Intraputamenal Cerebral Dopamine Neurotrophic Factor in Parkinson's Disease: A Randomized, Double‐Blind, Multicenter Phase 1 Trial

Abstract

Background Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD). Objective The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity. Methods We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone‐anchored transcutaneous port connected to four catheters. This phase 1 trial was divided into a placebo‐controlled, double‐blind, 6‐month main study followed by an active‐treatment 6‐month extension. Eligible patients, aged 35 to 75 years, had moderate idiopathic PD for 5 to 15 years and Hoehn and Yahr score ≤ 3 (off state). Seventeen patients were randomized to placebo (n = 6), 0.4 mg CDNF (n = 6), or 1.2 mg CDNF (n = 5). The primary endpoints were safety and tolerability of CDNF and DDS and catheter implantation accuracy. Secondary endpoints were measures of PD symptoms, including Unified Parkinson's Disease Rating Scale, and DDS patency and port stability. Exploratory endpoints included motor symptom assessment (PKG, Global Kinetics Pty Ltd, Melbourne, Australia) and positron emission tomography using dopamine transporter radioligand [18F]FE‐PE2I. Results Drug‐related adverse events were mild to moderate with no difference between placebo and treatment groups. No severe adverse events were associated with the drug, and device delivery accuracy met specification. The severe adverse events recorded were associated with the infusion procedure and did not reoccur after procedural modification. There were no significant changes between placebo and CDNF treatment groups in secondary endpoints between baseline and the end of the main and extension studies. Conclusions Intraputamenally administered CDNF was safe and well tolerated, and possible signs of biological response to the drug were observed in individual patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

CDNF and MANF in the brain dopamine system and their potential as treatment for Parkinson’s disease

“…In cells, CDNF and MANF localize in the endoplasmic reticulum (ER) (19,20), where they regulate protein homeostasis and ER stress-induced unfolded protein response (UPR) signaling (21)(22)(23)(24)(25). As a potential therapeutic factor for dopamine neurons, CDNF was tested in Phase I-II clinical trials in 17 PD patients, where it was shown to be safe and well tolerated (26,27).…”

Combining fibril‐induced alpha‐synuclein aggregation and 6‐hydroxydopamine in a mouse model of Parkinson's disease and the effect of cerebral dopamine neurotrophic factor on the induced neurodegeneration

“…Cerebral dopamine neurotrophic factor (CDNF) is a protein with neurotrophic factor properties that has reached its safety and tolerability endpoint in its first phase I/II clinical trials in PD patients (Huttunen et al, 2023;ClinicalTrials.gov identifier: NCT03295786, NCT03775538). CDNF is a 161 amino acid long protein, endogenously present in the brain and various nonneuronal tissues such as skeletal muscle and testis of both humans and mice (Lindholm et al, 2007).…”