The ALS Association’s TREAT ALS (Translational Research Advancing Therapies for ALS) Portfolio is a research endeavor enabling important global research to progress from the laboratory to the bedside. The focus of the program is to support novel ideas, build tools, partner with academia and industry to identify new potential therapies, and support the infrastructure for clinical trials with the goal to find meaningful treatments and a cure for ALS. The Association is pleased to announce a number of new grants focused on identifying new genes linked to the disease, the development of animal models following on from the recent exciting finding of mutations in C9orf72 linked to greater than 25% of familial ALS cases, the identification of novel compounds through the development of models systems in a dish, the identification of biomarkers for ALS, and important clinical studies to help develop treatments for the disease.
Genome wide Association and Exomic Sequencing in Ashkenazi Jews with Amyotrophic Lateral Sclerosis
Dan McGowan, M.D., Albert Einstein College of Medicine at Beth Israel Medical Center, New York, NY
Stephen Scelsa, M.D., Albert Einstein College of Medicine at Beth Israel Medical Center, New York, NY
Funding provided by The Greater New York Chapter of The ALS Association
Genetic causes have been determined in a 5-10% of ALS patients. The most common genetic mutation is in a gene called C9orf72 followed by Superoxide Dismutase-1 (SOD-1), Fused in Sarcoma, (FUS), TAR DNA binding protein 43, (TDNABP-43), Valsolin containing protein, (VCP), and Optineurin, (OPN), genes. These are the most frequently reported genetic mutations that have been found to cause ALS. Most, more than 90%, of ALS cases appear to be sporadic with no reported family history. The study of human genetics has been revolutionized by sequencing of the entire human genome with the newer techniques of genome wide association studies, GWAS, and exomic sequencing. GWAS may be used in large populations of patients to compare the frequency of shared DNA sequences in patients compared with controls, narrowing down the area of the genome that may harbor a disease causing mutation. The study of genetically homogenous groups, such as Ashkenazim, increases the odds of finding such a sequence in a much smaller number of patients. Indeed similar studies by Bryan Traynor, M.D. at NIA focusing on the Finnish population led to the identification of mutations on chromosome 9 (C9orf72) accounting for 50 % of the Finnish population.
Mechanisms for Stimulating Proteosomal and Autophagic Degradation to Clear Misfolded Protein
Alfred Goldberg, Ph.D. Harvard Medical School, Boston, MA
Jinghui Zhao, Ph.D. Harvard Medical School, Boston, MA
Funding provided by The Greater Philadelphia Chapter of The ALS Association
Amyotrophic lateral sclerosis (ALS) is one of several major neurodegenerative diseases that result from an accumulation of misfolded aggregation-prone proteins. The ubiquitin-proteasome pathway and the autophagy-lysosome pathway are the cell’s two major protein degradative systems, and both appear to be important in host defense against the accumulation of such potentially toxic molecules. Identification of selective and safe means to activate the ubiquitin-proteasome pathway and/or autophagy could be of great value for prevention or slowing the progression of ALS. However, this endeavor has been hindered by our lack of understanding of the molecular mechanisms by which these two proteolytic systems are regulated. The investigators recent studies have established that these two proteolytic systems are coordinately regulated and suggest several novel ways to enhance proteolysis by the proteasome and/or autophagy. They propose to investigate in depth the biochemical mechanisms underlying these new modes of regulating proteolysis and to determine whether these mechanisms can enhance the clearance by neurons of aggregation-prone proteins implicated in ALS.
Autophagy as a Therapeutic Target for ALS
Steven Finkbeiner, M.D., Ph.D. Gladstone Institute of Neurological Disease, San Francisco, CA
Funding provided by the Golden West Chapter of The ALS Association
Autophagy is a pathway in healthy cells that removes damaged or worn out proteins and organelles, including mitochondria. Abnormal protein aggregation is found in several neurodegenerative diseases including ALS. The investigators recently discovered a series of small molecules, some of which are FDA approved drugs, which stimulate autophagy in neurons, including human neurons made from induced pluripotent stem cells from healthy volunteers. They tested them in one neurodegenerative disease called Huntington’s disease, and they promoted the clearance of misfolded protein and protected neurons from neurodegeneration. In this proposal, they will investigate the role of autophagy in models of ALS. The investigators have developed primary neuron models of ALS based on familial mutations in TDP43. They will investigate the pathways in neurons by which these proteins are cleared and will test whether the autophagy inducers that they have discovered protect neurons from degeneration induced by ALS-associated forms of TDP43. If successful, these studies would provide evidence that stimulation of autophagy could be a beneficial therapeutic strategy for ALS and justify further development of autophagy stimulators as therapies.
Evaluation of Banyan Biomarkers in ALS
Andreas Jeromin, Ph.D., Banyan Biosciences Inc, Alachua, Florida
This pilot study is to determine utility of Banyan Biomarkers as diagnostic and surrogate markers of disease progression for Amyotrophic lateral sclerosis (ALS). ALS is an adult-onset, rapidly progressive and fatal neurodegenerative disease characterized by selective death of motor neurons in the cortex, brainstem and spinal cord that causes muscle weakness, atrophy and spasticity. Since the only diagnosis of ALS is neuropathologic and there is a delay of about one year from onset of symptoms to diagnosis, early diagnostic biomarkers would not only prove useful for detecting disease in those at risk before clinical symptoms appear, but also would help in development of therapies, risk assessment management and patient care planning. The study proposed intends to determine whether quantitative measurement of CNS-enriched proteins detected in biofluids (CSF and serum) by ELISA can be correlated with disease onset and/or progression. The selected biomarkers are proteins normally localized to neurons and glia that have been shown to translocate to biofluids upon CNS injury reflecting neuropathology. Development of early diagnostic or surrogate disease progression biomarkers of this and other chronic neurological disorders would be clinically revolutionary.
