MSA Coalition Research Grants – Funded Projects

Listed below are the research projects funded by The Multiple System Atrophy Coalition as part of the MSA Research Grant Program.  The below projects were selected from many applications after bing reviewed and ranked by The MSA Coalition’s Scientific Advisory Board (SAB).  These projects are deemed to have strong scientific merit toward accomplishing The MSA Coalition’s primary mission of identifying a cause and a cure for MSA.

2015 MSA Research Grant Award Recipients:

“Global MSA Registry & Natural History Study – Year 2”: Gregor Wenning, M.D, Ph.D. (Innsbruck Medical University) and Lucy Norcliffe-Kaufmann, Ph.D. (New York University)

This project aims to establish the first-ever global registry dedicated to Multiple System Atrophy patients.  Facilitating future worldwide clinical trials, the registry will be used to notify all patients that meet study entry criteria for clinical trials in MSA on an international scale.  The registry will also provide a means for sharing anonymous patient information to define the disease specific characteristics and establish the definitive natural history of MSA.  Registered patients will be followed thoroughly and periodically to identify potential biological markers of disease risk and severity in a global, worldwide longitudinal prospective study.

“Combination of immunotherapy against alpha-synuclein and anti-inflammatory treatment for Multiple System Atrophy”: Eliezer Masliah, M.D. (University of California San Diego)

Multiple system atrophy (MSA) is a rare and devastating neurological disease that impairs body functions and that shares many Parkinson’s disease symptoms. Sadly, there is no treatment that stops the evolution of MSA and current therapies are focused on managing its symptoms. At the molecular level, MSA is characterized by the abnormal accumulation of the protein alpha-synuclein within brain cells, and it is believed that this accumulation is behind the cell death and inflammation observed in the brain. Therefore, our objective is to explore the potential use of the combination of two therapies in order to restore normal alpha-synuclein and inflammation levels. These therapies are immunization against alpha-synuclein, in order to reduce its levels, together with the use of a potent anti-inflammatory drug, lenalidomide, aimed to reduce pathological brain inflammation. We believe that the combined use of both therapies will have synergistic protective effects in an animal model of MSA, and that such approach could be applied to the treatment of MSA patients.

“Understanding the degradation of alpha-synuclein protein in MSA”: Janice Holton, M.D, Ph.D. (University College of London)

In multiple system atrophy (MSA) a protein called αlpha-synuclein sticks together in oligodendrocytes to form glial cytoplasmic inclusions (GCIs). Oligodendrocytes are specialized brain cells that are crucial for supporting neurons. There is no increase in the production of αlpha-synuclein in MSA, so we believe that the breakdown of αlpha-synuclein from the brain may not be working properly.  We will look at 2 substances, known as proteases, called cathepsin D (CTSD) and kallikrein 6 (KLK6), which breakdown αlpha-synuclein. CTSD and KLK6 are particularly relevant to MSA because they are found in neurons, oligodendrocytes and inside GCIs. Alpha-synuclein also clumps together in Parkinson’s disease (PD) where nerve cells are the main target. CTSD and KLK6 may have reduced activity in PD contributing to the accumulation of αlpha-synuclein in neurons and damaging them. This strongly suggests a role for dysfunction of CTSD and KLK6 in MSA. We will analyze the activity of CTSD and KLK6 in 10 regions of 20 MSA and 20 control brains and determine how this relates to the number of GCIs. Next we will grow oligodendrocytes and control their levels of CTSD and KLK6 to see if we can improve the breakdown of αlpha-synuclein. As the first study to examine proteases in MSA we will improve understanding of αlpha-synuclein breakdown and help to find new avenues for research and potential treatments.

“Gene expression & methylation as a route to MSA biomarkers and drug targets”: Henry Houlden, Ph.D. (University College of London)

Multiple system atrophy (MSA) is a neurodegenerative disorder with an overall prevalence of 2-4/100,000 people. MSA is characterized by abnormal movements (parkinsonism), unsteadiness (ataxia) as well as alterations in blood pressure control and urinary problems (autonomic failure). In the initial stages of the disease, MSA can be difficult to distinguish from Parkinson’s disease and some forms of ataxia. However, MSA has additional clinical features and an aggressive progression, with an average time to death being 8-9 years. The brain of MSA patients presents accumulation of a protein called alpha-synuclein, and loss of neurons in specific regions of the brain. The causes of MSA are largely unknown. There are small families with this condition but the majority of cases are not known to be inherited from generation to generation (sporadic disease). An increased risk of MSA has been proposed as associated with variations in certain genes – SNCA and COQ2. This study aims to investigate how genes make products that are needed for cells, and which variations those products show that can be related to the disease. This will eventually identify candidate genes and measurable indicators (biomarkers) of the disease, and reveal target pathways for therapeutic intervention.

