Drug discovery in focal and segmental glomerulosclerosis

Abstract

Despite the high medical burden experienced by patients with focal segmental glomerulosclerosis (FSGS), the etiology of the condition remains largely unknown. FSGS is highly heterogeneous in clinical and morphological manifestations. While this presents challenges for the development of new treatments, research investments over the last two decades have yielded a surfeit of potential avenues for therapeutic intervention. The development of many of those ideas and concepts into new therapies, however, has been very disappointing. Here, we describe some of the factors that have potentially contributed to the poor translational performance from this research investment, including the confidence we ascribe to a target, the conduct of experimental studies, and the availability of selective reagents to test hypotheses. We will discuss the significance of genetic and systems traits as well as other methods for reducing bias. We will analyze the limitations for a successful drug development. We will use specific examples hoping that these will guide a consensus for investment and drive greater translational quality. We hope that this substrate will serve to exemplify the tremendous opportunity for intervention as well as facilitate greater collaborative effort between industry, academia and private foundations in promoting appropriate validation of these targets. Only then will we have achieved our goal for curative therapies for this devastating disease.

A systems pharmacology workflow with experimental validation to assess the potential of anakinra for treatment of focal and segmental glomerulosclerosis

“…FSGS is very heterogeneous and no model covers all major disease nodes relevant in its pathophysiology [16, 39]. To reduce this basic limitation, we chose two unrelated models covering different pathophysiologic aspects of FSGS [26, 40].…”

“…In line with this, anakinra had beneficial effects including reduction of proteinuria in off-label use in patients with Familial Mediterranean fever, rheumatoid arthritis and Muckle-Wells (urticaria-deafness-amyloidosis) syndrome, a subtype of CAPS [13–15]. As the efficacy of anakinra in FSGS has not yet been evaluated [5, 12, 16], we decided to analyze it in a drug repurposing approach by network-based drug-disease target interference at the molecular level [17]. Our approach based on an algorithm using data from scientific literature consolidation integrates information from unbiased data mining and was recently used to test the potential of the immunosuppressive drug tacrolimus in diabetic nephropathy in silico [18].…”

Renal cell markers: lighthouses for managing renal diseases

“…However, in the diseased condition, the podocytes are reorganized into a flattened shape with effacement of podocyte FPs and loss of SD sub-structures, culminating in massive proteinuria (>3.5 g albumin/day). Since podocytes are the key cells that are involved not only in glomerular physiology but also in the pathology underlying several nephropathies (15,172,215,348), researchers have studied and identified specific podocyte proteins that have direct association with either the disease outcome or its prognosis and suggested new agents or therapies specific to podocytes (179,259,266).…”

Modulation of radiation‐induced damage of human glomerular endothelial cells by SMPDL3B

“…Numerous studies conducted by our group highlighted the importance of sphingolipids in preserving normal renal function 6,13‐16 . The sphingomyelin phosphodiesterase acid‐like 3b (SMPDL3b) enzyme is of particular interest to our work.…”