1. ¹The Waisman Center, University of Wisconsin–Madison, Madison, Wisconsin, USA
2. ²Stem Cell Research Group, Royal Manchester Children's Hospital, Manchester, UK
3. ³Brain and Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
4. ⁴Department of Anatomy, University of Wisconsin–Madison, Madison, Wisconsin, USA
5. ⁵Department of Neurology, University of Wisconsin–Madison, Madison, Wisconsin, USA

Correspondence: Masatoshi Suzuki, T611 Waisman Center, 1500 Highland Avenue, Madison, Wisconsin 53705-2280, USA. E-mail: suzuki@waisman.wisc.edu or svendsen@waisman.wisc.edu

Received 29 June 2008; Accepted 15 August 2008; Published online 16 September 2008.

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.