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 being 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.

2016 MSA Research Grant Award Recipients:

“Global MSA Registry & Natural History Study – Year 3”: Lucy Norcliffe-Kaufmann, Ph.D. (New York University NY) and Gregor K. Wenning, M.D., Ph.D. (Innsbruck Medical University, Austria)  

This project has now established 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.

Our international partnership began with Austria and the US and is now expanding to a global collaborative effort.  Ongoing support from the MSA Coalition and access to the MSA patient community is fundamental for the ongoing success of this project.  Our continued partnership with the MSA Coalition will allow patient recruitment at partnering sites within the framework of the Natural History Study.  We are working to ensure the natural history study can provide the backbone for additional projects focused on MSA to test new drugs to stop the progression of the disease.

Multiple System Atrophy patients (from any country) may now register in the GLOBAL MSA REGISTRY

The Global Multiple System Atrophy Registry (GLOMSAR)
msa-registry-2
msa-registry-3

https://www.rarediseasesnetwork.org/rdnwebapp/registry/descriptionandpurpose.aspx?ownerid=3573&diseasetype=127

“The role of hemoglobin overexpression in molecular pathology of MSA”: Michael Janitz, M.D., Ph.D. (University of New South Wales, Australia) and Ronald Melki, Ph.D. (Paris-Saclay Institute of Neuroscience, France)

Multiple system atrophy (MSA) is a distinct member of the group of neurodegenerative diseases called alpha-synucleinopathies whereby the fibrillar protein alpha-synuclein aggregates in oligodendroglia.  Although well-defined clinically, the molecular pathophysiology of MSA has not yet been elucidated.  We recently discovered that hemoglobin genes are highly expressed in the MSA white matter in the cerebral cortex, which is the primary target structure for MSA-specific neurodegeneration.  Hemoglobin transports oxygen throughout our tissues.  It is the largest source of peripheral iron in the human body and it may play a role in iron homeostasis throughout the brain.  We hypothesize that the overexpression of hemoglobin causes oxidative stress, which leads to impairment of oligodendrocyte functionality, which is a white matter major cellular component.  Moreover, oxidative stress together with increased levels of hemoglobin proteins might have a direct impact on alpha-synuclein aggregation.  In this project two internationally recognized research teams will combine their expertise in brain transcriptome and proteome analysis to elucidate a mechanism through which hemoglobin overexpression leads to MSA pathology.  This ambitious goal will be achieved through determination of cell types involved in this pathology, physiological effects of hemoglobin overexpression in oligodendrocytes and relationship between hemoglobin expression and alpha-synuclein deposits.  This project, for the first time, will establish a link between white matter pathology in MSA, iron homeostasis and alpha-synuclein metabolism.  This collaborative proposal is significant because it will not only provide insights into MSA pathology but also will lead to identification of new molecular targets for MSA early diagnosis and therapeutic intervention.

“COQ2 mutation and methylation dysfunction leading to alpha-synuclein pathology”: W. Scott Kim, Ph.D. (University of Sydney, Australia), Glenda Halliday, Ph.D. (University of Sydney, Australia) and Poul Jensen, M.D., Ph.D. (University of Aarhus, Denmark)

Multiple system atrophy (MSA) is a rapid-onset brain disorder impacting on multiple functions of the body, including blood pressure, heart rate, balance and muscle movement.  The cause of MSA is unknown, no specific risk factors have been identified, and there is no cure or effective treatment.  Autopsies of MSA brains show deposits of a protein called alpha-synuclein in oligodendrocyte cells, which are the support cells of the brain.  Alpha-synuclein deposits are believed to be toxic to oligodendrocytes. Without the proper functioning oligodendrocytes, neurons, the nerve cells of the brain, will eventually all die.  The cause of alpha-synuclein deposition in oligodendrocytes remains poorly understood.  Recent reports indicate that variants of the COQ2 gene are associated with an increased risk for MSA in certain populations.  The known function of COQ2 is in the production of coenzyme Q10 (anti-oxidant) and ATP (energy storage molecule).  However, the role of COQ2 in MSA context is unknown.  Our preliminary data showed that both COQ2 and ATP levels were significantly decreased in disease-affected regions of MSA brain, providing strong evidence for impairment of COQ2 synthesis or function in MSA brain.  We therefore proposed a hypothesis that impaired function of COQ2 contributes to alpha-synuclein pathology in MSA.  In this project we will determine if the COQ2 gene is altered in Caucasian MSA patients.  We will also determine if coenzyme Q10 treatment prevents or reduces α-synuclein deposition in oligodendrocytes.  Our study will reveal pathways to control α-synuclein deposition that may lead to developing treatments for MSA.

