title: Synergistic effects of GDNF and VEGF on lifespan and disease progression in a familial ALS rat model.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons in the brain and spinal cord. We have recently shown that human mesenchymal stem cells (hMSCs) modified to release glial cell line-derived neurotrophic factor (GDNF) decrease disease progression in a rat model of ALS when delivered to skeletal muscle. In the current study, we determined whether or not this effect could be enhanced by delivering GDNF in concert with other trophic factors. hMSC engineered to secrete GDNF (hMSC-GDNF), vascular endothelial growth factor (hMSC-VEGF), insulin-like growth factor-I (hMSC-IGF-I), or brain-derived neurotrophic factor (hMSC-BDNF), were prepared and transplanted bilaterally into three muscle groups. hMSC-GDNF and hMSC-VEGF prolonged survival and slowed the loss of motor function, but hMSC-IGF-I and hMSC-BDNF did not have any effect. We then tested the efficacy of a combined ex vivo delivery of GDNF and VEGF in extending survival and protecting neuromuscular junctions (NMJs) and motor neurons. Interestingly, the combined delivery of these neurotrophic factors showed a strong synergistic effect. These studies further support ex vivo gene therapy approaches for ALS that target skeletal muscle.
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Krakora
authors.forename: Patrick
authors.initials: P
authors.lastname: Mulcrone
authors.forename: Michael
authors.initials: M
authors.lastname: Meyer
authors.forename: Christina
authors.initials: C
authors.lastname: Lewis
authors.forename: Ksenija
authors.initials: K
authors.lastname: Bernau
authors.forename: Genevieve
authors.initials: G
authors.lastname: Gowing
authors.forename: Chad
authors.initials: C
authors.lastname: Zimprich
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
authors.forename: Clive N
authors.initials: CN
authors.lastname: Svendsen
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Suzuki
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000401:mortality; D000818:Animals; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics*; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism; D051381:Rats; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D042461:Vascular Endothelial Growth Factor A