Class of Lipids Merit ‘High Priority’ Attention as Possible Treatment Route in Huntington’s, Study Says

Increasing evidence links a specific fat to Huntington’s disease, and it “merits more attention” as a “high priority” target for potential disease treatments, a review study reports.

The study, “The S1P Axis: New Exciting Route for Treating Huntington’s Disease,” was published in the journal Trends in Pharmacological Sciences.

Changes in the metabolism of a class of lipids (fat) — called sphingolipids — has been reported as a contributing factor in several neurodegenerative diseases, including Huntington’s.

The sphingosine-1- phosphate (S1P) is the most potent of all sphingolipids, regulating several signaling pathways important for the proper functioning of the brain and overall central nervous system (CNS).

In the CNS, S1P is crucial to support glial cell survival — cells providing support for motor nerve cells — to the formation of new nerve cells, and the integrity of the blood–brain barrier (BBB). This barrier is a selective and semipermeable membrane that works as a protective shield, separating the central nervous system from the rest of the body.

A growing body of evidence has shown that alterations in the metabolism of sphingolipids are present in Huntington’s patients brains, leading researchers to establish a ‘lipid signature’ for the disease.

However, according to researchers, “whether such a defect may contribute to the development of this condition remains to be elucidated.”

Studies in both animal models and post-mortem brain tissue from Huntington’s patients have shown alterations in S1P metabolism and a decrease in S1P levels during early disease stages, suggesting defective S1P metabolism is a likely key contributor to disease development and progression.

How the mutant huntingtin protein (mHtt) — the underlying cause of Huntington’s disease — may affect S1P’s metabolism remains unclear, but researchers hypothesize that altered gene expression may play a role.

In the last four years, an increasing number of studies have reported that of targeting S1P metabolism may be of therapeutic potential in Huntington’s disease. However, the benefits of such an approach is not yet fully appreciated. “[I]t is now imperative to put together available evidence supporting the general idea that modulation of the S1P axis may constitute a novel and alternative effective therapeutic approach in HD,” the researchers wrote.

Multiple studies have also shown that pharmacological modulation of proteins controlling S1P metabolism have had several benefits in Huntington’s animal models, including enhancing nerve cell survival.

Stimulating S1P receptors with FTY720 — an approved therapy for relapsing-remittent multiple sclerosis, sold under the brand name Gilenya — slowed the gradual worsening of motor function in a Huntington’s mouse model, significantly prolonging survival with no adverse events.

“In our opinion, the plausible ‘druggability’ of S1P has huge therapeutic potential for HD and the great competitive advantage is due to the evidence that some drugs whose molecular targets belong to its related pathways are already available and some of them are either on the market or in clinical trials for various diseases,” yjr researchers wrote.

“[T]he S1P axis is an emerging area of investigation for the development of new therapeutic agents that – we would argue – merits more attention and should be considered with higher priority in HD, mostly in relation to its potential proximity to cure,” they concluded.