“Unravelling the mechanism of alpha-synuclein seeding in oligodendrocytes”: Maria Xilouri, Ph.D. (Biomedical Research Foundation of the Academy of Athens, Greece)

Multiple system atrophy (MSA) is a neurological disorder associated with the degeneration of nerve cells in specific brain areas.  MSA is characterized by the accumulation of cytoplasmic inclusions filled with the neuronal protein alpha-synuclein within oligodendrocytes.  Oligodendrocytes are a selective type of glial cells that provide support and insulation to axons, creating the myelin sheath around them. Accumulation of alpha-synuclein together with the oligodendrocyte-specific protein TPPP/p25 alpha, which may result from a failure of proteolytic systems, leads to oligodendroglial degeneration.  Since oligodendrocytes do not normally express alpha-synuclein, a prevailing hypothesis is that the protein is entering oligodendroglial cells following its release by neurons that normally express alpha-synuclein.  Up to now the precise species of alpha-synuclein responsible for the formation of these inclusions and the proteolytic machineries capable of their removal remain unknown.  We plan to identify the mechanisms that control the transmission of alpha-synuclein in oligodendrocytes and to assess the role of p25 alpha in this process.  To investigate this, we will use various forms of alpha-synuclein produced in bacteria (recombinant) or produced in neurons, apply them to oligodendrocytes and assess their uptake and turnover, using selective pharmacological and molecular means to inhibit the major proteolytic systems inside the cell.  Moreover, we will do the same experiments in primary oligodendrocytes isolated from a mouse model of MSA that overexpresses alpha-synuclein only in oligodendrocytes, and in mice that normally do not express alpha-synuclein in any cell (knock-out mice) or mice that express the protein normally in neurons.  This line of research is important in pinpointing the factors that regulate the transfer, accumulation and clearance of alpha-synuclein within oligodendrocytes and the role of p25 alpha in these processes.  The major outcome will be the identification of the mechanisms that can clear abnormal forms of alpha-synuclein in oligodendrocytes that might represent potential therapeutic targets for MSA.

“Targeting alpha-synuclein pathology with the molecular tweezer CLR01 in MSA: optimization of drug delivery and biochemical analysis”: Nadia Stefanova, M.D, Ph.D. (Innsbruck Medical University, Austria) and Gal Bitan, Ph.D. (University of California Los Angeles CA)

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 alpha-synuclein aggregates which are believed to have a causative role in the pathogenesis of MSA. The drug has shown promising results in pre-clinical 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.  In a proof-of-concept study supported by the MSA Coalition (2015), we demonstrated that when delivered directly into the brain, the drug reduced the density of toxic alpha-synuclein aggregates in the brains of MSA mice.  The current follow-up project has the goal to expand these studies and test the ability of the new drug to prevent and/or reverse the formation of the alpha-synuclein aggregates when applied subcutaneously – a route of administration with higher relevance to future clinical applications.  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 preclinical model of MSA that reproduces the specific pathology of this disorder in the mouse brain.

“GRK2 targeted knock-down as therapy for multiple system atrophy”: Erwan Bezard, Ph.D. (University of Bordeaux, France)

Developing neuroprotective and disease-modifying treatments for multiple system atrophy (MSA) is an urgent unmet need.  Insulin and related factors act as neuromodulators in the brain.  Neurodegenerative diseases are characterized by impaired insulin/insulin like growth factor-1 (IGF-1) signaling and insulin resistance (i.e. Decreased insulin/IGF-1 signaling).  We recently demonstrated that such insulin resistance is a key feature of (MSA) in the brain of MSA patients as well as in in the gold-standard transgenic mice model of MSA, the PLP-synuclein mouse.  Counteracting such insulin resistance thus bears the potential of being neuroprotective and of improving autonomic failure such as orthostatic hypotension.  The insulin signaling is notably transduced by an integrator protein named G protein–coupled receptor kinase 2 (GRK2).  Both mouse models of insulin resistance and humans with metabolic syndromes display increased levels of GRK2.  Even more interestingly, a recent attempt to knock-down the peripheral expression of GRK2 resulted into a reversal of diet-induced obesity and insulin resistance in a model of diabetes.  We will test the hypothesis that knocking-down the expression of GRK2 in the whole body or specifically in the brain has positive effects on insulin resistance, cell survival and alpha-synuclein pathology in the gold-standard transgenic mouse model of MSA, the PLP-synuclein mouse.  If successful, we would then move this strategy to our newly developed non-human primate model of MSA for finalizing the preclinical validation of the GRK2 target.

