MAPK AND AKT/MTOR INHIBITION IMPROVES CHILDHOOD RASOPATHY-ASSOCIATED CARDIOMYOPATHY

BackgroundNo causal therapies exist for severe pediatric-onset cardiomyopathy associated with germline mutations in RAS/mitogen-activated protein kinase (MAPK) pathway (RAS-CM). In order to evaluate the benefit of small molecule inhibitors target rapamycin (mTORi) or MAPK (MEKi) RAS-CM patients, we have sought compile cases compassionate use these agents.Methods and ResultsCase series collecting pre-defined variables on safety clinical outcome 25 children progressive receiving off-label mTORi MEKi after exhaustion standard 17 European North-American centers. Over a follow-up period 296 patient-months (median, 5.5 months; range, 1.5-50), transplant-free survival critically ill patients < 6 months age treated and/or was 75% compared 39% natural history controls (p=0.031). Freedom from surgical intervention 52% (11 21 whom outflow tract resection indicated), improvement functional status decrease NT-proBNP z-score by at least 20% baseline occurred 85% 70.6% respectively (median [range] change Ross classification -1.3 [-2 – 0] -1.8 [-3.7 - +0.4], p< 0.001, before treatment versus last timepoint). No life-threatening adverse events related were observed. Skin mucous membranes most common organs affected side effects, requiring cessation reduction therapy 16% patients.ConclusionSelected RASopathy may novel mechanism-informed therapeutics targeting RAS/MAPK pathway. Clinical trials are needed substantiate findings reported this case series. agents. Methods patients. Case ConclusionSelected Selected