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ARRA Investments in Amyotrophic Lateral Sclerosis (ALS)

Public Health Burden
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder in which loss of motor neurons leads to fatal paralysis. ALS is one of the most common neuromuscular diseases worldwide, and people of all races and ethnic backgrounds are affected. An estimated 5, 000 adults in the U.S. are diagnosed with ALS each year. No cure has yet been found, and most people diagnosed with the disease die from respiratory failure within 3 to 5 years from the onset of symptoms.

Disease Mechanisms
Scientists do not fully understand what causes ALS. About 5 to 10 percent of all ALS cases are inherited. The familial form of ALS usually results from a pattern of inheritance that requires only one parent to carry the gene responsible for the disease. ARRA-funded researchers are investigating the genetic contribution to the onset of the disease in both animal models and humans:
  • A challenge grant recipient is producing new animal models of ALS based on mutations found in ALS patients and making them available for the research community to study the mechanism of the disease. This is extremely important, because the single existing animal model is representative of only a small number of ALS cases.1
  • A GO grant recipient is performing full sequencing of the genome in 40 individuals with ALS, in order to identify DNA variants that may contribute to the onset and development of ALS.  This is an important new technology that will allow researchers to discover genes involved in ALS and release the full sequencing data to other ALS research teams.2
No test can provide a definite diagnosis of ALS. With current methods, the average time from onset of symptoms to diagnosis is around 12 months. Improved diagnostic markers may lead to earlier diagnosis, allowing patients to receive early treatments and allowing for clinical trials to begin at an earlier stage of the disease. Although biological markers (biomarkers) that correlate with ALS clinical symptoms have been identified, these findings need to be studied further before they can be used for diagnosis in the clinic. ARRA-funded projects are seeking to address these needs:
  • ARRA-funded researchers are collecting blood samples at ALS clinics throughout the country to confirm that specific antibodies to spinal cord proteins are present only in ALS patients.3
  • To better understand the natural history and onset of ALS symptoms, researchers are using magnetic resonance imaging (MRI) and spectroscopy (MRS) in a rat model to better understand neurochemical markers of ALS pathology, disease progression, and the degeneration of motor circuitry. This study will lead to a set of markers to better quantify disease diagnosis and progression that will be directly applicable to human studies.4
Improving Treatment
Rilutek, the only FDA-approved drug for ALS, is only partially effective, and does not slow the progression of the disease. Scientists are developing and testing novel therapeutic strategies and creating new animal models that can better predict ALS patient responses to therapies. ARRA-funded projects are exploring the following prospective treatments:
  • Researcher are developing silencing RNAs, small molecules that interfere with the expression of genes involved in familial ALS, and testing them in ALS animal models.5
  • Studies are underway to identifying safe and effective compounds that reduce the uptake of the neurotransmitter glutamate into cells, which may prevent the excessive exposure to glutamate that can lead to neuronal injury or death. One project is using the glutamate transporter EAA T2 to enhance glutamate reuptake.6 Another is using high-throughput screening to identify compounds which can activate EAA T2 expression, which regulate the level of neurotransmitter present in the cell.7
  • ARRA-funded researchers are generating a zebrafish model of ALS and using this model to identify new drug targets and test new drugs.8
  • A GO grant recipient is developing new methods to efficiently target neurons involved in movement and their support cells within the brain and spinal cord. These studies are investigating how to deliver genes into motor neurons, in order to develop therapies for motor neuron diseases such as ALS.9
  • ARRA funds are supplementing an ongoing pilot trial to assess the feasibility of performing a large-scale, definitive clinical trial of nocturnal noninvasive positive pressure ventilation (NIPPV) to treat respiratory muscle weakness in ALS patients. This trial is important because respiratory failure is the most common cause of death in ALS patients.10

  1. 1RC1NS068391-01 -- Transgenic Mouse Models of FUS/TLS-Mediated Amyotrophic Lateral Sclerosis- Brown, Robert H; Hayward, Lawrence J (contact); Xu, Zuoshang (MA)
  2. 1RC2NS070342-01 -- Full Human Genome Sequencing in ALS- Brown, Robert H. (MA)
  3. 1RC1NS068179-01 -- Multi-Center Validation of Biomarkers for Motor Neuron Disease- Bowser, Robert P (contact); Cudkowicz, Merit E. (PA)
  4. 1R21NS059644-01A2 -- Functional and Chemical Markers for ALS Progression- Chio, Ji-Kyung (MA)
  5. 1R01NS060856-01A2 -- RNAi-Based Therapy of ALS -- Rana, Tariq (CA)
  6. 1R01NS064275-01A1 -- Translational regulation of glutamate transporter EAAT2 & therapeutic application -- Lin, Chien-Liang Glenn (OH)
  7. 2R01NS044292-07A2 -- Impairment of the glial glutamate transporter GLT1 in ALS- Trotti, Davide (PA)
  8. 1R21NS065153-01 -- Development of a zebrafish assay for the identification of ALS drug targets- Beattie, Christine (OH)
  9. 1RC2NS069476-01 -- Delivery of therapeutic genes in motor neuron disease- Burghes, Arthur H.M. (contact); Cleveland, Don W. (OH)
  10. 3K23NS055200-03S1 -- Pilot Placebo-Controlled Trial of Early Noninvasive Ventilation for ALS- Gruis, Kirsten L. (MI)

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Page Last Updated on June 30, 2018 NIH...Turning Discovery Into Health®