Motor Neuron Diseases

National Institute of Neurological Disorders and Stroke NINDS Research
The NINDS supports a broad range of research aimed at discovering the cause(s) of MNDs, finding better treatments, and, ultimately, preventing and curing the disorders. Various MND animal models (animals that have been designed to mimic the disease in humans) are being used to study disease pathology and identify chemical and molecular processes involved in cellular degeneration.

Research options fall largely into three categories:  drugs, growth factors, and stem cells.

Clinical trials (using human participants) are testing whether different drugs are safe and effective in slowing the progression of MNDs.  Drugs currently under investigation include creatine (a naturally occurring substance that may slow neurodegeneration) and coenzyme Q10 (an antioxidant that may slow neuronal death).

• The amino acid creatine and the antibiotic minocycline, which have been studied in animal models, can significantly slow neurodegeneration, improve motor performance, and prolong survival. Clinical trials of the drugs, sponsored by the NINDS, will measure change in motor function, strength, pulmonary function, survival, and quality of life.
• The antibiotic ceftriaxone has been shown to protect nerves by reducing glutamate toxicity -- believed by many scientists to play a critical role in the development of ALS -- in a mouse model of the disease. One study found that cellular ability to manage glutamate can alter the course of ALS. A multi-center human clinical trial of ceftriazone is being planned.
• Interrupting the inflammation process -- which plays an important role in the development and course of ALS -- might improve outcome in ALS patients. Research using mice found that the anti-inflammatory drug pioglitazone improved motor performance and reduced weight loss and the loss of motor neurons. Another study found that the drug also slowed disease progression. Pioglitazone is well tolerated in humans and is currently used to treat diabetes.
• Increased doses of vitamins E and C may benefit some patients, according to studies using animal models of MND. Additional research is needed before vitamin therapy is tested in humans.

Growth factors are proteins that aid cell survival. Growth factors have had some success in fighting MNDs. Investigators overseas found that vascular endothelial growth factor (VEGF) delivered to spaces in the brain can delay symptom onset in a rat model of ALS.

• Scientists are studying a number of possible treatments for PPS, including a number of growth factors such as insulin-like growth factor (IGF-1). IGF-1 is essential for normal development of the nervous system and has been shown to protect motor neurons in animal models and cell culture studies. Scientists are also trying to determine if there is an immunological link to PPS. And some experimental drug treatments, including pyridostigmine and seligiline, show promise in treating symptoms of PPS.
• Researchers also hope to determine whether IGF-1 slows progression of weakness in ALS.
• Scientists are studying how neurotrophic factors may be used to fight MNDs. Neurotrophic factors are chemicals found in the brain and spinal cord that are essential to neuron development and protection. The drug xaliproden may improve the release of neurotrophic factors. Ciliary neurotrophic factor and brain-derived neurotrophic factor have been shown to slow neuron degeneration in animal models but are not effective in humans.

Cellular and molecular studies, some of which involve stem cells, seek to understand the mechanisms that trigger selective motor neurons to degenerate. This work includes studies in animals to identify the means by which SOD1 mutations lead to the destruction of neurons.

• In July 2006, NINDS-funded scientists announced a study in which -- for the first time -- transplanted embryonic stem cell-derived motor neurons connected with muscle in the spinal cords of adult paralyzed rats to restore limited function. The researchers used a combination of transplanted motor neurons, drugs that block naturally occurring signals that hinder axon grown, and a nerve growth factor to attract axons to muscles. The preliminary results of this study will be tested in larger animals to determine if the nerves can reconnect over longer distances and to insure that the treatment is safe before any trials in humans can begin. Results suggest that similar techniques may be useful for treating other conditions such as spinal cord injury, transverse myelitis, ALS, and SMA.
• Researchers have used gene therapy to halt motor neuron destruction and slow disease progression in a mouse model of inherited ALS. Cell culture experiments have shown increased production of the proteins that can reduce the severity of the disease following gene therapy on skin cells of patients with SMA.
• An international study found that RNA interference-used to target and silence a messenger gene-can improve motor neuron survival in a mouse model of ALS.
• The excessive accumulation of free radicals, which has been implicated in a number of neurodegenerative diseases including ALS, is being closely studied. Free radicals are highly reactive molecules that bind with other body chemicals and are believed to contribute to cell degeneration, disease development, and aging.