TY - JOUR T1 - PET imaging of enzyme pharmacokinetics in rats after IV and IT administration JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1226 LP - 1226 VL - 50 IS - supplement 2 AU - Mikhail Papisov AU - Vasily Belov AU - Alan Fischman AU - Ali Bonab AU - Marc Wiles AU - Hongsheng Xie AU - Michael Heartlein AU - Pericles Calias Y1 - 2009/05/01 UR - http://jnm.snmjournals.org/content/50/supplement_2/1226.abstract N2 - 1226 Objectives Hunter Syndrome, Metachromatic Leukodystrophy and Sanfilippo Syndrome are genetic lysosomal storage diseases (LSD) characterized by CNS degeneration as well as somatic symptoms. There are no effective treatments to alleviate the neurological component of these diseases. Literature indicates that delivery of enzymes into the cerebrospinal fluid (CSF) may result in reduced levels of their substrates in the brain and spinal cord. The objective of this study was to investigate the pharmacokinetics of three respective enzyme replacement therapeutics after intrathecal (IT) administration. Methods Human recombinant enzymes, idursulfase, arylsulfatase A, and sulfamidase, were labeled with 124I and administered at 1 and 10 mg/kg via two routes, IV and IT. Dynamic imaging data and multiple static images were acquired over 8 days, and processed to determine the principal PK parameters. FITC labeled sulfamidase was also utilized to investigate brain cryosections by photoimaging. Results IT administration resulted in rapid protein distribution over the entire CSF volume, including distal spine. The initial label content in the brain was 0.20%, 0.15% and 0.05% of injected dose/g after IV and 45%, 70% and 35% after IT administration for Idursulfase, arylsulfatase A, and sulfamidase, respectively. Idursulfase was cleared from both the brain and spinal cord with a half-life of ca. 7h, while the other two enzymes of ca. 24h. Photoimaging studies indicated enzyme deposition in pia mater as well as in the deeper layers. Conclusions The data suggest that enzyme administration to CSF can be beneficial for therapy of the CNS component of LSD. ER -