Journal Article

Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson’s disease patients

Lind, Göran, Paul, Gesine, Almqvist, Per, Jerling, Markus, Widner, Håkan, Svensson, Mikael, Mercer, Katarina Jansson, Varrone, Andrea, Linderoth, Bengt, Halldin, Christer, Rehncrona, Stig, Forsberg, Anton, Coffey, Robert, Shafer, Lisa L., Frisén, Jonas, Zachrisson, Olof, Bjartmarz, Hjalmar, Svenningsson, Per, Haegerstrand, Anders, Pålhagen, Sven

2015

Overview

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).

• Publisher: American Society for Clinical Investigation
• Subject: Aged / Antiparkinson Agents - administration & dosage / Antiparkinson Agents - adverse effects / Behavior / Biomedical research / Care and treatment / Catheters / Cell growth / Clinical Medicine / Dopamine Plasma Membrane Transport Proteins - metabolism / Dose-response relationship (Biochemistry) / Double-Blind Method / Drug dosages / Drug therapy / Health aspects / Humans / Injections, Intraventricular / Klinisk medicin / Male / Medical and Health Sciences / Medicin och hälsovetenskap / Middle Aged / Neurologi / Neurology / Parkinson Disease - drug therapy / Parkinson's disease / Pharmacology, Experimental / Platelet-derived growth factor / Protein Binding / Proto-Oncogene Proteins c-sis - administration & dosage / Proto-Oncogene Proteins c-sis - adverse effects / Putamen - drug effects / Putamen - metabolism / Rodents / Studies / Surgical outcomes / Treatment Outcome