Table 1.

Approaches for NF1 Gene Therapy

Approach	Targeted Mutations	Advantages	Disadvantages/Challenges	Successes	NF1 Status
Gene replacement	all loss of function mutations	might target the largest mutation spectrum	mNF1 cDNA; efficient delivery using nanoparticles	Luxterna for retinal dystrophy associated with loss of RPE65, and Zolgensma for SMA and loss of SMN1	development of full-length mNf1 cDNA and development of model systems for testing
Genome editing	most small mutations	permanent cell editing	efficiency of editing; non-specific gene editing; delivery using nanoparticles	ex vivo CCR5 deletion to block HIV infection	testing CRISPR-Cas9 and CRISPR Prime in nanoparticles and development of model systems for testing
RNA editing	most small mutations in 5′ and 3′ regions	does not change DNA	efficiency of editing, non-permanence; delivery using virus or nanoparticles	β-globin and DMPK repair in vitro	defining high-efficiency splice sites within NF1 and evolving ribozymes and development of model systems for testing
Exon skipping	select exons	low toxicity	each exon must be considered/designed separately; delivery using cell-penetrating peptides	Exondys 51 (eteplirsen) and Vyondys 53 for DMD; Spinraza for SMA	definition of selected exons and testing of AOs and development of model systems for testing
NST	nonsense ~20%	low toxicity; may be able to repurpose other drugs	efficiency of readthrough; NMD	Ataluran for cystic fibrosis	small molecule drug screens for NSTs and development of model systems for testing