ALS Milestones Timeline

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

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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 familial ALS (where there is a history of ALS in more than one family member)

• 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

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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 (muscle-controlling nerve cells) versus glia (nervous system support cells) studied in ALS

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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

• 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 (not effective)

• 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

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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)

• A clinical trial shows that the "antisense" therapy ISIS-SOD1-Rx, designed to block production of toxic SOD1 protein molecules in people with the SOD1-related form of familial ALS, is well-tolerated

• The MDA-supported ALS Therapy Development Institute opens a new avenue of therapeutic investigation after findings show that blocking the immune system CD4OL pathway delays disease onset and extends survival in mice with an ALS like disease

• 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 and sporadic ALS, familial frontotemporal dementia (FTD) and ALS with FTD

• Mutations in the profilin 1 (PFN1) gene are identified as the cause of familial ALS in 1 to 2 percent of people with the disease

• A clinical trial is launched to determine whether the NeuRx Diaphragm Pacing System, an implanted device that stiumulates the diaphragm muscle, can improve respiratory function and quality of life in people with ALS (ongoing)

• Low levels of Immune system cells known as regulatory T cells — T-regs for short — and reduced FOXP protein production are associated with faster disease progression

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