Intracerebroventricular (ICV) Injection: Precision CNS Delivery For Preclinical Research

Intracerebroventricular (ICV) injection is a direct-to-CNS administration route where therapeutic agents are delivered into the brain's ventricular system. By bypassing the blood-brain barrier, ICV administration allows drugs to distribute widely throughout the central nervous system via the flow of cerebrospinal fluid (CSF), potentially reaching areas like the cerebral cortex and spinal cord. This route offers advantages for achieving broad CNS exposure, strong target engagement, and potentially durable therapeutic effects.

Accurate delivery is paramount for successful ICV administration in non-clinical studies.

Stereotaxic Guidance: Before injection, precise coordinates must be determined using a stereotaxic apparatus to ensure the needle reaches the target ventricle at the correct depth and angle. Successful placement can often be confirmed by observing CSF backflow or gentle aspiration.

Controlled Infusion: The injection rate must be carefully controlled. Excessively rapid infusion can lead to uneven drug distribution, localized tissue damage, or even microthrombi formation.

Peri-Operative Care: Rigorous pre-operative, intra-operative, and post-operative care is essential.

Rodents: Procedures are relatively straightforward. Key considerations include appropriate anesthetic choice and dosage, maintaining body temperature using heating pads during surgery, and strict aseptic technique around the surgical site to minimize infection risk.

Large Animals (e.g., NHPs): Due to anatomical and physiological similarities to humans, including more complex brain structures, requirements are more stringent. This includes maintaining a sterile environment throughout, administration of prophylactic antibiotics and analgesics, and close post-operative monitoring for any adverse signs requiring intervention. Expertise in large animal neurosurgery, such as that offered by Prisys Biotech, is crucial.

Clinical Guidance: Clinically, MRI is often employed to assist ICV administration. Pre-operative scans allow for precise targeting, while post-operative imaging can confirm drug distribution and monitor patient recovery, helping to manage potential complications.

The choice between ICV and other direct CNS routes like intrathecal (IT) injection often depends on the species and study goals.

Rodent Studies: ICV is frequently the preferred route for direct CSF delivery in mice. Their lumbar cistern is very small, making repeat IT injections challenging. While the cisterna magna offers a larger space, puncture carries a significant risk of damaging the brainstem. Therefore, ICV provides a more reliable and safer alternative for mouse studies. Repeat ICV injections in mice are typically limited (e.g., <5 times) to minimize cumulative tissue damage, often using the same needle trajectory for subsequent doses.

Large Animal Studies: IT injection is generally preferred for larger species like NHPs due to easier access to the lumbar cistern. This is reflected in the non-clinical development pathways for drugs like Nusinersen and Tofersen, where mouse efficacy studies often utilized ICV, while NHP toxicology studies employed IT administration.

Clinical Scenarios: ICV may be chosen clinically when IT administration fails to achieve adequate drug concentrations in the ventricles, when CSF circulation is obstructed, or when the target site is near the ventricles (e.g., intraventricular lesions). Examples include ICV administration of thrombolytics for intraventricular hemorrhage (potentially more effective than IT for clot clearance) or enzyme replacement therapies for lysosomal storage diseases like mucopolysaccharidoses, ensuring penetration into brain tissue. ICV is sometimes considered relatively lower risk in neonates compared to adults, achieving broad distribution across the brain, cerebellum, and spinal cord.

The invasive nature of repeated stereotaxic injections limits the feasibility of chronic ICV dosing. The Ommaya reservoir was developed to address this. It consists of a subcutaneous reservoir connected to a catheter inserted into a lateral ventricle, providing direct, repeatable access to the CSF. Originally designed for administering antifungal agents for meningitis, it is beneficial for patients requiring long-term treatment or those for whom lumbar puncture is difficult (e.g., severe scoliosis).

Advantages: Compared to repeated punctures, the Ommaya reservoir allows for potentially more uniform drug distribution, potentially higher drug concentrations in the subarachnoid space, long-term access for multiple administrations or CSF sampling.

Limitations: Drug penetration into the brain parenchyma beyond a few millimeters from the ependymal surface can be limited. Furthermore, implantation carries risks of long-term complications, including catheter blockage, hemorrhage, and infection.

