Intraputamenal Cerebral Dopamine Neurotrophic Factor in Parkinson's Disease: A Randomized, Double-Blind, Multicenter Phase 1 Trial.
clinical trial
convection-enhanced delivery
movement disorder
neurotrophic factor
synucleinopathy
transcutaneous port
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
07 2023
07 2023
Historique:
revised:
27
03
2023
received:
19
10
2022
accepted:
13
04
2023
medline:
31
7
2023
pubmed:
22
5
2023
entrez:
22
5
2023
Statut:
ppublish
Résumé
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). 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. 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 [ 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. 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.
Sections du résumé
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 [
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.
Substances chimiques
Dopamine
VTD58H1Z2X
Nerve Growth Factors
0
Types de publication
Randomized Controlled Trial
Multicenter Study
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1209-1222Informations de copyright
© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Références
Kalia LV, Lang AE. Parkinson's disease. Lancet 2015;386(9996):896-912.
Poewe W, Seppi K, Tanner CM, et al. Parkinson disease. Nat Rev Dis Primers 2017;3:17013.
Tarakad A, Jankovic J. Diagnosis and management of Parkinson's disease. Semin Neurol 2017;37(2):118-126.
Höllerhage M, Klietz M, Höglinger GU. Disease modification in parkinsonism: obstacles and ways forward. J Neural Transm (Vienna) 2022;129(9):1133-1153.
Airaksinen MS, Saarma M. The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 2002;3(5):383-394.
Huang EJ, Reichardt LF. Neurotrophins: roles in neuronal development and function. Annu Rev Neurosci 2001;24:677-736.
Nutt JG, Burchiel KJ, Comella CL, et al. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 2003;60(1):69-73.
Slevin JT, Gerhardt GA, Smith CD, Gash DM, Kryscio R, Young B. Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J Neurosurg 2005;102(2):216-222.
Lang AE, Gill S, Patel NK, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 2006;59(3):459-466.
Whone A, Luz M, Boca M, et al. Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson's disease. Brain 2019;142(3):512-525.
Marks WJ Jr, Bartus RT, Siffert J, et al. Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial. Lancet Neurol 2010;9(12):1164-1172.
Paul G, Zachrisson O, Varrone A, et al. Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients. J Clin Invest 2015;125(3):1339-1346.
Salvatore MF, Ai Y, Fischer B, et al. Point source concentration of GDNF may explain failure of phase II clinical trial. Exp Neurol 2006;202(2):497-505.
Bartus RT, Johnson EM Jr. Clinical tests of neurotrophic factors for human neurodegenerative diseases, part 2: where do we stand and where must we go next? Neurobiol Dis 2017;97(Pt B):169-178.
Barker RA, Bjorklund A, Gash DM, et al. GDNF and Parkinson's disease: where next? A summary from a recent workshop. J Parkinsons Dis 2020;10(3):875-891.
Björklund A. GDNF therapy: can we make it work? J Parkinsons Dis 2021;11(3):1019-1022.
Lindholm P, Voutilainen MH, Lauren J, et al. Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo. Nature 2007;448(7149):73-77.
Lindahl M, Chalazonitis A, Palm E, et al. Cerebral dopamine neurotrophic factor-deficiency leads to degeneration of enteric neurons and altered brain dopamine neuronal function in mice. Neurobiol Dis 2020;134:104696.
Chalazonitis A, Li Z, Pham TD, et al. Cerebral dopamine neurotrophic factor is essential for enteric neuronal development, maintenance, and regulation of gastrointestinal transit. J Comp Neurol 2020;528(14):2420-2444.
Airavaara M, Harvey BK, Voutilainen MH, et al. CDNF protects the nigrostriatal dopamine system and promotes recovery after MPTP treatment in mice. Cell Transplant 2012;21(6):1213-1223.
Voutilainen MH, Back S, Peranen J, et al. Chronic infusion of CDNF prevents 6-OHDA-induced deficits in a rat model of Parkinson's disease. Exp Neurol 2011;228(1):99-108.
Lindholm P, Saarma M. Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism. Mol Psychiatry 2022;27(3):1310-1321.
