Rationale for haploinsufficiency correction therapy in neurofibromatosis type 1

Abstract

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

Gene-targeted therapy for neurofibromatosis and schwannomatosis: The path to clinical trials

“…Alternatively, small molecules and antisense oligonucleotides can target transcription and translation enhancers to increase protein expression from a remaining wild-type allele, or modulate protein degradation, each ultimately resulting in more functional protein. 27 At the RNA level, target mRNAs may be edited using trans-splicing ribozymes [40][41][42][43][44] or SMaRT (Switching Mechanism at the 5# end of RNA Template) technology, 43,45,46 a strategy that does not permanently change the genome. mRNA splicing, as well as miRNA function, can also be modulated with antisense oligonucleotides, to control gene expression in a targeted manner.…”

“…17 Alternatively, targeting the haploinsufficient tumor microenvironment may help delay or reverse tumor growth. 27 NF1 gene replacement, nonsense suppression therapy, and modulation of transcription and translation by antisense oligonucleotides are approaches that are well positioned for human studies in the next decade. Genome editing and protein replacement remain attractive options but will require more development before launching clinical trials.…”

“…First, NF1 has a highly variable inter- and intrafamilial phenotypic expression, likely related to family-specific NF1 PVs, unknown epigenetic, environmental, and stochastic factors, as well as involvement of multiple organ systems. 3,24 Loss of heterozygosity for NF1 and resulting diploinsufficiency is required for manifestations such as tumors and pseudoarthrosis, 25,26 while haploinsufficiency can drive tumors 27 and cause other phenotypes, such as neurocognitive problems (Figure 1). In addition, structural abnormalities such as those involving the bone and brain may not be reversible after a defined developmental timepoint.…”