Advantages:

Direct CNS Access: Similar to IT, ICV bypasses the BBB, delivering drugs directly into the CSF.

High CNS Concentrations: Facilitates achieving therapeutic drug levels throughout the CNS. For example, ICV administration of Nusinersen in mouse models resulted in significant SMN protein upregulation within the CNS, proving more effective for targeting CNS motor neurons than systemic (IV or SC) routes which led to broader, less targeted systemic expression.

Disadvantages & Potential Toxicities:

Invasive Procedure: Requires stereotaxic neurosurgery, carrying inherent risks of infection, hemorrhage, and potentially increased intracranial pressure (ICP).

Technical Skill: Demands significant surgical expertise for accurate and safe placement.

Limited Parenchymal Penetration: Diffusion from the CSF into deeper brain tissue can be limited for some molecules.

Potential Pathological Changes: Non-clinical studies have reported various findings associated with ICV procedures or administered agents, including acute hemorrhage, neuronal vacuolation, reactive gliosis, ventriculomegaly (ventricular enlargement), mononuclear or mixed inflammatory cell infiltrates, macrophage infiltration, and granuloma formation. These changes may correlate with behavioral or cognitive alterations. Rigorous neurohistopathology assessment is a critical component of safety evaluation programs conducted by specialized CROs like Prisys Biotech.

Enzyme replacement therapy (ERT) delivered directly to the CNS via ICV injection is a vital strategy for genetic metabolic disorders affecting the brain. Brineura® is the first FDA-approved CNS-targeted ERT, indicated for CLN2 disease (a form of neuronal ceroid lipofuscinosis). CLN2 is a rare, inherited neurodegenerative disorder caused by deficient TPP1 enzyme activity, leading to lysosomal dysfunction.

Brineura® is administered via ICV infusion (typically every two weeks) using an implanted reservoir system (similar to Ommaya). The recombinant human TPP1 enzyme enters neuronal cells, is transported to lysosomes, and is activated to restore lysosomal function, reducing the accumulation of storage material. Clinical studies demonstrated that Brineura® significantly slowed functional decline in children with CLN2 disease, with efficacy maintained over long-term treatment (up to 240 weeks). Common adverse events included fever, vomiting, headache, meningitis signs, CSF protein changes, ECG abnormalities, seizures, and hypersensitivity, with several potentially related to the administration procedure or device.

Recognizing the challenges of precise CNS delivery, Prisys Biotech has invested in advanced technologies. We have installed a leading image-guided drug delivery platform, the first of its kind in China for preclinical applications, specifically designed to optimize the delivery of investigational agents (including gene and cell therapies) directly into the brain.

Leveraging Prisys Biotech's in-house MRI capabilities, this system combines specialized MRI-compatible hardware and software for meticulous planning of surgical trajectories and real-time guidance of infusion cannulas to the intended target. Key advantages include:

Sub-millimetric Accuracy: Ensuring precise placement critical for efficacy and safety.

Target Accessibility: Enabling reliable access to multiple deep anatomical targets via minimally invasive procedures performed by our skilled team.

Optimized Micro-infusion: Facilitating techniques like Convection-Enhanced Delivery (CED) to improve drug distribution within the target structure.

Translational Continuity: Providing consistency in methodology from preclinical studies through potential clinical trials.

This commitment to precision technology underscores Prisys Biotech's dedication to supporting the development of novel CNS therapies by addressing the technical challenges inherent in routes like ICV administration.

Conclusion

Intracerebroventricular (ICV) injection is a valuable, albeit technically demanding, route for delivering therapeutics directly to the CNS in preclinical research and specific clinical situations. Its ability to achieve widespread CSF distribution makes it suitable for certain disease models and therapeutic strategies. However, careful consideration of procedural specifics, species differences, potential toxicities, and the need for specialized surgical expertise and technologies, like those offered by Prisys Biotech, are essential for successful and safe implementation. Rigorous non-clinical evaluation is critical for advancing CNS therapies utilizing this important delivery pathway.