WHAT RESEARCH IS BEING DONE?
Scientists are seeking to understand the mechanisms that selectively trigger motor neurons to degenerate in ALS, and to find effective approaches to halt the processes leading to cell death. This work includes studies in animals to identify the molecular means by which ALS-causing gene mutations lead to the destruction of neurons. To this end, scientists have developed models of ALS in a variety of animal species, including fruit flies, zebrafish, and rodents. Initially, these genetically modified animal models focused on mutations in the SOD1 gene but more recently, models harboring other ALS-causing mutations also have been developed. Research in these models suggests that depending on the gene mutation, motor neuron death is caused by a variety of cellular defects, including in the processing of RNA molecules and recycling of proteins, as well as impaired energy metabolism, and hyperactivation of motor neurons. Increasing evidence also suggests that various types of glial support cells and inflammation cells of the nervous system play an important role in the disease.
Overall, the work in familial ALS is already leading to a greater understanding of the more common sporadic form of the disease. Because familial ALS is virtually indistinguishable from sporadic ALS clinically, some researchers believe that familial ALS genes may also be involved in sporadic ALS. For example, recent research has shown that the defect in the C9orf72 gene found in familial ALS is also present in a small percentage of sporadic ALS cases. Further, there is evidence that mutant SOD1 is present in spinal cord tissue in some sporadic cases of ALS.
Another active area of research is the development of innovative cell culture systems to serve as “patient-derived” or “precision medicine” model systems for ALS research. For example, scientists have developed ways of inducing skin cells and/or blood cells from individuals with ALS into becoming pluripotent stem cells (cells that are capable of becoming all of the different cell types of the body). In the case of ALS, researchers have been able to convert pluripotent stem cells derived from skin/blood into becoming motor neurons and other cell types that may be involved in the disease.
Scientists are also working to develop biomarkers for ALS that could serve as tools for diagnosis, as markers of disease progression, or could be correlated with therapeutic targets. Such biomarkers can be molecules derived from a bodily fluid (such as spinal fluid), an imaging assay of the brain or spinal cord, or an electrophysiological measure of nerve and muscle ability to process an electrical signal.
Potential therapies for ALS are being investigated in a range of animal models, especially in rodent models. But many research projects are surrounding patient’s own cells as testing resources. The use of skin or blood samples to replicate the patient’s specific form of ALS through induced pluripotent stem cells (also known as iPS cells) could potentially accelerate drug testing and trials and mark a significant change in all disease research. This work involves the testing of drug-like compounds, gene therapy approaches, antibodies and cell-based therapies. At any given time, a number of exploratory treatments are in clinical testing in ALS patients. Investigators are optimistic that these and other basic, translational, and clinical research studies will eventually lead to new and more effective treatments for ALS.
Since the discovery of the first ALS gene 25 years ago and the creation of the first ALS mouse model, much has been learned about the disease. Yet despite these discoveries and critical research tools, truly effective therapies and good biomarkers absolutely required to make progress have not been forthcoming.
It is clear that single research labs and simple animal models are not sufficient in finding the root cause of ALS in a large majority of patients, identifying subtypes of disease and defining the pathophysiological pathways and drug targets along with highly relevant biomarkers.
Only a large scale concerted and coordinated collaborative effort will make a difference in a timely manner.
The Answer ALS Research Program brings together world experts across many disciplines needed to tackle ALS: iPSC technologies, cell biology, drug screening, genomics, proteomics, clinical observation, big data and machine learning. We believe that research is accelerated and more effective with cross-institutional and cross-sector collaboration. We invite all researchers from around the globe to help us work on the data generated from Answer ALS. If we want to finally end ALS, we will have to use every resource available, perhaps resources we never considered.