TY - JOUR
T1 - Intrathecal delivery of protein therapeutics to the brain
T2 - A critical reassessment
AU - Calias, Pericles
AU - Banks, William A.
AU - Begley, David
AU - Scarpa, Maurizio
AU - Dickson, Patricia
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Blood-brain barrier
KW - Central nervous system
KW - Drug delivery
KW - Intracerebroventricular
KW - Intrathecal
KW - Recombinant proteins
UR - http://www.scopus.com/inward/record.url?scp=84907885590&partnerID=8YFLogxK
U2 - 10.1016/j.pharmthera.2014.05.009
DO - 10.1016/j.pharmthera.2014.05.009
M3 - Article
C2 - 24854599
AN - SCOPUS:84907885590
SN - 0163-7258
VL - 144
SP - 114
EP - 122
JO - Pharmacology and Therapeutics
JF - Pharmacology and Therapeutics
IS - 2
ER -