angiogenin and Motor-Neuron-Disease

Motor neuron disorders (MND) form a heterogeneous group of neurodegenerative affections: phenotypic description is based on selective injury to the upper motor neuron or lower motor neuron or both. Phenotypic heterogeneity is also present concerning genetic features: genetic factors involved in MND may be causative or susceptibility factors. Consequences of genetic abnormalities lead to metabolic or functional cellular disturbances that are apparently specific for motor neuron disorder. Genetics greatly contribute to our understanding of the pathophysiological mechanisms of motor neuron degeneration. Genetic studies provide pathological hypotheses considering the function of protein encoded. Moreover, when a gene mutation is identified, animal models can be developed to search for modifications induced by the mutation. We propose to detail causative and susceptibility genetic factors involved in MND and to discuss pathological mechanisms that may explain motor neuron death.

Topics: Adaptor Proteins, Signal Transducing; Amyotrophic Lateral Sclerosis; Guanine Nucleotide Exchange Factors; Humans; Motor Neuron Disease; Motor Neurons; Ribonuclease, Pancreatic; Spinal Cord Diseases; Superoxide Dismutase; Superoxide Dismutase-1

Motor neuron disease (MND), or amyotrophic lateral sclerosis, is a fatal neurodegenerative disorder characterized by a progressive loss of motor neurons in the spinal cord and the brain. Several angiogenic and neurogenic growth factors, such as the vascular endothelial growth factor (VEGF), angiogenin (ANG), insulin-like growth factor (IGF) and others, have been shown to promote survival of the spinal motor neurons during ischemia. We constructed recombinant vectors using human adenovirus 5 (Ad5) carrying the VEGF, ANG or IGF genes under the control of the cytomegalovirus promoter. As a model for MND, we employed a transgenic mice strain, B6SJL-Tg (SOD1*G93A)d11 Gur/J that develops a progressive degeneration of the spinal motor neurons caused by the expression of a mutated Cu/Zn superoxide dismutase gene SOD1. Delivery of the therapeutic genes to the spinal motor neurons was done using the effect of the retrograde axonal transport after multiple injections of the Ad5-VEGF, Ad5-ANG and Ad5-IGF vectors and their combinations into the limbs and back muscles of the SOD1(G93A) mice. Viral transgene expression in the spinal cord motor neurons was confirmed by immunocytochemistry and RT-RCR. We assessed the neurological status, motor activity and lifespan of experimental and control animal groups. We discovered that SOD1(G93A) mice injected with the Ad5-VEGF + Ad5-ANG combination showed a 2-3 week delay in manifestation of the disease, higher motor activity at the advanced stages of the disease, and at least a 10% increase in the lifespan compared to the control and other experimental groups. These results support the safety and therapeutic efficacy of the tested recombinant treatment. We propose that the developed experimental MND treatment based on viral delivery of VEGF + ANG can be used as a basis for gene therapy drug development and testing in the preclinical and clinical trials of the MND.

Topics: Adenoviridae; Animals; Disease Models, Animal; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Mice; Mice, Transgenic; Motor Neuron Disease; Motor Neurons; Ribonuclease, Pancreatic; Somatomedins; Spinal Cord; Vascular Endothelial Growth Factor A