Innovative direct delivery strategies to unlock oligonucleotide therapeutics for CNS disorders
Oligonucleotide (oligo) therapies have been in development for decades. Recent advances in molecular design, chemistry, delivery systems, targeted delivery, reduced immunogenicity, and enhanced efficacy are significantly accelerating their potential to treat central nervous system (CNS) disorders, including neurodegenerative diseases, epilepsy, psychiatric disorders, and certain rare genetic disorders.
When administered directly to the CNS, oligos can offer several advantages, such as rapid onset of action, enhanced delivery to target sites, minimised systemic side effects and toxicity, lower dosage requirements, and reduced dosing frequency.¹ Consequently, oligo therapies are emerging as promising therapeutics with the potential to address previously untreatable conditions. Nevertheless, achieving effective delivery in the CNS remains technically demanding and physiologically complex.
One of the key components of CNS drug discovery and development during non-clinical research is understanding the pharmacokinetics of a drug – how it enters, distributes, and eventually exits the body. Accurate characterisation of these processes is critical to understand the drug's absorption, distribution, metabolism, and excretion (ADME) profile, which is essential for determining the optimal delivery method and predicting the body's reaction in humans. These activities are vital not only during the initial phases of drug development, but also throughout the product's life cycle, facilitating the progression to subsequent development phases.
Among the most promising strategies for CNS-targeted oligo delivery is intrathecal lumbar (IT-L) administration via catheter-port systems – a method that enables direct dosing into the subarachnoid space and offers greater control over drug exposure.² By examining the performance and verification of this approach in non-clinical models, researchers can better address delivery precision, optimise pharmacokinetics, and de-risk early development efforts.
Verifying CNS exposure
IT-L administration of oligos is widely used because it can bypass the blood-brain barrier and deliver the drug directly into the cerebrospinal fluid, enabling rapid and effective action on the CNS. However, the procedure can be technically demanding, as the injection space is small, leaving little room for error and increasing the risk of missed or unknowingly partial dosing. Verifying the extent of drug delivery to the target site is critical.
The most reliable method for this verification is by analysing drug concentrations in the CSF post-dosing. A practical benchmark involves using the total CSF volume and dose to estimate the theoretical maximum concentration (TMC) – the highest concentration achievable if the entire dose is completely administered and distributed evenly throughout the CSF.³ Delivery is considered successful if at least 25% of the TMC is achieved within the first hour. These evaluation criteria assist researchers in evaluating delivery techniques and identifying potential issues early in the development process.
Improving reliability through dual catheter-port techniques
Scientists have developed a dual catheter-port approach to improve the consistency of IT-L dosing. This method enhances administration accuracy and sampling efficiency, making it more reliable and less complicated. This approach's key features include using catheter-ports for lumbar intervertebral space drug delivery and CSF collection via the cisterna magna. Subcutaneous ports facilitate repeated dosing and sampling in conscious test articles.
As stands, the success rate of administration for current test articles is 100%, based on the 25% TMC standard. Through IT catheterisation, infusion and bolus methods can achieve the same high exposure levels. Compared with traditional industry IT puncture administration, the dual catheter model can serve as a more reliable method for evaluating CNS-targeted therapies in non-clinical research.
Why tissue sampling still matters
Measuring drug levels in CSF is crucial, though it does not always accurately reflect the drug's distribution throughout the CNS. Studies indicated that oligos often exhibit high concentrations in the lumbar spinal cord near the injection site, with lower concentrations observed in the cervical spinal cord closer to the brain.4
Researchers can examine tissue samples from different segments of the spinal cord, brain, liver, and kidneys to better understand this distribution. By analysing time-concentration profiles, they can map drug distribution and movement trends, which helps guide adjustments in dosing strategies. This approach supports a more comprehensive understanding of therapeutic exposure, aiming to enhance CNS-targeted treatments' efficacy.
Considerations for subject selection
Test articles should be carefully selected based on physiological and pharmacokinetic (PK) similarities to humans to obtain more relevant and translatable data and improve the overall validity of research findings. While reusing previously dosed large subjects may reduce expenses, it is crucial to consider potential immune responses or changes in drug behaviours that could impact results. Using non-naïve test articles, not previously administered oligos, could be valuable for oligo PK studies during the early discovery phase and is essential for the Investigational New Drug (IND) phase. This strategy aims to balance the need for accuracy and cost-efficiency.
A final word on the oligos in CNS
Developing oligo therapies for CNS disorders offers exciting potential and presents critical challenges. Direct delivery into the subarachnoid space is the most effective way to bypass the blood-brain barrier. Yet, it requires precise and reliable dosing, as well as accurate tracking of drug levels. Advances such as dual catheter-port methods and standardised success criteria ensure more consistent and reliable results.
Early testing of plasma and CSF concentrations, along with well-chosen test subjects, provides a comprehensive understanding of these drugs' PK profiles. As these therapies progress beyond the non-clinical stage, it is imperative that the tools for testing them be improved. Enhanced delivery methods and evaluation strategies will be crucial for supporting accurate data and making informed decisions throughout the development phases.
References
¹ Madadi AK, Dalmasson CM, Rashidi H, et al. Advances in intrathecal nanoparticle delivery: targeting the central nervous system directly and minimizing systemic exposure. Pharmaceutics. 2024.
² Hammond SM, et al. Delivery of oligonucleotide‑based therapeutics. Mol Ther Nucleic Acids. 2021
³ Burla GR, et al. Evaluating the effect of injection protocols on intrathecal solute dispersion in NHPs. Fluids and Barriers of the CNS. 2024.
4 Mazur C, Powers B, Kamme F, et al. Brain pharmacology of intrathecal antisense oligonucleotides: distribution in spinal cord and brain after lumbar IT dosing. J Neurosci Methods. 2019.
About the author
Dr Shoutao Liu is senior director in the DMPK Department at WuXi AppTec, where he leads the development of strategies to evaluate pharmacokinetics and drug delivery for oligonucleotide therapies. He earned his PhD in pharmacokinetics from West China University of Medical Sciences and focuses on optimising CNS-targeted administration techniques in large animal models to support translational drug development.
