Intrathecal delivery of Macromolecules: Clinical status and emerging technologies

The proximity and association of cerebrospinal fluid (CSF) and the intrathecal (IT) space with deep targets in the central nervous system (CNS) parenchyma makes IT injection an attractive route of administration for brain drug delivery. However, the extent to which intrathecally administered macromolecules are effective in treating neurological diseases is a question of both clinical debate and technological interest. We present the biological, chemical, and physical properties of the intrathecal space that are relevant to drug absorption, distribution, metabolism, and elimination from CSF. We then analyze the evolution of IT drug delivery in clinical trials over the last 20 years. Our analysis revealed that the percentage of clinical trials assessing IT delivery for the delivery of biologics (i.e., macromolecules, cells) for treatment of chronic conditions (e.g., neurodegeneration, cancer, and metabolic diseases) has steadily increased. Clinical trials exploring cell or macromolecular delivery within the IT space have not evaluated engineering technologies, such as depots, particles, or other delivery systems. Recent pre-clinical studies have evaluated IT macromolecule delivery in small animals, postulating that delivery efficacy can be assisted by external medical devices, micro- or nanoparticles, bulk biomaterials, and viral vectors. Further studies are necessary to evaluate the extent to which engineering technologies and IT administration improve CNS targeting and therapeutic outcome.

Automated summary

The proximity and association of cerebrospinal fluid (CSF) and the intrathecal (IT) space with deep targets in the central nervous system (CNS) parenchyma makes IT injection an attractive route for brain drug delivery. However, the effectiveness of intrathecally administered macromolecules in treating neurological diseases is still debated. Our analysis of clinical trials over the past 20 years shows an increasing interest in using IT delivery for the treatment of chronic conditions with biologics. Engineering technologies have not been extensively evaluated in these trials, but recent pre-clinical studies suggest their potential in improving CNS targeting and therapeutic outcome.