Mutation-Directed Therapeutics for Neurofibromatosis Type I

Abstract

Significant advances in biotechnology have led to the development of a number of different mutation-directed therapies. Some of these techniques have matured to a level that has allowed testing in clinical trials, but few have made it to approval by drug-regulatory bodies for the treatment of specific diseases. While there are still various hurdles to be overcome, recent success stories have proven the potential power of mutation-directed therapies and have fueled the hope of finding therapeutics for other genetic disorders. In this review, we summarize the state-of-the-art of various therapeutic approaches and assess their applicability to the genetic disorder neurofibromatosis type I (NF1). NF1 is caused by the loss of function of neurofibromin, a tumor suppressor and downregulator of the Ras signaling pathway. The condition is characterized by a variety of phenotypes and includes symptoms such as skin spots, nervous system tumors, skeletal dysplasia, and others. Hence, depending on the patient, therapeutics may need to target different tissues and cell types. While we also discuss the delivery of therapeutics, in particular via viral vectors and nanoparticles, our main focus is on therapeutic techniques that reconstitute functional neurofibromin, most notably cDNA replacement, CRISPR-based DNA repair, RNA repair, antisense oligonucleotide therapeutics including exon skipping, and nonsense suppression.

Perspective of mesenchymal transformation in glioblastoma

“…Genomic aberrations in neurofibromin 1 (NF1) gene have been reported as one of the major characteristics of the mesenchymal GBM, and NF1 deficiency has been shown to recruit TAMs to the tumor site, indicating that reconstituting functional NF1 may prevent mesenchymal transformation in GBM [ 155 , 161 ]. As reviewed by Leier et al biotechnology-based therapeutic strategies, such as cDNA replacement, CRISPR-based DNA repair and exon skipping, are being developed as a form of mutation-directed therapies to repair the NF1 gene [ 71 ]. Furthermore, since the loss of NF1 in glial cells has been found to be associated with increased RAS activity, targeting the RAS-downstream signaling pathways (e.g., the RAF-MEK-ERK signaling cascade) through MEK inhibition may be another viable therapeutic strategy to prevent NF1-associated mesenchymal transformation in GBM [ 17 , 57 , 78 ].…”

Understanding the Biological Activities of Vitamin D in Type 1 Neurofibromatosis: New Insights into Disease Pathogenesis and Therapeutic Design

“…A variety of mutation-directed therapeutics, which can be potentially used to treat NF1, are currently at different stages of clinical development [ 381 ].…”

Ataluren and aminoglycosides stimulate read-through of nonsense codons by orthogonal mechanisms

“…Are the in vitro results presented here indicative of ataluren's effect in cells and relevant for ongoing efforts to develop new, more potent TRIDs as therapies for PSC diseases (10,13,(46)(47)(48)(49)? Supporting cell biological and health care relevance is the straightforward manner in which restricting ataluren's effect to inhibition of termination explains its lack of stimulation of misreading at normal codons in cellular assays (50).…”

“…The best characterized therapeutic agents inducing read-through, currently referred to as TRIDs [translational read-through–inducing drugs ( 9 )], are ataluren (Translarna), a hydrophobic substituted oxadiazole, and the highly polar class of aminoglycoside antibiotics (AGs) ( 10 ). Only ataluren has been approved for clinical use.…”