Intrathecal delivery of protein therapeutics to the brain: a critical reassessment.
Disorders of the central nervous system (CNS), including stroke, neurodegenerative diseases, and brain tumors, are the world's leading causes of disability. Delivery of drugs to the CNS is complicated by the blood-brain barriers that protect the brain from the unregulated leakage and entry of substances, including proteins, from the blood. Yet proteins represent one of the most promising classes of therapeutics for the treatment of CNS diseases. Many strategies for overcoming these obstacles are in development, but the relatively straightforward approach of bypassing these barriers through direct intrathecal administration has been largely overlooked. Originally discounted because of its lack of usefulness for delivering small, lipid-soluble drugs to the brain, the intrathecal route has emerged as a useful, in some cases perhaps the ideal, route of administration for certain therapeutic protein and targeted disease combinations. Here, we review blood-brain barrier functions and cerebrospinal fluid dynamics and their relevance to drug delivery via the intrathecal route, discuss animal and human studies that have investigated intrathecal delivery of protein therapeutics, and outline several characteristics of protein therapeutics that can allow them to be successfully delivered intrathecally.
Shire, Lexington, MA, USA. Electronic address: pcalias@shire.com.
Pericles
P
Calias
Geriatrics Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care Center, Seattle, WA, USA; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA.
William A
WA
Banks
Institute of Pharmaceutical Science, King's College London, London, UK.
David
D
Begley
Department of Paediatrics, University of Padova, Padova, Italy.
Maurizio
M
Scarpa
Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA, USA.
Patricia
P
Dickson
D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002493:Central Nervous System Diseases / Q000188:drug therapy*; D002555:Cerebrospinal Fluid / Q000378:metabolism*; D006801:Humans; D057446:Hydrodynamics; D007278:Injections, Spinal; D011994:Recombinant Proteins / Q000008:administration & dosage*
D011994:Recombinant Proteins
Blood–brain barrier; Central nervous system; Drug delivery; Intracerebroventricular; Intrathecal; Recombinant proteins