“Glucagon like peptide-1 agonists for treating MSA: a preclinical POC study”: Wassilios Meissner, M.D, Ph.D.  (University of Bordeaux)

Developing neuroprotective and disease-modifying treatments for multiple system atrophy (MSA) is an urgent unmet need. As of late, interest has been given to insulin and insulin like growth factor-1 (IGF-1) in the neurodegenerative disorder field as both mediate numerous pro-survival actions through their brain receptors. Studies in animal models and postmortem human brain tissue of patients suffering from Alzheimer’s disease (AD) and Parkinson’s disease (PD) have found impaired insulin/IGF-1 signaling and insulin resistance. Moreover, several FDA-approved anti-diabetics have shown positive effects on behavior and surrogate markers of neurodegeneration in preclinical models of AD and PD. These encouraging findings have motivated the conduction of several pilot studies in patients with AD and PD. In this view, a clinical trial assessing the effects of the glucagon-like peptide-1 agonist exendin-4 in PD patients reported beneficial effects on motor symptoms and cognition. A follow up study showed persisting positive effects one year after the end of the study. Interestingly, patients with multiple system atrophy (MSA) show a significant increase in insulin/IGF-1 serum levels suggesting that insulin/IGF-1 signaling may also be impaired in MSA. Our preliminary findings in postmortem brain tissue of MSA patients suggest impaired insulin/IGF-1 signaling and brain insulin resistance. This study aims at assessing the effects of exendin-4 on motor symptoms and surrogate markers of neurodegeneration in a transgenic mouse model of MSA. In case of positive results, our ultimate goal is to test this compound in MSA patients, in line with our major objective to develop disease-modifying or neuroprotective treatments for MSA.

“Defining diagnostic brain MRI markers in early MSA with a novel toolbox”: Florian Krismer, M.D. (Innsbruck Medical University)

Multiple system atrophy (MSA) is a rare and devastating neurological condition. There is currently no therapy that can halt or slow the progression of the disease. Clinical trials with a large number of patients are required to test the efficacy of candidate agents. One of the prerequisites of clinical trials is that the patients enrolled in them should be as homogeneous as possible. In addition, potential treatments should be applied as early as possible. Hence, an early and reliable diagnosis of MSA is critical. However, it is difficult to discriminate different parkinsonian disorders at very early disease stages on clinical symptoms only. Thus, for the purpose of patient counseling and clinical research, additional investigations are inevitable. Based on emerging findings in favor of specific sequences of brain magnetic resonance imaging (MRI) as early diagnostic markers of MSA pathology, we propose to develop a MRI toolbox that consistently separates MSA from other degenerative parkinsonian disorders.

“Preclinical Evaluation of Novel Therapeutic for MSA”: Ruth Perez, Ph.D. (Texas Tech University Health Sciences Center)

Multiple system atrophy (MSA) is a rapidly progressing brain disease with no treatment or cure. My laboratory is studying an FDA-approved drug that is used worldwide to treat patients with multiple sclerosis, a brain disorder that like MSA damages the myelinating cells of the brain. MSA, like MS, tends to strike a younger

population than those who develop a more common movement disorder Parkinson’s disease (PD). MSA and PD have limited overlapping pathology and symptoms, and both may benefit by treatments that protect the brain’s signaling and support cells. In this grant, we will test an FDA-approved drug and two new compounds based on the FDA-approved drug in animal and cellular models of MSA. This will allow us to assess their ability to protect both the signaling neurons and the supporting myelinating cells. If data from this preclinical assessment are supportive, the FDA-approved drug can be rapidly repurposed for MSA, providing the first therapy that may slow disease progression and improve the quality of life.

“Detection of pathological alpha-synuclein aggregates in CSF by qRT-QuIC”: Armin Giese, M.D. (Ludwig-Maximilians-University Munich)

 

Reliable molecular biomarkers for early diagnosis and monitoring the disease progression in MSA are urgently needed, but are lacking to date. Deposits of aggregated alpha-synuclein (aSyn) are the pathological hallmark of MSA. However, reliable tools for the quantification of pathological aSyn in body fluids such as cerebrospinal fluid (CSF) are currently missing. We have established a rapid and reliable tool, qRT-QuIC (quantitative real-time quaking-induced conversion), to be able to sensitively and specifically detect and quantify even minute amounts of pathological protein aggregates, which we now want to apply to CSF samples of MSA patients.

