Genomics in the News

Deoxysphingolipids (1-deoxySLs) are neurotoxic sphingolipids associated with obesity and diabetic neuropathy (DN) and have been linked to severity of functional peripheral neuropathies. L-serine supplementation can reduce 1-deoxySL accumulation and improve insulin sensitivity and sensory nerve velocity, but long-term outcomes have not yet been examined. In this work published by CGM investigator Florian Eichler and colleagues, a preclinical model of diabetic neuropathy was treated oral l-serine and longitudinally quantified the extent of functional neuropathy progression. Functional neuropathy and sensory modalities were significantly improved in the treatment group well into advanced stages of disease, however, structural assessments revealed prominent axonal degeneration, apoptosis and Schwann cell pathology, suggesting that neuropathy was ongoing. Thus, despite significant functional improvements, L-serine does not prevent chronic degenerative changes specifically at the structural level, pointing to other processes such as oxidative damage and hyperglycemia that may have additional pathological effects in DN.

Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies. In this manuscript by CGM investigator Vijaya Ramesh and colleagues, data from previous high-throughput drug screening in NF2 preclinical models was leveraged to identify a class of compounds targeting the ubiquitin-proteasome pathway (UPP) that may have utility in NF2. Through a series of elaborate investigation of these UPP targeting agents in vitro and in vivo, the group found that treatment delayed tumor growth, suggesting a therapeutic potential. This important work in preclinical models lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.

Clonal hematopoiesis of indeterminate potential (CHIP), a condition defined by a set of aging-related genetic mutations in blood cells, is associated with an increased risk of several conditions. A team led by CGM PI Pradeep Natarajan and colleagues from Centro Nacional de Investigaciones Cardiovasculares, Stanford University, and Vanderbilt University explored the relationship between CHIP and atherosclerosis in the peripheral arteries. Individuals with mutations in DNA damage repair genes had an increased risk, and mouse data indicated that such mutations may drive increased aortic plaque size and accumulation of macrophages within plaques.