Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by an autosomal dominant mutation in Exon 1 of the Huntingtin gene (Htt). There are no approved treatments for HD. Oligonucleotide therapeutics (ASOs and siRNAs) offer a new strategy to treat genetically defined CNS diseases. These therapeutics aim to attenuate disease pathogenesis by targeting Htt mRNA to reduce the toxic mutant protein. Recent technological advancements now enable robust distribution and efficacy throughout mouse, sheep, and NHP brains. However, oligonucleotides can cause acute neurotoxicity when injected directly into the CSF. This dissertation aims to optimize oligonucleotide delivery for the treatment of HD by addressing safety issues across species. We used electroencephalography (EEG) and electromyography (EMG) in awake animals to confirm that direct CSF injection of oligonucleotides induces seizures. We hypothesized that this was due to the negatively charged oligonucleotides changing the delicate balance of divalent cations in the CSF. To address this issue, we developed an artificial CSF (aCSF) buffer supplemented with Ca2+ alone, Mg2+ alone, or Ca2+ and Mg2+ in the injected solution to prevent the imbalance. Real-time EEG monitoring in awake mice and lambs confirmed the absence of seizures when oligonucleotides were delivered in the new aCSF buffer. In summary, this dissertation identified a potential cause of oligonucleotide-induced acute neurotoxicity, developed a method to safely deliver oligonucleotides to the CNS with Ca2+/Mg2+-enriched buffers, and demonstrated the viability of this formulation in a large animal model. These findings support a new method for safely delivering oligonucleotides to the CNS to treat neurological diseases.