Older Projects

ALS Drug Discovery
The ATA has contributed to the NeuroDiscovery Center at Harvard Medical School. The goal at Harvard is to raise $1.9 million to help launch its ALS drug discovery program, which is projected to start in June of 2008. This new research collaboration will create a robust pipeline of new ALS drug discovery leads and deliver the most promising ideas to industry partners for further development, testing and regulatory approval. The program’s overseers will attract the best ALS drug discovery theories from across the world and ultimately choose eight projects to champion. The principal investigators on those projects will collaborate with the drug discovery experts at the NeuroDiscovery Center’s well-established Laboratory for Drug Discovery in Neurodegeneration (LDDN). For each selected project, a post doctoral scientist will temporarily relocate to the LDDN, taking full advantage of the state-of-the-art robotics and related infrastructure, and working hand in hand with the LDDN’s 14-person, industry-seasoned staff. Close collaboration with the LDDN will ensure that projects receive the support needed to advance through screening, medicinal chemistry, animal testing and development.

Clinical trials of high-dose creatine
ATA funds were awarded in 2006 and disbursed in the spring of 2007 to the Neurology Clinical Trials Unit at the Massachusetts General Hospitalfor a study by Dr. Allitia DiBernardo of potential benefits of high-dose creatine monohydrate in subjects with ALS. Several animal studies have found that creatine increases the available energy to muscles and nerve cells, which helps protect them from injury or premature death. Dr. BiBernardo is testing the hypothesis that augmented energy reserves will be neuroprotective in ALS, ultimately slowing the course of disease progression. The study, an open-label pilot study involving six research participants with ALS who escalated through three different dosage levels, is a prelude to a larger multi-center study of this compound in ALS. Funds were also awarded in 2009 for a trial of the comparative effects of high dose creatine and tamoxifen.  This study employs a novel study design intended to determine which of two drugs appears more beneficial.

The role of ATF3 in motor neuron survival
The ATA contributed funding to Drs. Rhona Seiffers and Clifford Woolf to examine another neuroprotective factor, known as “activating transcription factor-3” or ATF3. These neuroscientists have completed prior studies documenting that high levels of ATF3 in mouse neurons enhance peripheral nerve regeneration after injury and induce genes that mediate nerve survival and growth. Dr. Seiffers had also observed that ATF3 is induced but fails to be maintained in the motor neurons of SOD1G93A mice. This led her to theorize that by turning on sustained, high levels of ATF3 in mice, she could protect motor neurons in the ALS mouse model. Understanding the mechanisms by which molecules like ATF3 govern motor neuron survival will assist in developing a treatment for ALS.

Alternative Splicing Regulation in ALS
Dr. Thomas Maniatis (Columbia University) received funding from the ATA to research how the pathology of a protein known as TDP43 (a molecule that binds DNA and RNA) may lead to ALS. Previous investigators had demonstrated that TDP43 collects in aggregates in ALS motor neurons. Moreover, recent reports have shown that mutations in the TDP43 gene and protein can cause some cases of ALS. To pursue these findings further, Dr. Maniatis’ team will first learn how TDP43 interacts with RNA by profiling a cell culture. That information may translate to biomarkers that will assist with early diagnosis of ALS or potential therapies for people with the disease. The second phase of the project will involve analysis of patient-derived material, using the protocols perfected in cell culture, with the hope that it will identify specific targets of TDP43 whose misregulation reflects or possibly causes ALS. Mice will then be used as animal models to test the role of TDP43 targets in motor neuron degeneration.  Dr. Melissa Moore (University of Massachusetts) has been funded by the ATA to test the hypothesis that levels of transcripts for critical proteins such as TDP43 are regulated by a negative feedback mechanisms involving nonsense mediate decay.  Additional funding has also been award to Dr. Robert Darnell at Rockefeller University to support additional analyses of RNA processing defects in ALS.

Biophysical alterations in the TDP43 protein in ALS
Dr. Jill Zitzewitz (University of Massachusetts Medical School) was awarded funding to study how mutations in the TDP43 protein perturb the folding and stability of TDP43. Dr. Zitzewicz will employ a range of tools that interrogate the physico-chemical properties of TDP43. 

Hydrophobicity of misfolded SOD1 mutants
Drs. Ashutosh Tiwari and Lawrence J. Hayward of the Department of Neurology at UMass Medical Schoolwere awarded ATA monies to study their hypothesis that SOD1 mutant proteins misfold into abnormal structures to promote toxic interactions with other cellular elements and produce motor neuron degeneration, causing a subset of ALS cases. These investigators have developed probes that allow them to study SOD1 in both its normal conformation and in a misfolded state. These scientists learned that mutations in SOD1 that can cause human ALS also promote accelerated misfolding of the protein. They have also created a sensitive assay system to detect such misfolding and to correlate it with the amounts of copper and zinc metals in the SOD1 protein, either in its normal state or with mutations. Results indicate that metal-deficient SOD1 proteins showed increased exposure of normally hidden, internal domains. Moreover, they have found conditions that either intensify or correct the misfolding of mutant SOD1 proteins. Experiments are in progress to map the regions of the protein that misfold using additional probes and a method known as mass spectrometry. It is hoped that additional studies of these toxic conformation(s) and their interactions will provide insight into why mutant SOD1 kills motor neurons and help researchers design therapies to stop the defect.

