ALS research milestones by decade

1874

French neurologist Jean Martin Charcot establishes amyotrophic lateral sclerosis as a distinct disease

Lou Gehrig made all Americans aware of the devastating effects of ALS.

1900s-1940s

• Cluster of ALS cases identified on Western Pacific island of Guam

• High incidence of ALS noted on Kii Peninsula off Japanese island of Honshu

• New York Yankees first baseman Lou Gehrig retires because of ALS in 1939

• Lou Gehrig dies of ALS in 1941

• ALS becomes widely known as Lou Gehrig’s disease

1950s

• MDA is founded and begins funding ALS research, focusing mainly on basic nervous system physiology

• Eleanor Gehrig, Lou Gehrig’s widow, becomes MDA National Campaign Chairman

1960s

• Studies of nerve-to-muscle signal transmission begin

• Studies continue of microscopic structures of nerve and muscle cells

1970s

• Studies of distribution of ALS cases on the island of Guam and the United States mainland raise questions about the possibility of environmental factors contributing to ALS

• Attempts to isolate viruses from ALS-affected tissue are unrevealing

• Studies continue of muscle and nerve structure and physiology in ALS

1980s

• Clinical trials in people with ALS of thyrotropin-releasing hormone, a substance secreted by the hypothalamus that stimulates the pituitary gland (not effective)

• Attempts to isolate viruses in ALS continue

• Possible role of polio virus infection in ALS ruled out

• Clinical trial of virus-fighting chemicals called interferons (not effective)

• Studies begin of the possible role of autoimmunity (an immune response to the body’s own tissues) in ALS

• Clinical trial of irradiation of lymph nodes, part of the immune system (not effective)

• Clinical trial of immunosuppressant cyclosporine (not effective)

• Studies start of inherited ALS in families with more than one case of the disease

• ALS genetics studied

• Isolation of genes related to ALS attempted

• Clinical trial of growth hormone (not effective)

• Clinical trial of branched chain amino acids (not effective)

• ALS clusters investigated

1990s

MDA research grantee W. King Engel at the University of Southern California in Los Angeles tested thyrotropin-releasing hormone in ALS.

• Clinical trial of immunosuppressant cyclophosphamide (not effective)

• Studies begin of the nervous system chemical glutamate

• Building on glutamate data, riluzole (Rilutek), a glutamate inhibitor, is approved for use in ALS; the drug modestly extends life span

• Clinical trial of gabapentin (Neurontin), a glutamate inhibitor (not effective)

• Factors in nerve cells that make them susceptible to ALS-related damage investigated

• Cellular waste disposal system studied

• Neurotrophic (nerve-nourishing) natural chemicals and spinal motor neurons examined

• Effect studied of immune system proteins taken from blood of those with ALS

• Mutations in the superoxide dismutase 1 (SOD1) gene on chromosome 21 identified as the cause of some inherited forms of ALS

• Mouse with mutated SOD1 gene developed as a research model of ALS

• Building on knowledge that SOD1 has antioxidant properties, many studies begin of free radical activity (which SOD1 combats)

• Clinical trial of SOD1 delivered into spinal fluid (not effective)

• Genetic regulation of programmed cell death, a potential cause of degeneration, investigated

• Study begins to identify ALS risk genes

• An imaging technique called magnetic resonance spectroscopy is used to study the ALS-affected brain

• Scientists transfer neuroprotective genes into mice with an ALS-like disease

• Investigations of the roles of insulin-like growth factor 1 (IGF1), ciliary neurotrophic factor (CNTF), glial-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) lead to industry-sponsored clinical trials of each of these; results from two IGF1 studies were conflicting; none of the other drugs was effective

• Role of motor neurons (nerve cells) versus glia (nervous system support cells) studied in ALS

2000s

• Scientists find that the alsin gene, when flawed, can cause a childhood form of ALS

• Clinical trial conducted of celecoxib (Celebrex), an anti-inflammatory drug (not effective)

• Clinical trials conducted of coenzyme Q10, an antioxidant that acts in cellular energy centers called mitochondria (ineffective)

• Findings suggest people with ALS make a variant form of glutamate transport protein

• Sodium phenylbutyrate and AEOL 10150 together extend life longer than either drug alone in mice with an ALS-like disease

