Biodistribution and delivery of oligonucleotide therapeutics to the central nervous system: Advances, challenges, and future perspectives

Abstract

Considerable advances have been made in the research and development of oligonucleotide therapeutics (OTs) for treating central nervous system (CNS) diseases, such as psychiatric and neurodegenerative disorders, because of their promising mode of action. However, due to the tight barrier function and complex physiological structure of the CNS, the efficient delivery of OTs to target the brain has been a major challenge, and intensive efforts have been made to overcome this limitation. In this review, we summarize the representative methodologies and current knowledge of biodistribution, along with the pharmacokinetic/pharmacodynamic (PK/PD) relationship of OTs in the CNS, which are critical elements for the successful development of OTs for CNS diseases. First, quantitative bioanalysis methods and imaging‐based approaches for the evaluation of OT biodistribution are summarized. Next, information available on the biodistribution profile, distribution pathways, quantitative PK/PD modeling, and simulation of OTs following intrathecal or intracerebroventricular administration are reviewed. Finally, the latest knowledge on the drug delivery systems to the brain via intranasal or systemic administration as noninvasive routes for improved patient quality of life is reviewed. The aim of this review is to enrich research on the successful development of OTs by clarifying OT distribution profiles and pathways to the target brain regions or cells, and by identifying points that need further investigation for a mechanistic approach to generate efficient OTs.

Large- and Small-Animal Studies of Safety, Pharmacokinetics, and Biodistribution of Inflammasome-Targeting Nanoligomer in the Brain and Other Target Organs

“…), use of more traditional pharmaceutical modalities such as small-molecule-based targeting is slow and low-throughput with mixed safety profile. On the other hand, high-throughput approaches such as design-based antisense oligonucleotides can potentially improve translation rates, but suffer from delivery challenges, especially for neurological diseases, , and accumulation in first-pass organs. , The emergence of new RNA-targeting antisense modalities such as Nanoligomers can have the combined advantage of high delivery and biodistribution profile of small molecules, extremely high target-binding affinity ( K D ∼ 3–5 nM) like antibodies, with the specificity and ease of design using nucleic acid-targeting. − Nanoligomers are peptide nucleic-acid-based RNA therapeutic modality that have shown targeted up- and downregulation of proteins, with extremely high specificity, minimal off-targets, and a high safety profile. − However, more detailed safety-toxicity and biodistribution studies need to be conducted across small- and large-animal models for these new modalities to gain greater acceptance toward human clinical translation and pharma adoption.…”

Large- and Small-Animal Studies of Safety, Pharmacokinetics (PK), and Biodistribution of Inflammasome-Targeting Nanoligomer in the Brain and Other Target Organs

“…), 11 use of more traditional pharmaceutical modalities such as small-molecule-based targeting is slow and low-throughput with mixed safety profile. On the other hand, high-throughput approaches such as design-based antisense oligonucleotides (ASOs) 12 can potentially improve translation rates, but suffer from delivery challenges, especially for neurological diseases, 13,14 and accumulation in first-pass organs. 15,16 The emergence of new RNA-targeting antisense modalities such as Nanoligomers can have the combined advantage of high delivery and biodistribution profile of small molecules, extremely high target-binding affinity (K D ~3-5 nM) like antibodies, with the specificity and ease of design using nucleic acid-targeting.…”

Nucleic acid-based therapeutics for the treatment of central nervous system disorders

“…CNS targeting by both ASOs and siRNAs can be achieved via direct brain delivery through IT (intrathecal) injection ( Goto et al, 2023 ). IT administration involves injecting the drug into the CFS within the spine and can be performed in a variety of ways, including intralaminar injection, transforaminal injection, or using a subcutaneously implanted catheter for repeat injections ( Figure 3 ) ( Lee et al, 2022 ; Alkosha, 2023 ).…”

“…IT administration involves injecting the drug into the CFS within the spine and can be performed in a variety of ways, including intralaminar injection, transforaminal injection, or using a subcutaneously implanted catheter for repeat injections ( Figure 3 ) ( Lee et al, 2022 ; Alkosha, 2023 ). IT injection is the indicated route of administration for 16 oligonucleotide therapeutics that are under development as of 2022 ( Goto et al, 2023 ) ( Table 2 ). However, IT injections are invasive procedures and carry risks of side effects such as headaches and back pain, which does not encourage wide clinical acceptance of NBTs.…”