Central nervous system delivery of large molecules: challenges and new frontiers for intrathecally administered therapeutics.

IMPORTANCE OF THE FIELD: Therapeutic proteins and DNA constructs offer promise for the treatment of central nervous system disorders, yet significant biological barriers limit the ability of these molecules to reach the central nervous system from the bloodstream. Direct administrations to the cerebrospinal fluid (intrathecal administration) comprise an emerging field to facilitate the efficient delivery of these biological macromolecules to central nervous system tissues. AREAS COVERED IN THIS REVIEW: Previous reports from 1990 to the present time describing the interactions and turnover of the cerebrospinal fluid within the intrathecal space, characterizations of the effects that therapeutic proteins and DNA have shown after intrathecal delivery through a lumbar route, and reports of emerging technologies to address the limitations of intrathecally administered macromolecules are reviewed. WHAT THE READER WILL GAIN: This review provides an overview of the limitations that must be overcome for intrathecally administered biological macromolecules and the recent advances and promising approaches for surmounting these limitations. TAKE HOME MESSAGE: Emerging approaches that stabilize and sustain the delivery of intrathecally administered biological macromolecules may enhance substantially the clinical relevance of promising therapeutic proteins and DNA constructs for the treatment of various central nervous system disorders.