Huttunen HJ, Saarma M. CDNF protein therapy in Parkinson's disease. Cell Transplant 2019;28(4):349-366.
Albert K, Raymundo DP, Panhelainen A, et al. Cerebral dopamine neurotrophic factor reduces alpha-synuclein aggregation and propagation and alleviates behavioral alterations in vivo. Mol Ther 2021;29(9):2821-2840.
Sidorova YA, Saarma M. Can growth factors cure Parkinson's disease? Trends Pharmacol Sci 2020;41(12):909-922.
Mätlik K, Vihinen H, Bienemann A, et al. Intrastriatally infused exogenous CDNF is endocytosed and retrogradely transported to substantia Nigra. eNeuro 2017;4(1):ENEURO.0128-16.2017.
Subramanian K, Lindholm P, Palm E, et al. CDNF improves general and fine motor performance and non-motor symptoms in MPTP lesion model of Parkinson's disease in non-human primates. Manuscript 2022.
Ebersbach G, Baas H, Csoti I, Mungersdorf M, Deuschl G. Scales in Parkinson's disease. J Neurol 2006;253 Suppl 4:IV32-IV35.
Poewe W. Clinical measures of progression in Parkinson's disease. Mov Disord 2009;24(Suppl 2):S671-S676.
Hollingworth M, Hurter C, Wooley M, Lewis O, Gill S, Zacharoulis S. DIPG-65. Preliminary experience of chronic intermittent convection enhanced delivery of carboplatin and valproic acid for the treatment of diffuse intrinsic pontine glioma following radiation therapy. Neuro Oncol 2018;20(Suppl 2):i62.
Fazio P, Svenningsson P, Forsberg A, et al. Quantitative analysis of (1)(8)F-(E)-N-(3-iodoprop-2-enyl)-2beta-carbofluoroethoxy-3beta-(4′-methyl-phenyl) nortropane binding to the dopamine transporter in Parkinson disease. J Nucl Med 2015;56(5):714-720.
Fazio P, Svenningsson P, Cselenyi Z, Halldin C, Farde L, Varrone A. Nigrostriatal dopamine transporter availability in early Parkinson's disease. Mov Disord 2018;33(4):592-599.
Kerstens VS, Fazio P, Sundgren M, et al. Reliability of dopamine transporter PET measurements with [(18)F]FE-PE2I in patients with Parkinson's disease. EJNMMI Res 2020;10(1):95.
Griffiths RI, Kotschet K, Arfon S, et al. Automated assessment of bradykinesia and dyskinesia in Parkinson's disease. J Parkinsons Dis 2012;2(1):47-55.
Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson's disease. Mov Disord 2010;25(15):2649-2653.
European Medicines Agency. EMA's final opinion confirms restrictions on use of linear gadolinium agents in body scans. EMA/625317/2017 2017.
Szychot E, Walker D, Collins P, et al. Clinical experience of convection-enhanced delivery (CED) of carboplatin and sodium valproate into the pons for the treatment of diffuse intrinsic pontine glioma (DIPG) in children and young adults after radiotherapy. Int J Clin Oncol 2021;26(4):647-658.
Moran C, Sarangmat N, Gerard CS, et al. Two hundred twenty-six consecutive deep brain stimulation electrodes placed using an “Asleep” technique and the neuro|MateTM robot for the treatment of movement disorders. Oper Neurosurg (Hagerstown) 2020;19(5):530-538.
Kiringoda R, Lustig LR. A meta-analysis of the complications associated with osseointegrated hearing aids. Otol Neurotol 2013;34(5):790-794.
Brown EG, Wood L, Wood S. The medical dictionary for regulatory activities (MedDRA). Drug Saf 1999;20(2):109-117.
van Putten EH, Wembacher-Schröder E, Smits M, Dirven CM. Magnetic resonance imaging-based assessment of gadolinium-conjugated diethylenetriamine penta-acetic acid test-infusion in detecting dysfunction of convection-enhanced delivery catheters. World Neurosurg 2016;89:272-279.
Whone AL, Boca M, Luz M, et al. Extended treatment with glial cell line-derived neurotrophic factor in Parkinson's disease. J Parkinsons Dis 2019;9(2):301-313.