Central and Peripheral Nervous System (CNS/PNS) tumors in the pediatric population represent diseases with complex physiologic and societal burdens. CNS tumors are the greatest cause of pediatric cancer related death, and PNS tumors have lifelong symptomatic burdens. We focus on Diffuse Intrinsic Pontine Glioma (DIPG) and Neurofibromatosis Type-I (NF1). Both have few successful therapies and none are curative. However, both have pathognomonic mutations, H3F3A and NF1 respectively, which drive disease development. We developed gene therapies for these diseases through modulation of their pathognomonic genes. For DIPG, we developed a siRNA-based therapy for H3K27M oncohistone knockdown, hypothesizing that allele-specific knockdown would result in tumor stasis or regression. We successfully developed compounds which cause knockdown of the mutant H3K27M mRNA. However, this knockdown does not impact mutant H3K27M protein expression nor broader cellular changes. For NF1, we developed a trans-splicing therapeutic to correct the first and final third of the mutant NF1 mRNA while NF1 mRNA production is maintained under endogenous regulation. We performed library-based screening to identify functional trans-splicing moieties. Unguided trans-splicing did not occur at appreciable rates. Re-designing the system with Cas13 guidance resulted in successful trans-splicing at a molecular level, but efficiency was minimal. In summary, we investigated novel gene therapy methodologies for DIPG and NF1 that have therapeutic potential in ideal circumstances, however inherent disease specific challenges prevent expanding their use. Further refinement of these technologies and greater understanding of the disease context surrounding their function is required for successful therapeutic development to improve the lives of patients.