PROJECT DESCRIPTION

(1) We will optimize the existing assay to detect pathological aSyn aggregates with high accuracy: This requires the adjustment of the assay conditions and its subsequent testing using recombinant and brain derived pathological aggregates as seeds.

(2) In a second step, validation of the assay will be carried out by analyzing patient CSF-samples from MSA patients (n=50), PD patients (n=50), and controls (n=100) including an independent cohort validation.

(3) Finally, we will further standardize and automate the assay resulting in a routine method for clinical diagnostics.

ANTICIPATED OUTCOME

The results of this study will be of crucial importance to find a reliable biomarker for MSA. If successful, this method would allow for precise early diagnosis and could be a powerful tool to track disease progression and to monitor therapeutic effects of novel therapeutics in MSA as well as in other synucleinopathies.

“Targeting alpha-synuclein pathology with the molecular tweezer CLR01 in MSA “: Nadia Stefanova, M.D, Ph.D. (Innsbruck Medical University) 

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder that currently lacks efficient therapy. We will test a novel drug candidate that blocks formation of toxic αlpha-synuclein aggregates, which are believed to have causative role in the pathogenesis of MSA. The drug has shown promising results in preclinical models of Alzheimer’s and Parkinson’s disease. As a necessary step towards human clinical trials, we will now test the drug in a pre-clinical model of MSA. The project has the goal to test the ability of the new drug to prevent and/or reverse the formation of the αlpha-synuclein aggregates that are believed to play a major role in the disease process of MSA. The mouse studies will be conducted in collaboration between the Stefanova laboratory at the Medical University of Innsbruck, Austria and the Bitan laboratory at UCLA using a well-established pre-clinical model of MSA which reproduces the specific pathology of this disorder in the mouse brain. These studies will establish the dose-dependent effects of the drug and its efficacy in MSA-like neurodegeneration. The data of this proof-of-concept study will be followed by behavioral studies and thorough characterization of neuroprotection effects generating a preclinical rationale for a future interventional trial in MSA.

“Mechanisms of Selective Neuronal Death in MSA: Focus on blood pressure controlling areas “: Eduardo Benarroch, M.D. (Mayo Clinic Rochester)

Despite extensive research in multiple system atrophy (MSA), the cause of death of neurons (nerve cells) controlling movement, blood pressure and other functions is yet unknown. Neuronal death may be due to their abnormal interaction with oligodendrocytes, the cells that produce myelin and provide nutrition to the neuronal portion called axons. Some neurons are affected early in the disease, but what makes these neurons vulnerable is still uncertain. Both neurons and oligodendrocytes accumulate the protein αlpha-synuclein (α-SYN), and this abnormal accumulation may propagate along connections between neurons. Therefore, it is important to determine what causes neuronal loss and whether this propagates along vulnerable pathways. Over the past several years we have studied brain areas controlling blood pressure in MSA, since a fall of blood pressure during standing (called orthostatic hypotension) is one of the most disabling MSA symptoms. We found that loss of one group of neurons controlling blood pressure is associated with α-SYN accumulation in surrounding oligodendrocytes and indices of abnormal iron metabolism. We hypothesize that there is a reciprocal interaction between neurons and oligodendrocytes leading to loss of both types of cells, including abnormal iron metabolism and nutrient deprivation. We plan to study four different brain areas controlling blood pressure; two containing cells that are potentially more vulnerable and two that may be more resistant but share similar connections. We will combine techniques to identify these neurons, and relate the severity of their loss with that of accumulation of α-SYN in surrounding oligodendrocytes, markers of iron metabolism, and nutrient transfer. The identification of the cause and interactions that make some neurons selectively vulnerable may help to develop treatments that protect vulnerable neurons and slow disease progression.

2014 MSA Research Grant Award Recipients:

“Global MSA Registry & Study Group”: Florian Krismer, M.D. (Innsbruck Medical University) and Lucy Norcliffe-Kaufmann, Ph.D. (New York University)
This project aims to establish the first-ever global registry dedicated to Multiple System Atrophy patients.  Facilitating future worldwide clinical trials, the registry will be used to notify all patients that meet study entry criteria for clinical trials in MSA on an international scale.  The registry will also provide a means for sharing anonymous patient information to define the disease specific characteristics and establish the definitive natural history of MSA.  Registered patients will be followed thoroughly and periodically to identify potential biological markers of disease risk and severity in a global, worldwide longitudinal prospective study.

