Date: January 2020
Prepared by SIC Member: Roy Alcalay, MD, MS
Authors: Eliezer Masliah, MD; David Arkadir, MD PhD; Brian Fiske, PhD
Editor: Un Jung Kang, MD
Many vitamins and food supplements have been tested for the treatment of Parkinson’s disease (PD), including vitamin E, coenzyme Q 10, inosine and others. The notion that a food supplement may be helpful for PD is very attractive. Vitamins and supplements are usually well tolerated, and if ever demonstrated to be beneficial to those with PD, they could potentially be used in at-risk population for PD prevention. Mannitol is a sweetener commonly used as a sugar substitute (approved for diabetics), and is made by hydrogenation of fructose. Treatment of PD with mannitol has received traction in Israel and worldwide with a double-blind trial expecting results in 2022. Here, three experts discuss the rational and the best methodology of testing mannitol for the treatment of PD. Dr. Eliezer Masliah discusses the basic science on the use of mannitol for PD. Drs. David Arkadir and Brian Fiske discuss the different methodologies (i.e., clinical trial, “crowd research,” others) to explore the potential role of mannitol in PD.
What is the science that may support testing mannitol for treatment of people with PD?
Eliezer Masliah, MD; National Institute on Aging, National Institutes of Health, Bethesda, MD, USA
The neurodegenerative process in PD and related disorders such as dementia with Lewy bodies and multiple system atrophy has been associated with progressive accumulation and propagation of the synaptic protein α-synuclein (α-syn), therefore there is interest in identifying compounds capable of interfering with this process. In a small-scale screen of small molecules (primarily polyols) capable of inhibiting the aggregation of α-syn in vitro the sugar mannitol was identified as one of the hits1. Using a ThT fluorescence assay and Transmission Electron Microscopy (TEM), mannitol was shown to inhibit fibrillization of α-syn at the lower concentrations tested (0.225M and 0.45M), while the higher concentration (0.9M) significantly decreased the formation of oligomers. Although the lower concentrations of mannitol did not inhibit formation of α-syn oligomers, they affected their secondary structure. Therefore, we presume that mannitol exerts effect by directing α-syn oligomers to an alternative pathway of aggregation although this possibility remains to be elucidated.
As an initial test in vivo1, the effects of mannitol were assessed in a transgenic Drosophila fruit fly model that expresses a highly aggregative variant of α-syn (A53T) in their nervous system and established as a model of PD. Mannitol markedly corrected their locomotion defects. This was accompanied by approximately 70% reduction in α-syn aggregates in the brains of mannitol-treated flies as compared with the non-treated group.
These results were subsequently corroborated in the mThy1-a-syn transgenic mice,1 which were injected IP with mannitol (1 g/kg) daily for four weeks, starting at an age of 16 weeks. Immunohistochemical analysis and western blotting revealed that mannitol treatment reduced a-syn accumulation in the hippocampus, basal ganglia and substantia nigra, which are the main brain regions affected in PD. Total accumulation of a-syn in the brain of the transgenic mice was decreased in both soluble and insoluble fractions as compared with non-treated transgenic mice. Moreover, mannitol treatment ameliorated the loss of dopaminergic fibers as evidence by the restoration of tyrosine hydroxylase immunoreactivity in the basal ganglia.
The mechanisms of neuroprotection mediated by mannitol are not fully understood. Certainly blocking aggregation and formation of toxic a-syn multimers might play a role; however other effects related such as the antioxidant properties might be important. Moreover, mannitol has been shown to increase the molecular chaperone HSP-70, which is a marker of cellular response to stress or injury and is part of the cell's protein folding and quality control machinery.
Dr. Arkadir, can you describe your experience and plans with regards to testing mannitol in people with PD?
David Arkadir, MD PhD; Hadassah Medical Center and the Hebrew University, Jerusalem, Israel
Non-patentable substances, such as mannitol, with a potential to slow the progression of PD, or even to revert it, are constantly suggested. Such suggestions are based on personal experience of patients and doctors, on theoretical assumptions, on epidemiological studies, and on in vitro or in vivo animal experiments. A 'critical mass' of evidence is required before efforts are given to robustly test the true effect of such substances in humans. But even when enough evidences are accumulated, in many cases, some non-patentable substances would never be tested. From the story of mannitol we can learn about the possible fates of non-patentable substances.
