Describe the ultimate applicability of the research.

Patients with early-onset amyotrophic lateral sclerosis (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 high and unregulated SPT activity resulting in elevated sphingolipids. The sphingolipids are highly enriched in the nervous system and are well known for causing neurological disease when not maintained at proper levels. Because elevated sphingolipids are seen in the serum (and likely all tissues) of patients, they are likely to be good biomarkers for testing efficacy of therapeutics in SPTCL1-associated ALS. The cell and animal models that we propose to develop will allow this to be tested. They will also provide platforms for screens designed to identify and test therapeutics for the treatment of the early onset SPTLC1 ALS patients. If our studies reveal that elevated sphingolipids are causative and/or biomarkers of disease in a broader class of ALS patients, these studies would significantly change the landscape with regard to treatments for this disease.

What type of ALS patients will it help and how will it help them?

The specific patients almost certain to benefit from these studies are young children with an early-onset form of ALS. These children have mutations in SPTLC1 that lead to inappropriately high accumulation of sphingolipids, implicated in the pathophysiology that ultimately leads to paralysis and death. It is significant that there have been numerous reports of perturbations in sphingolipids in ALS patients and animal models with mutations in a wide variety of ALS disease genes. Thus, although the SPTLC1-ALS patient cohort is very small, if elevated sphingolipids are a common feature also seen in non-SPTLC1 ALS patients, the types of ALS patients who stand to benefit from this work would be much broader. It is also important to point out, though beyond the scope of this study, the models will be useful for determining the pathophysiological consequences of elevated sphingolipids and thereby suggest additional therapeutic approaches targeting the pathways or processes that are dysregulated by elevated sphingolipids. Thus, even if elevated sphingolipids are not a common feature of ALS, the sphingolipid-induced pathology may be similar in other ALS patients; if this is the case, therapies identified using these models may also benefit them.

What are the potential clinical applications, benefits, and risks?

The discovery that early onset ALS patients with mutations in SPTLC1 have elevated SPT activity suggests that inhibitors of SPT might be an effective therapeutic. The cell and animal models that will be developed are necessary for preclinical studies to determine whether this is the case. They can also be exploited for the identification of new therapeutic approaches. As the work matures, preclinical trials using the mouse models are likely to follow.

What is the projected time it may take to achieve a patient-related outcome?

If existing inhibitors of sphingolipid synthesis or dietary modifications (e.g., low serine) prove beneficial in the mouse models, clinical trials might follow relatively quickly. However, it is important to reiterate that the SPTLC1 ALS patient population is very small, which will confound clinical trials. Of course, if our studies indicate that elevated sphingolipids 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.

The interim outcomes will be the development of robust cell and animal models of ALS that can be used for identifying new candidate therapeutics and for testing existing and newly identified drugs for efficacy. These models will also be valuable for studying the mechanisms of sphingolipid-induced cell death expected to suggest additional therapeutic targets. Resolving whether perturbations in sphingolipid homeostasis are involved in the pathophysiology of other forms of ALS will be a very significant interim outcome of the proposed studies.

What are the likely contributions of this study in advancing the development of therapeutics for ALS?

These studies are focused on developing new cell and animal models for testing therapeutics for the treatment of SPTLC1-associated ALS. The models will also be pivotal to the goal of advancing therapeutics by providing platforms for identifying new drugs and targets. These studies are the first to focus on SPTLC1-associated ALS. A frustrating limitation in the field of ALS research is the lack of a unifying mechanism of pathophysiology across the myriad of ALS disease genes. If this work were to establish perturbed sphingolipid synthesis as a common mechanism underlying ALS in other patients, the impact with regard to advancing therapeutics would be very significant.