Current Basic and Translational Research
Two of Dr. Ferrante’s research interests in ALS are characterizing biomarkers of ALS and in drug development to translate therapeutic strategies to patients with ALS. Dr. Ferrante has funding that supports biomarker analysis. Biomarkers are urgently needed for diagnosis, following disease progression, and for their utility in measuring outcome measures using potential disease-modifying therapies that are being developed and evaluated in clinical trials, especially at the early stages of disease. While the development of early biomarkers is of great importance, as these may improve the power of clinical trails, it is likely that more than one biomarker will be needed for early diagnosis and similarly for evaluation of disease progression for therapeutic trials. Thespecific aims of this work are designed to identify and follow biomarkers that correspond to disease activity, disease progression, and disease modification in ALS mouse models in parallel with human ALS patients. The utility and validity of peripheral biomarkers (blood and urine) are critically vital in facilitating lead screening in mouse models and in human therapeutic clinical trials. The project analyzes and compares peripheral (blood and urine sample) to CNS biomarker profiles (brain tissue and csf) in ALS mice throughout presymptomatic and symptomatic disease and compares these findings to human ALS patients. These studies have demonstrated that peripheral biomarker profiles reflect changes in the CNS. By using ALS mice, we can examine complementary processes in the brain and periphery with much greater precision and much greater control of post-mortem and other technical factors. We have sufficient correspondence so far between ALS mouse models and ALS subjects to provide confidence that the animal studies will greatly facilitate the overall program. The current technologies allow for the measurement of multiple known and hypothesized biomarkers within the same individual and across comparable groups of humanpatients and animal models with ALS. This information will help to create adata set of multiple markers that can be used to develop a unique biochemical signature relating to ALS subjects that will provide a powerful means to assess therapeutic treatments in ALS patients and predict the potential magnitude of benefits in these patients.
In addition, Dr. Ferrante also has funding to develop novel drug therapies for ALS patients for use in human clinical trials. This work investigates protein aggregation inhibition as a potential therapeutic strategy for ameliorating disease progression in ALS. Dr. Ferrante and his colleagues at Northwestern University and Boston perform high throughput screens to identify compounds that protect cells against the toxic effects of mutant superoxide dismutase (SOD1) aggregation. SOD mutations are the cause of familial forms of ALS. They have identified three lead chemotypes that protect cells from aggregated mutant SOD1. Dr. Ferrante found that CMB-021805, a PYT analog, when administered to G93A ALS mice, improved survival and extended the life of the mice by 26%. Pathological findings in untreated G93A mice, including gross spinal cord atrophy and neuronal loss in the ventral horns from the lumbar spinal cord, were significantly reduced by CMB-021805, as compared to untreated ALS mice. In addition, when mice were treated with CMB-021805 at 10 mg/kg twice daily, survival was extended by approximately 31% in the G93A mice, as compared to untreated ALS mice. These findings are better than any current drug trial in ALS mice. He and his colleagues are developing this compound for use in clinical trials in ALS patients. While additional experiments are needed, the findings described above may lead to a better understanding of the disease mechanisms that initiate ALS, as well as identifying targets for potential biomarkers and new therapies to combat ALS.
High Field MRI
High definition fiber tracking studies. We do not fully understand the progression of the loss of motor neurons and their tracks (pathways) in brain and spinal cord areas in ALS. Greater knowledge of these events will allow us to predict events and provide better clinical care for ALS patients and potentially to help slow the disease progression. Using high field magnetic resonance imaging (MRI), we can track the fibers in these pathways in ALS patients over time and understand what areas are effected earliest and how the disease spreads. Doing these studies in the spinal cord is a new undertaking. We are currently enrolling patients in this study.
Growing Stem Cells
Novel stem cells studies. Studying rat and mouse models of ALS has not predicted which drugs will be successful in humans. We propose new studies of HUMAN motor neurons derived from individuals with ALS by taking skin cells (called pleuripotent stem cells) obtained by simple skin biopsy and then turning these skin cells into motor neurons and supportive glial cells that are similar to those found in human spinal cord. This process takes months. The biology of the cells should tell us about disease mechanisms and why some patients with longer. They will also provide a foundation for testing drugs to predict which ones should move forward and be tested in patients. We are currently enrolling subjects with ALS and normal controls.
Discovery and Validation of Biomarkers
Subjects are being recruited to provide serial samples of blood and spinal fluid to study for markers of ALS that can help us learn more about the cause and lead to treatments. We are sharing samples with investigators from 4 other Centers
Optimizing Nasal Ventilation for People with ALS
In this research study, we are comparing standard monitoring of nasal ventilation use to an enhanced approach. In the enhanced approach, patients and caregivers are given information on how effectively they are using devices. The study is no longer recruiting and is in the data analysis phase.