Grant given to CCHMC in January 2015 for $50,000 : Identifying small molecule enhancers of cytotoxic lymphocyte killing in patients with HLH

Lay Abstract:

Our laboratory is interested in taking an entirely novel approach to enhance cytotoxic function in children with defects in Natural Killer (NK) and Cytotoxic T cell (CTL) function leading to HLH. We havedeveloped and executed the first known pilot screen for small-molecule enhancers of NK and CTL function in collaboration with the NIH Molecular Libraries Small Molecule Repository Program. We identified a novel class of pharmacologic compounds in our screening assay that uses cultured human NK cells and a surrogate of NK killing. We now need to 1) validate whether enhancers of luciferase signal are true enhancers of NK cytotoxic function using  patient-derived freshly isolated and cultured NK cells and 2) identify the mechanism by which the compounds are working. Our ultimate goal is identify molecular pathways that will permit new drugs to be developed for HLH.  This research effort has the potential to ultimately change the outcome for children with inherited defects in cytotoxic function associated with the potentially fatal disorder, hemophagocytic lymphohistiocytosis (HLH), especially for those children and/or adults who have residual NK function.


Anticipated Benefits of funding:

Children with rare genetic disorders that disable NK and CTL function may develop malignancies, severe viral infections, or HLH. We predict that CTL/NK modulators will improve the function of CTL/NK in HLH and other immunodeficiencies conditions marked by impaired cytotoxic function and therefore provide an alternative or augmented therapy for these devastating conditions. We are particularly interested in the development of new drugs for children with HLH as this is our laboratory’s and hospital’s area of clinical and research expertise. The Risma laboratory has been focused on understanding perforin-dependent NK and CTL killing in children with HLH with the hopes to identify small molecule chaperones and/or correctors that would be useful to develop for clinical applications.