Axonal transport defects in ALS caused by SOD1 gene mutations
Dr. Gerardo Morfini (University of Illinois) and associates have completed novel studies documenting that mutant SOD1 protein adversely affects axonal transport in the squid giant axon. Dr. Morfini is now funded by the ATA to investigate how specific signaling molecules (e.g. axoplasmic kinases) may mediate this effect of mutant SOD1 protein.

The involvement of DNA variations in ALS
The ATA contributed funding to Dr. John E. Landers and the Center for ALS Genetics in the Day Neuromuscular Laboratory at the Massachusetts General Hospital to use high-throughput technologies to identify gene variants that contribute to the development of ALS, in both is familial and non-familial forms. This team of researchers is using DNA signatures to analyze variations in human DNA and thereby identify such genes. To date, the group has examined 300,000-plus variations in more than 1,800 ALS patients and 2,200 healthy controls for a total of more than one billion variations. The overall goal is to identify variations that are more prevalent within ALS patients as compared to healthy individuals. This increased prevalence is a kind of guilt-by-association that implicates the variants in the disease, either as causative factors or as modifiers of aspects of the disease, such as the rate of its progression. Information gained through this study will lead to a better understanding of the cause of some subsets of ALS and may lead to an earlier diagnosis.

Northeast ALS Consortium (NEALS) Annual Meeting
The Northeast ALS Consortium (NEALS) received monetary support from the ATA for its 6th Annual Meeting in Bostonin September of 2007. More than 100 members from 60 NEALS sites attended the event to learn about new initiatives, findings, training and trials pertaining to ALS research and therapy. The group also discussed five current NEALS clinical projects. These include treatment trials and a study of biomarkers in ALS fluids (serum and spinal fluids). The NEALS Consortium is developing a Web-based platform to gather data for clinical trials and streamline the sharing of pertinent research information between its members. The organization has also created training modules on relevant ALS outcome measures and clinical trial conduct.

Isometric strength testing device to measure ALS progression
The Neurology Clinical Trials Unit at Massachusetts General Hospital is using ATA funding to design and build a muscle strength testing device called the Accurate Test of Limb Isometric Strength (ATLIS). This device uses isometric strength testing to accurately measure modest disease progression rates in ALS patients. This machine, which is more portable and cost-effective than its predecessors, allows evaluators to calculate and digitally capture data that will ultimately help researchers screen potential ALS drugs more efficiently. The Neurology Clinical Trials Unit is currently carrying out validation studies to assess the reliability of ATLIS in healthy adults and patients with ALS.

ALS-SOD1 Database
ATA funding was awarded to Prof. Ammar Al-Chalabi at Kings College in London, that jointly with funding from the ALS Association and the British Motor Neurone Disease association, will support a database that tracks all known mutations in the gene superoxide dismutase. This resource is freely available via the web to any investigators; at present there are more than 155 different mutations tracked in this database.

ALS Biomarkers
Among the most important tools in analysis the causes and activity of a disease is the availability of one or more quantitative biological assays that accurately mirror the disease process.  Such compounds can point to primary triggers of a disorder and also accelerate treatment trials. For this reason, Funding was awarded to Dr. Robert Ferrante at the Bedford Veterans’ Administration Hospitalto undertake additional studies of biomarkers of ALS in human biological specimens (blood, cerebrospinal fluid).  Dr. Merit Cudkowicz (Massachusetts General Hospital) has also received funding to support ALS biomarker studies in large sets of ALS specimens.

Angiogenin in ALS
Recent studies in genetics have implicated defects in the protein angiogenin as a susceptibility factor in ALS. Data suggest that angiogenin may be neuroprotective, acting directly or indirectly to enhance the viability of motor neurons. For this reason, several investigators have examined the potential benefit of angiogenin as a therapeutic in ALS mice. Toward this end, the ATA has funded Dr. Guo-Fu Hu at Harvard Unversity to investigate angiogenin as an ALS therapy using transgenic angiogenin mice.

New small animal models of ALS
One of the more unexpected and provocative recent findings in ALS genetics has been that some ALS cases are caused by mutations in an RNA binding protein known as FUS/TLS. The ATA has supported two projects to develop new small animal models of FUS-mediated ALS. Dr. Greg Petsko (Brandeis University) will study a yeast-based model of FUS pathology, using a system that is readily adapted to high through-put screening of drugs that may be beneficial in this type of ALS.  Dr. Larry Hayward received ATA funding to develop a zebrafish model of FUS pathology. The small size and rapid breeding capacity of zebrafish make this a powerful vertebrate model in which to study the genetics and pathophysiology of a disease like ALS.

Silencing the SOD1 gene
Michele Maxwell (Massachusetts General Hospital) received funding to extend her studies of RNA silencing as an approach to ameliorating ALS caused by neurotoxic mutations in the protein superoxide dismutase.

Analysis of synaptic defects in ALS mice
Drs. Eric Frank (Tufts University) and Zhigang He (Boston Childrens’ Hospital) have received funding for a joint project studying synaptic dysfunction in ALS mice. 

Peripheral nerve inflammation in ALS mice
One of the more important observations in ALS research in the last five years has been the finding that reactive, inflammatory cells are activated in ALS and, importantly, that these cells contribute to the demise of motor neurons.  A related recent observation is that this process of neuroinflamation arises not only in the central nervous system, but also in the peripheral nervous system, along the motor nerves.  Drs. Isaac Chiu and Tom Maniatis were awarded ATA funding to determine whether suppression of peripheral inflammation is beneficial in ALS mice.