“Nilotinib for treating MSA: a preclinical proof of concept study”: Pierre-Olivier Fernagut, Ph.D. (University of Bordeaux, France) and Wassilios Meissner, M.D., Ph.D. (University of Bordeaux, France)

No disease-modifying treatment is available for multiple system atrophy (MSA). Nilotinib, a drug used to treat leukemia, inhibits the enzyme activity of a protein tyrosine kinase called Abelson (c-Abl).  Recent studies in preclinical models of Parkinson’s disease (PD) suggest that inhibition of c-Abl activity by nilotinib might help increase the clearance of alpha-synuclein, reducing neuroinflammation and provide neuroprotection.  A pilot clinical trial in PD and Dementia with Lewy Body (DLB) patients further suggests that nilotinib may prove useful as a disease-modifying drug in neurodegenerative diseases associated with alpha-synuclein aggregation.  A larger, randomized, placebo-controlled trial is expected to start in 2017.  Whether this strategy may work in MSA is unknown.  This study aims at assessing the effects of nilotinib on motor symptoms, alpha-synuclein aggregation and surrogate markers of neurodegeneration and neuroinflammation in a transgenic mouse model of MSA.  If positive, this preclinical proof of concept study will pave the way for validating nilotinib as a candidate neuroprotective drug to be tested in a clinical trial in MSA patients.

“A serum miRNAs signature as potential biomarker for MSA”: Anna Maria Vallelunga, MSc (University of Salerno, Italy) and Maria Teresa Pellecchia, M.D., Ph.D. (University of Salerno, Italy)

At the moment, there is no specific diagnostic test for the early diagnosis of multiple system atrophy (MSA).  Moreover, a major challenge in developing effective treatments for MSA is the difficulty to predict how the disease will evolve over time.  To overcome these limitations, current research focuses on the development of reliable biomarkers, biological molecules present in bio-fluids and easily measurable in order to reflect disease processes.  A new class of molecules called miRNAs has been recently studied in several neurodegenerative diseases.  miRNAs are a class of small RNA molecules which modulate gene expression and protein production, and whose levels often change during the disease.  Many miRNAs are present in different brain regions, cross the blood-brain barrier and can be detected in several bio-fluids such as blood and urine. miRNAs can be analyzed using simple technology present in the molecular clinical laboratory.  Recently, we ran a pilot study evidencing that a set of miRNAs could distinguish patients with MSA from healthy individuals simply based on blood sample analysis.  We also identified a set of three miRNAs that allowed the discrimination between patients with MSA and Parkinson’s disease (PD).  We hypothesize that they could facilitate the diagnosis of these conditions.  The overall objective of this proposal is to assess the usefulness of those miRNA panels for the early diagnosis of MSA.  The validation of our miRNA panels could be a first step to develop a new test for early diagnosis of MSA based on blood miRNAs.  Moreover, the identification of biomarkers that reflect the underlying disease process or progression would also be very useful for designing future clinical trials that assess compounds with putative disease-modifying properties.

“Inside the gait – a new era on the horizon for atypical parkinsonian disorders”: Gregor K. Wenning, M.D., Ph.D. (Innsbruck Medical University, Austria)  

Multiple system atrophy (MSA) and Progressive Supranuclear Palsy (PSP) are rare and devastating neurological conditions.  There is currently no therapy that can halt or slow the progression of these diseases.  Clinical trials with a large number of patients are urgently needed to test the efficacy of therapeutic agents.  In addition, an early and reliable diagnosis of MSA and PSP and the discrimination of these diseases from the more benign idiopathic Parkinson’s disease can be a challenge for the neurologist, especially at early stages.  Emerging data show that instrumented gait analysis using wearable sensors can provide a great amount of clinically relevant information which could help to better characterize these diseases and to quantify their progression characteristics and rates in an objective, rater-independent way.  Moreover, new findings show that these sensors may be able to detect risk-of-fall associated gait parameters.  This is particularly relevant in the clinical assessment and in the follow-up of patients with atypical parkinsonian disorders where the gait impairment and the risk of fall are even more prominent compared to idiopathic Parkinson’s disease.  Based on emerging findings in favor of the feasibility of wearable sensors in the clinical practice, we aim to propose a new objective tool in the diagnostic workup, individualized progression assessment, and therapeutic response of atypical parkinsonian disorder patients.