Developing Cellular and Animal Models of mutant C9orf72 mediated ALS-FTD
Chris Shaw, M.D., The Institute of Psychiatry, King's College London, London, UK
Pieter de Jong, Ph.D., Children’s Hospital & Research Center Oakland, CA
Robert Brown, Jr., M.D., Univ Mass Medical School, North Worcester, MA
There are no effective treatments for ALS because so little is known about what causes it. Most ALS is sporadic, occurring out of the blue, but in 10% of cases it runs in families (familial ALS) due to a single defective gene, passed down from generation to generation. Until very recently, only three genes were known to cause ALS named SOD1, TARDBP and FUS. Each of these genes was first discovered by two of the Investigators for this project, Robert Brown, M.D. and Chris Shaw, M.D. Mutations in these three genes account for ~25% of all familial and~5% of all sporadic ALS cases. In the last few months a massive DNA expansion has been identified in the C9orf72 gene. This expansion mutation is detected in >25% familial and ~10% of sporadic ALS cases, making it the most common known cause of ALS and a related condition known as fronto-temporal dementia (FTD). DNA is made up from four different bases named C, A, T and G which are copied to make mRNA, which is the genetic blueprint telling the cell how to make a specific protein. The new expansion mutation involves a stretch of six DNA bases (GGGGCC), which is repeated between 600 and 1,000 times in the C9orf72 gene. When the ALS-linked C9orf72 gene is read, it contains this abnormal stretch within its mRNA. This may cause ALS and FTD by disrupting protein synthesis or by being directly toxic to neurons. The purpose of this study is to discover how the expansion mutation in C9orf72 is causing neurons to degenerate by develop cellular and animal models of disease. From an earlier ALSA-funded project the other applicant Pieter De Jong, Ph.D. has managed to clone the massive expansion mutation by cutting out DNA fragments from patient cells. He has exceptional expertise in manipulating these clones so that they can be injected into the DNA of cells and animals. Working with Brown and Shaw, De Jong will develop disease models in neurons derived from mouse and human embryonic stem cells. They will also generate fruit fly, zebrafish and mouse models of disease by knocking down the C9orf72 gene or expressing the human copy carrying the expansion mutation. Each of these cellular and animal models will contribute to our understanding of precisely how the expansion mutation damages neurons and will be used to accelerate drug discovery programs to find a cure for ALS and FTD.
Cervical Intraspinal Human Neural Stem Cell Transplantation for the Treatment of ALS
Eva Feldman, M.D., University of Michigan, Anne Arbor, MI
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with no effective treatments. Introduction of human spinal cord derived stem cells (HSSCs) into the spinal cord of ALS patients represents a potentially powerful way to prevent motor neuron death and prolong life. This study is a continuation of the currently ongoing Neuralstem trial at Emory University, Atlanta, Georgia. This Phase 1b trial will determine the safety and maximum tolerated dose of HSSC injections into the cervical spinal cord of ALS patients, directed at preserving the motor neurons that control breathing. This Phase 1b trial is a necessary stepping stone toward more definitive therapeutic trials of HSSCs in patients with ALS. Pre-clinical and clinical studies strongly support the feasibility and approach in the proposed studies. Pre-clinical studies demonstrated that multiple intraspinal cell injections along cervical segments are safe and feasible for human testing. In the current Phase 1 trial, investigators have shown that lumbar multi-level intraspinal transplantation of HSSCs is safe in humans with ALS. The investigators will increase the number of HSSCs delivered to the cervical cord; however, there will be no change in the fluid volume used for each injection. HSSCs will be injected into C3-C5 cervical cord segments in escalating doses from 5 x 105 total cells in 5 injections up to 4 x 106 total cells in 20 injections. Dose-escalation will be graded across 5 groups of 3 patients each for a maximum of 15 ALS patients. Subjects will be assessed for adverse events including pain and infection, neurologic function, and quality of life in order to determine the maximum tolerated dose and safety of intraspinal HSSC transplantation.
The Experimental Treatment of Bulbar Dysfunction in ALS
Richard Smith, M.D., Center for Neurologic Study, San Diego, CA
Muscle weakness, the cardinal feature of ALS, leads to progressive loss of motor function affecting the limbs, tongue, respiratory and pharyngeal muscles. Symptomatic treatments such as the placement of a feeding tube can compensate for the inability to swallow. Riluzole, the only approved treatment for ALS, may slow disease progression, but no treatment is curative, and none have improved function. Unexpectedly, a drug (Nuedexta) that is approved for the treatment of labile emotionality that occurs in association with ALS and other neurological disorders has been observed to improve bulbar function, primarily speech and swallowing, in a number of neurological disorders, including ALS. The basis for this is conjectural but likely due to a direct effect of the drug on motor neurons in the part of the brain that controls speech and swallowing. The same part of the brain appears to modulate the expression of emotions, and, interestingly, the site of action of the drug is the same as a site that has been implicated in a juvenile form of ALS. Since the effect of Nuedexta on speech and swallowing has not been rigorously evaluated, a clinical trial has been designed to scientifically determine the effect of Nuedexta on bulbar functions. If successful, the study should provide new insight into ALS and its treatment. The study is being funded in partnership with The North East ALS Consortium and will make use of the TREAT ALS/ NEALS Clinical Trials Network.