As neurological therapies evolve, so does the need for more direct and effective drug delivery to the central nervous system. Intrathecal (IT) administration is emerging as a preferred route for delivering complex therapeutics (e.g. gene therapies, neurodegenerative treatments, and antisense oligonucleotides) that cannot reliably cross the blood-brain barrier through traditional systemic routes. Preclinical research is rapidly expanding in this space, with a focus on innovation, precision, and long-term safety

Developing and Optimizing Novel Therapeutics

Preclinical studies are at the forefront of testing new and modified therapies using the IT route, including:

• Gene therapies, such as recombinant adeno-associated virus serotype 9 (rAAV9), designed to target genetic causes of neurological diseases.
• Nucleic acid-based therapies, including siRNAs, antisense oligonucleotides (ASOs), and RNAi technologies.
• Monoclonal antibodies for neuroinflammatory or degenerative targets.
• Nanomedicines and lipid-based carriers aimed at improving solubility and sustained release.
• Reformulated or derivatized versions of approved drugs, optimized for prolonged effect.

Each of these modalities requires careful evaluation in preclinical models to assess CSF dynamics, biodistribution, and potential neurotoxicity.

Investigating the Impact of Age at the time of Intrathecal Delivery

Age-related variables are also a growing focus. Preclinical studies are exploring how age at the time of administration influences CNS exposure, especially in gene therapy approaches where developmental biology can affect both distribution and response. Understanding these factors is critical for pediatric and geriatric applications.

Advanced Dosing Strategies and Study Designs

With delivery optimization in mind, researchers are leveraging creative study designs that go beyond standard bolus dosing. These include:

• Controlled infusion rates and variable dosing volumes
• Use of implanted catheters or pumps for sustained delivery
• Cross-species modeling to evaluate translation to clinical settings
• Use of preservative-free, isotonic formulations

The goal: maximize therapeutic exposure while preserving CNS integrity and minimizing invasive interventions.

Minimizing Side Effects and Optimizing Therapeutic Index

Whether targeting with a well-defined genetic cause, chronic pain, neuroinflammation, or rare diseases, IT therapies require a balance between potency and safety. Current studies must be focused on achieving the lowest effective dose, reducing systemic side effects, and exploring synergistic combinations.

Key Points to Consider for Intrathecal Dosing

• Anatomical features: Test System age, and weight can have impact on spinal cord length and uniform dose administration. Locating the precise intrathecal space is essential.
• Injection Procedure: Needle size, location of injection, and verification of the dose is critical. Aseptic procedures must be utilized. Rates of injection should be slow and steady and are generally small. Pressure must not be altered to avoid damage to nerves.

Looking Ahead with Attentive Science

As the future of intrathecal dosing continues to take shape, Attentive Science is uniquely positioned to help you navigate this dynamic landscape. At Attentive Science, we support sponsors with nonclinical studies designed to evaluate the feasibility, safety, and pharmacokinetics of intrathecal dosing. Our programs begin with careful model selection to evaluate clinically relevant delivery mechanics and CSF exposure. Our team brings a forward-thinking approach grounded in decades of experience with CNS-targeting therapies, complex formulations, and innovative delivery technologies.

From concept to IND submission, we collaborate closely with you the Sponsor to design preclinical programs that reflect not only current best practices, but also what’s next.

We don’t just conduct studies, we anticipate challenges, adapt to your therapeutic goals, and deliver data you can trust. Contact us to experience the Attentive difference