Targeting Excessive Sphingolipid Synthesis for Treatment of ALS
Abstract
Ultimate applicability of the research: A cohort of patients with juvenile ALS have mutations in SPTLC1, which is a subunit of SPT, the enzyme that catalyzes the first step in the synthesis of sphingolipids. The mutations cause unrestrained SPT activity that leads to excessive accumulation of sphingolipids (SLs). This understanding of the fundamental problem points to an obvious target for a therapy, reducing SPT activity back to the levels seen in unaffected people. Fortunately, inhibitors of SPT are available, including some that have already proven useful in the treatment of mice that have elevated SLs for other reasons. In addition, we have generated cell and animal models of juvenile ALS that will be used in the proposed preclinical studies aimed at identifying the most promising SPT inhibitor(s) for eventual use in clinical trials. What type of ALS patients will it help and how will it help them? The specific patients most likely to benefit from these studies are the cohort with SPTLC1-related juvenile ALS. Although the SPTLC1-related ALS patient cohort is very small, if preliminary findings of elevated SLs in a broader class of ALS patients holds up, these studies could significantly change the landscape with regard to strategies for treating this intractable disease. What are the potential clinical applications, benefits, and risks? The discovery that juvenile ALS patients with mutations in SPTLC1 have elevated SPT activity suggest inhibition of SPT as a potential therapy. The cell and animal models that we have developed will be used in the proposed preclinical studies to determine whether this is the case. If we are successful in restoring normal SL levels in the animal models, the stage will be set for moving forward with clinical trials. Because SPT is an essential enzyme, there are risks associated with reducing activity too much, which is why it will be important to establish safe but efficacious dosing in the mouse models. In addition, as with any drugs, there are risks of off-target effects. What is the projected time it may take to achieve a patient-related outcome? If the SPT inhibitor D-cycloserine (already U.S. Food and Drug Administration-approved for treatment of tuberculosis) or dietary modifications (e.g., high alanine) prove beneficial in the mouse models, clinical trials might follow relatively quickly. In addition, although myriocin is not approved for human use, extracts of the fungus, Cordyceps, used in traditional Chinese medicine, contain myriocin. Significantly, commercially available extracts of Cordyceps are routinely used as a supplement and treatment of mice with comparable doses have proven effective in the treatment of metabolic diseases (diet-induced obesity) associated with excessive SLs. However, it is important to point out that the SPTLC1 ALS patient population is very small, which will confound clinical trials. Of course, if our studies indicate that elevated SLs underlie pathophysiology in a broader class of ALS patients, this will not be an issue. If the research is too basic for clinical applicability, describe the interim outcomes. These studies are necessary preclinical studies that take advantage of the robust cell and animal models of SPTLC1-ALS we have generated. We hope to unequivocally demonstrate that one or more of the SPT inhibitors is both safe and efficacious for reducing SLs in mice. As mentioned above, numerous neurodegenerative and metabolic diseases are associated with perturbations in SLs, and thus these studies which are focused on strategies for regulating SLs will also impact other important areas of translational research. What are the likely contributions of this study in advancing the development of therapeutics for ALS? These studies take advantage of new cell and animal models for testing therapeutics for the treatment of SPTLC1-related juvenile ALS. They will be pivotal to identifying mechanism-based treatments for the juvenile ALS
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310375
Entities
People
- Teresa Dunn
Organizations
- Uniformed Services University of the Health Sciences
- United States Army