• Flaws in VEGF gene implicated as ALS disease factor

• Flawed senataxin gene identified as a cause of juvenile ALS

• Through its Augie’s Quest research initiative, MDA and the ALS Therapy Development Institute join forces to fund an ALS drug discovery effort

• National Institutes of Health funds trial of ceftriaxone, a possible glutamate transport enhancer, based on MDA-funded basic science research

• Variations in enzymes that help detoxify nerve gas and pesticides linked to ALS

• Clinical trials of high-dose coenzyme Q10, Myotrophin (IGF1) and thalidomide, based on MDA-supported early-stage research, showthese drugs are ineffective in human ALS

• Clinical trial of minocycline, an antibiotic (not effective)

• Trial of lithium carbonate conducted after a small Italian study suggests it may slow ALS progression (not effective)

• Trial of sodium phenylbutyrate shows it was safe and well-tolerated in people with ALS

• An industry-sponsored trial of the glutamate-blocking drug talampanel begins, based on MDA research, showing excess glutamate around nerve cells may contribute to ALS (not effective)

• Researchers find evidence to support the presence of a leakier-than-normal barrier between spinal cord nerve cells and blood vessels in people with ALS

• Scientists create nerve cells from the skin cells of an ALS patient as a way to study disease development on the cellular level

• Investigators find immune system T cells are involved in protecting motor neurons in mice with an ALS-like disease

• An industry-sponsored trial of arimoclomol in the SOD1 form of familial ALS opens at MDA/ALS centers in Atlanta and Boston; the drug is designed to increase levels of molecular “chaperones,” which help cells that are under stress

• Investigators find a variant version of the gene for a protein called KIFAP3 increases survival time in people with ALS by an average of 14 months

• An industry-sponsored clinical trial of stem cells in people with ALS begins at the MDA/ALS Center at Emory University in Atlanta (ongoing)

• Scientists develop mice with a mutation in the TAR DNA binding protein (TDP43) gene, which can cause ALS in humans, giving the field an additional research tool

• Two DNA sequences on chromosome 9 and one on chromosome 19 are found to be significantly different in people with ALS compared to those without the disease

2010s

MDA-supported researcher and clinician Stanley H. Appel was among the first to suspect a major role for the immune system in ALS.

• A study of the safety and possible benefits of a high-fat, high-calorie diet in people with ALS is launched by the MDA ALS Clinical Research Network (ongoing)

• An MDA-supported clinical trial begins of ISIS-SOD1-Rx, designed to block production of toxic SOD1 protein molecules in people with the SOD1-related form of familial ALS (ongoing)

• The MDA-supported ALS Therapy Development Institute finds that its experimental drug ALSTDI-00846, which interrupts one of the activities of the immune system, is beneficial in mice with an ALS-like disease, opening a new avenue of therapeutic investigation

• Emphasis placed on identifying and developing clinical biological indicators called “biomarkers” as a way to derive more reliable results in ALS clinical trials

• Abnormalities in immature ‘NG2+’ nervous system cells in mice with an ALS-like disease appear to play a role in the ALS disease process

• A large-scale study begins to examine the relationship between cell-damaging oxidative stress and the ALS disease process

• Focus of ALS research expands from motor neurons to central nervous system support cells (glia), which include astrocytes, microglia and oligodendrocytes

• TDP43-related biology proves fruitful for uncovering possible disease mechanisms and targets at which to aim experimental therapies in sporadic and some familial forms of ALS

• Researchers identify mutations in the valosin-containing protein (VCP) gene as a cause of some cases of familial ALS

• Scientists find that normally supportive nervous system cells called astrocytes are toxic to motor neurons when taken from people with SOD1-releated ALS or sporadic ALS, supporting the idea that SOD1-related familial ALS and sporadic ALS share disease mechanisms

• In work built on earlier MDA-supported findings, mutations in the ubiquilin 2 gene on the X chromosome are found to cause ALS, and accumulations of the ubiquilin 2 protein, even without gene mutations, also are associated with the disease

• An expanded section of repeated DNA elements on chromosome 9 in a gene called C9ORF72 is identified as the most common known genetic cause of familial ALS, familial frontotemporal dementia (FTD) and ALS with FTD