“Stem cell-based Therapeutics Platform for MSA”: Vikram Khurana, M.D, Ph.D. (Massachusetts General Hospital)
This project aims to develop new models of Multiple System Atrophy by utilizing stem cell technology to generate human patient-derived stem cell models of the disease.  This will enable the study of the biology of an individual patient’s disease in the dish by creating their neurons and oligodendrocytes and then looking for signatures of alpha-synuclein toxicity.   If alpha-synuclein toxicity signatures are identified it will further assess whether it’s possible to reverse this toxicity with genes and small molecules.  This work may lead to a new way of testing and discovering potential therapies for MSA beyond the current mouse models of the disease.

Research Update (December 2015): 

It is now possible to convert cells from our patients (like blood or skin cells) into embryonic-like stem cells that can be coaxed into forming cells from complex tissue like the human brain. So, for the first time in history we can take, say, a skin cell from a patient with MSA and make that same patient’s brain cells in the dish. Just a few years ago no one would have dreamed this was possible – to get brain cells from patients we had to wait until after death. The stem cell-based approach allows us to study in the lab the abnormalities associated with a living patient’s disease in the lab, and find ways to reverse it.

The MSA Coalition seed grant allowed me to build on my existing work in Parkinson’s disease to create stem cell models from my patients with MSA. We have started to identify abnormalities in these cells and to test potential therapies that can reverse them. We have a long way to go before these findings in the dish reach the clinic, but, thanks to the MSA Coalition, we have made a good start. For a disease like MSA – where there are no clear gene mutations – it is vital that we collect more stem cell lines from patients, and we are beginning to do that. We have high hopes to generate a national stem cell bank for the disease that will provide a critical research tool for the MSA research community and speed up the tempo of drug discovery for this devastating disorder.

 “Mechanisms of Excessive Daytime Sleepiness and Sleep Related Respiratory Dysfunction in MSA”: Eduardo Benarroch, M.D. (Mayo Clinic Rochester)
Excessive daytime sleepiness and sleep related respiratory disorders such as sleep apnea and laryngeal stridor are prominent symptoms in patients with Multiple System Atrophy. This study aims to uncover the underlying mechanisms of these sleep disorders through pathological studies.  Understanding the underlying causes of sleep disorders associated with MSA can provide rationale for development of pharmacological approaches for treatment of these conditions. This can potentially lead both to improvement of quality of life and prevention of premature death in MSA patients.

“Peripheral delivery of brain-targeted neurosin as a novel treatment for MSA”: Eliezer Masliah, M.D. (University of California San Diego)
Recent studies suggest that abnormal accumulation of the protein alpha-synuclein in brain cells leads to cellular dysfunctional and neurodegeneration in Multiple System Atrophy and it is increasingly evident that the toxicity of extracellular alpha-synuclein might be related to its ability to be taken up by neighboring cells and act in a prion-like manner.  This behavior could be a key event in the origin and progression of the disease.
Compounds that reduce intracellular alpha-synuclein aggregation have received significant attention in recent years but the possibility of reducing the spread of alpha-synuclein from cell to cell by degrading extracellular alpha-synuclein has not been explored in such depth.  This project aims to increase the brain levels of an extracellular alpha-synuclein degrading enzyme in mouse models of MSA by means of peripheral gene therapy and targeted delivery to the central nervous system (CNS). Delivery of brain targeted neurosin into the CNS might represent a potential therapeutic option for neurodegenerative disorders including Multiple System Atrophy.

“Biomarker Development in MSA”: Roy Freeman, M.D. (Beth Israel Deaconess Medical Center)
There is currently an unmet need for a biomarker in Multiple System Atrophy. A reliable biomarker could contribute to the diagnosis, treatment and disease modification of MSA by improving diagnostic accuracy, defining disease progression and providing an objective measure of the response to disease modifying interventions.

Successful development of a biomarker for MSA would therefore assist in the evaluation and enhance the efficacy of drugs or other interventions that have neuroprotective qualities and offer the possibility of slowing, halting or reversing the rapid progression of MSA.

This study in human subjects, will determine whether alpha-synuclein deposits in cutaneous autonomic nerves is a valid biomarker for multiple system atrophy.