Project details

Click here to search on field of study or keyword

A Randomized controlled trial: The efficacy of Ambroxol on the Parkinson’s disease motor symptoms in patients carrying a GBA mutation.
Keywords: Parkinson&#039;s disease Disease modifying therapy GBA1-gene
Researchers: prof. dr. T. van Laar O. Siemeling
Type of project: Stage Wetenschap / Researchproject of MD/PhD programme
Nature of the research: Experimental, Therapeutic exploratory, Randomized, placebo-controlled trial
Fields of study: neurology

Background / introduction

The pathological cause of Parkinson’s disease (PD) is related to aggregation of the protein alpha-synuclein (aSyn) in the nervous system. The most common genetic risk factor for PD is a heterozygous mutation of the GBA1 (GBA) gene, encoding the lysosomal enzyme glucocerebrosidase (GCase). Reduced GCase activity in the brain is associated with increased levels of aSyn. Currently, there are no therapies available that slow down disease progression, which is the most important unmet need in PD treatment. Ambroxol has potential as a neuroprotective drug for the treatment of patients with Parkinson’s disease both with and without GBA1 mutation. In vivo and in vitro studies showed that high dosages of Ambroxol increases GCase enzyme activity and reduces aSyn levels. This prospective placebo-controlled trial aims to determine the effect of Ambroxol on the clinical PD motor symptoms of patients carrying a GBA mutation.

Research question / problem definition

This study investigates the efficacy and safety of high dosages of Ambroxol on the clinical Parkinson’s disease motor symptoms of patients carrying a GBA mutation compared to placebo. Furthermore we are interested in the effect of Ambroxol on the striatal F-DOPA uptake as measured by FDOPA-PET, integrity of the nigrostriatal fibers measured by MR imaging, GCase activity measured in peripheral blood mononuclear cells, cognition, nonmotor symptoms and quality of life.

Workplan

This randomized, placebo-controlled trial will be conducted in the department of Neurology, University Medical Center Groningen. The student will participate in collecting data, data-analysis and writing process. Baseline measurements consist of a motor assessment, neuroimaging including MRI and FDOPA-PET, a blood draw, neuropsychological assessment and questionnaires on nonmotor symptoms and quality of life. Every 12 weeks motor assessment is repeated. Data-analysis and writing will also be performed within the longitudinal Dutch Parkinson Cohort (DUPARC) study in the periods that the clinical drug trial is ongoing. Research questions will focus on better phenotyping Parkinson’s disease patients with GBA mutations and the disease modifying properties and side-effects of Ambroxol. Besides a master thesis, publication of the results in a scientific journal is encouraged and the ambition to continue this line of research in a (MD-)PhD trajectory is preferred.

References

1. Kalia L V., Lang AE. Parkinson’s disease. Lancet. 2015;386(9996):896–912.
2. den Heijer JM, Cullen VC, Quadri M, Schmitz A, Hilt DC, Lansbury P, et al. A Large-Scale Full GBA1 Gene Screening in Parkinson’s Disease in the Netherlands. Mov Disord. 2020;35(9):1667–74.
3. McNeill A, Magalhaes J, Shen C, Chau KY, Hughes D, Mehta A, et al. Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain. 2014;137(5):1481–95.
4. Mullin S, Smith L, Lee K, D’Souza G, Woodgate P, Elflein J, et al. Ambroxol for the Treatment of Patients with Parkinson Disease with and Without Glucocerebrosidase Gene Mutations: A Nonrandomized, Noncontrolled Trial. JAMA Neurol. 2020;77(4):427–34.

top