The potential of high-dose mannitol to reduce aggregation of a-synuclein (in vivo and in vitro) and to restore the motor activity in the fruit-fly model of Parkinson's disease was published in 2013 (by Shaltiel-Karyo and colleagues1). Following this publication, a small number of Parkinson's patients around the world started taking mannitol. At that point, the lack of interest of the medical community in studying the effects of mannitol led a group of enthusiastic friends with personal connections to Parkinson's disease to establish Clinicrowd, a free website to collect data regarding the use of mannitol from patients. The fate of mannitol took a different course when in 2016 a famous Israeli patient publically reported that he suffered from PD and described a dramatic benefit he had from mannitol. Large number of Parkinson's patients started taking mannitol following this, with variable subjective reports regarding the relief of symptoms.
This situation where a large number of patients consuming a substance that was pre-clinically shown to be effective in experimental models, but the lack of robust clinical trials to test this hypothesis, required a change. Luckily, public funding (from the Israeli ministry of science and technology) that would support such a trial was received. The first double-blind clinical trial of mannitol in PD started in our center (Hadassah Medical Center, Jerusalem, Israel, ClinicalTrials.gov Identifier: NCT03823638) in late 2018 and is expected to end by early 2022.
So what did I learn from the mannitol story? That public and philanthropic support is crucial for testing the true potential of non-patentable substances; that enthusiastic individuals can advocate for trials; and that a bit of luck can always help, even for chemical substances.
Some websites (such as CLINICROWD and Fox Insight) provide an online platform for people with PD to report the effect of interventions like mannitol on their symptoms. Should we consider such alternative tools to test vitamins and supplements in PD, or should we stick to clinical trials?
Brian Fiske, PhD; The Michael J. Fox Foundation for Parkinson’s Research, New York, NY, USA
The gold standard for assessing clinical benefit of therapeutic interventions is the randomized controlled trial. Traditionally, such trials are conducted in clinic, where variables that might influence study endpoints can be more carefully controlled, ultimately increasing confidence in trial results. However, there are challenges to this approach. Participants must reside within reasonable geographic distance from clinical sites, which limits inclusion of participants (including often more diverse and under-represented communities) and can be a delay to study recruitment timelines. Participants are usually assessed in artificial surroundings, providing a brief ‘snapshot’ of their current health status that may not adequately reflect issues they experience in the home or real-world environment. Additionally, costs for supporting clinical site staff and other study expenses (e.g., transportation, parking, etc.) can increase the overall expense for doing clinical trials. These issues can limit how many trials are funded and performed, reducing the number of potentially promising ideas that can be tested at any time.
With technological advances, the ability to conduct studies remotely through online platforms has become an area of increasing interest. These platforms offer opportunities to engage people wherever they live, increasing the involvement and diversity of patient input and accelerating the collection of data. Paired with other technologies (e.g., remote monitoring devices), such approaches can increase the kinds of data and information collected in a trial. As an example, at The Michael J. Fox Foundation for Parkinson’s Research, we have been using our own online portal Fox Insight (https://foxinsight.michaeljfox.org/) to survey people with Parkinson’s disease (as well as healthy controls) on a variety of issues related to their disease. More recently, we’ve begun — in collaboration with leading clinical experts — to ask participants about their experience with various types of interventions, such as mindfulness and meditation, as a way to obtain more insight on the impact of these approaches where some data exist that could be clarified with real-world information from a larger and diverse population of people with Parkinson’s.
Importantly, it is not an either/or debate about whether in-clinic or online trial methods are better for testing interventions such as mannitol. Online platforms can provide insight that may not be seen in the clinic and at a scale that traditional studies could never achieve, but by their nature they are ‘messy’: many confounds (e.g., treatment compliance, ability to use properly blinded controls) are much harder to address in remote environments. If robust, rigorous and well-controlled data are critical for making important decisions about future drug development investment or medical care, a trial must still meet high standards regardless of where and how data are obtained. Online platforms currently offer the ability to obtain data on questions that can guide understanding of the experience and impact of a potentially promising intervention and with inclusion of remote monitoring devices and even ability to collect basic biosamples through mailed kits, might even allow answering more sophisticated questions. But additional investment, design consideration and community buy-in may be needed to create platforms that can truly replace the rigor of traditional trials.
So how do we proceed with mannitol? A Phase II trial is already underway in Israel which may address many important questions around safety, tolerability and potential effects on disease and symptom progression. One consideration would be to explore whether additional data around some of the clinical outcomes currently planned for the trial could be enhanced (or at least informed) by data collected from online platforms to further verify or understand signals seen in the formal trial. Such a hybrid model might be a useful way to understand more fully the value and impact of mannitol (or other drugs like it) while also providing data on the realistic potential of online platforms for testing future promising Parkinson’s therapies.
1Shaltiel-Karyo R, Frenkel-Pinter M, Rockenstein E, Patrick C, Levy-Sakin M, Schiller A, Egoz-Matia N, Masliah E, Segal D, Gazit E. J Biol Chem. 2013 Jun 14;288(24):17579-88. PMC3682557