Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is a genetic disorder with wide range of manifestations and severity. Currently, the few available NF1 treatments target specific manifestations, no therapies targeted to correct underlying driver all manifestations. Evidence supports that haploinsufficiency in caused by decreased amount wild-type (WT) neurofibromin Nf1+/- cells directly causes or facilitates Consequently, correction therapy (NF1-HCT) represents potentially effective approach treat some NF1-HCT would normalize level WT NF1-haploinsufficient cells, including those integral phenotype such as Schwann (SCs), melanocytes, neurons, bone tumor microenvironment. This altered cellular signaling pathways and, turn, restore normal function retained allele. will not NF1-/- cells; however, restoring surrounding microenvironment predicted have beneficial effect on cells. expected clinical follows: (i) prevention, delay onset, potential manifestations; (ii) reversal, halting/slowing progression, established review describes rationale for NF1-HCT, considerations (e.g., phenotype, function/regulation, mutational spectrum, genotype-phenotype correlation, impact NF1), HCT other haploinsufficient diseases, drug treatment strategies, advantages/challenges NF1-HCT.