title: Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients.
abstract: BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 μg rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD. TRIAL REGISTRATION. Clinical Trials.gov NCT00866502. FUNDING. Newron Sweden AB (former NeuroNova AB) and Swedish Governmental Agency for Innovation Systems (VINNOVA).
authors.forename: Gesine
authors.initials: G
authors.lastname: Paul
authors.forename: Olof
authors.initials: O
authors.lastname: Zachrisson
authors.forename: Andrea
authors.initials: A
authors.lastname: Varrone
authors.forename: Per
authors.initials: P
authors.lastname: Almqvist
authors.forename: Markus
authors.initials: M
authors.lastname: Jerling
authors.forename: Göran
authors.initials: G
authors.lastname: Lind
authors.forename: Stig
authors.initials: S
authors.lastname: Rehncrona
authors.forename: Bengt
authors.initials: B
authors.lastname: Linderoth
authors.forename: Hjalmar
authors.initials: H
authors.lastname: Bjartmarz
authors.forename: Lisa L
authors.initials: LL
authors.lastname: Shafer
authors.forename: Robert
authors.initials: R
authors.lastname: Coffey
authors.forename: Mikael
authors.initials: M
authors.lastname: Svensson
authors.forename: Katarina Jansson
authors.initials: KJ
authors.lastname: Mercer
authors.forename: Anton
authors.initials: A
authors.lastname: Forsberg
authors.forename: Christer
authors.initials: C
authors.lastname: Halldin
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
authors.forename: Håkan
authors.initials: H
authors.lastname: Widner
authors.forename: Jonas
authors.initials: J
authors.lastname: Frisén
authors.forename: Sven
authors.initials: S
authors.lastname: Pålhagen
authors.forename: Anders
authors.initials: A
authors.lastname: Haegerstrand
mesh_terms: D000368:Aged; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000077214:Becaplermin; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004311:Double-Blind Method; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy*; D011485:Protein Binding; D020574:Proto-Oncogene Proteins c-sis / Q000008:administration & dosage* / Q000009:adverse effects; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000978:Antiparkinson Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin