664
references.citation: Ann Neurol. 2006 Jul;60(1):32-44
references.pmid: 16802299
references.citation: J Cell Biol. 2005 Jan 17;168(2):193-9
references.pmid: 15657392
references.citation: Curr Opin Pharmacol. 2002 Jun;2(3):296-301
references.pmid: 12020474
references.citation: J Comp Neurol. 1998 Feb 2;391(1):42-9
references.pmid: 9527540
references.citation: Science. 1998 Mar 13;279(5357):1725-9
references.pmid: 9497292
references.citation: Hum Gene Ther. 2005 Apr;16(4):509-21
references.pmid: 15871682
references.citation: Mol Ther. 2008 Jun;16(6):1056-64
references.pmid: 18388910
references.citation: Trends Neurosci. 2008 Apr;31(4):192-8
references.pmid: 18329734
references.citation: Amyotroph Lateral Scler. 2007 Feb;8(1):20-5
references.pmid: 17364431