“Toward the in situ proteome of normal and pathologic alpha-synuclein in human neurons and glial cells”: Vikram Khurana, M.D., Ph.D. (Brigham and Women’s Hospital, Boston MA)

Multiple System Atrophy (MSA) is an incurable and devastating neurodegenerative disease.  It is known as a “synucleinopathy” because its hallmark pathology is the misfolding and aggregation of a small protein known as alpha-synuclein within distinct cell­types of the brain.  More common synucleinopathies include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB).  While alpha-synuclein aggregates predominantly in distinct populations of neurons (nerve cells) in PD and DLB, the characteristic pathology of MSA is strikingly different.  In MSA, alpha-synuclein characteristically aggregates in both neurons and in glial cells known as oligodendrocytes.  Oligodendrocytes “insulate” and increase the speed of electrical conduction along nerve fibers in the brain.  How alpha synuclein triggers dysfunction and death of distinct cell­types is poorly understood. Recently, we hypothesized that if we could map where alpha­synuclein was in a cell, and which other proteins it interacts with, we could develop insights into how it was harming those cells.  We optimized a novel mapping method for proteins within living rodent neurons, and created such a map for alpha-synuclein.  We found that alpha-synuclein interacted with proteins that were critical in mediating its cellular toxicity. Now, in this proposal, we seek to apply a similar strategy for human neurons and oligodendrocytes from MSA patients.  We plan to develop such alpha-synuclein maps within oligodendrocytes generated from MSA patient stem cells.  Furthermore, we make use of MSA patient brain tissue to capture the distinct types of misfolded alpha-synuclein implicated in this disease.  Knowledge gained from these studies will enable us in time to understand disease mechanisms within distinct cell types of the brain, and open up the possibility of patient­targeted therapies 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, Austria) and Lucy Norcliffe-Kaufmann, Ph.D. (New York University NY)

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.

Update (April 2015): A published paper from this project is now available.

“Multiple System Atrophy: The case for an international collaborative effort”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497581/

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

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.

Research update by Eliezer Masliah (December 2015):

The main objective of this project is to determine the behavioral and neuropathological effects of immunotherapy against α-syn plus pharmacological reduction of neuroinflammation in a MSA model, and investigate the mechanism of action of such combination of therapies.  For this purpose we selected the use of a single-chain variable fragment antibody against alpha-synucleincontaining the ApoB motif (sD5-apoB), and the anti-inflammatory and immunomodulatory drug lenalidomide.

During this first year we have performed animal experiments in the MBP-hα-syn tg mouse Line 1 (MBP1-hα-syn) and are ready to proceed to the neuropathological, biochemical and mechanistic analysis of those brain samples.  Moreover, we have also validated the use of both lenalidomide and α-syn-targeted therapies using the ApoB motif in the MBP1-hα-syn mouse model of MSA, both necessary steps to confirm the feasibility of our proposed research.  A summary of the research performed this first year is as follows:

1. Combination therapy using immunotherapy against α-syn plus pharmacological reduction of neuroinflammation in MBP1-hα-syn transgenic mice

For the combination therapy experiments we have used MBP1-hα-syn transgenic mice, which express medium levels of alpha-synucelein in oligodendrocytes.  Non-tg and tg animals were divided in 4 groups each: vehicle injected with lentivirus (LV) control, vehicle injected with LV-sD5-apoB, lenalidomide injected with LV control, and lenalidomide injected with LV-sD5-apoB (n=8 per group).  The lentiviral preparations were injected intra-peritoneally at 10 month/old, one week before lenalidomide treatment in order to avoid a possible inhibitory effect of lenalidomide on antibody production.  Subsequent lenalidomide treatment (100 mg/kg) was performed orally by gavage daily for 4 weeks. Mice were behaviorally analyzed before and after the treatments (11 month/old).

We are currently analyzing behavioral data and performing the initial neuropathological analysis (Aim 1).  For that purpose, we will perform immunohistochemistry using antibodies against alpha-synucelein, neuronal markers (NeuN, MAP2), glial markers (GFAP, Iba-1) and synaptic markers (synaptophysin).  We will also use immunoblot and ELISA analysis for the quantitative and semi-quantitative analysis of alpha-synucelein degradation and protein levels, to confirm and implement immunohistochemical results. We will also analyze the expression level of genes involved in autophagy (Becn1, Atg3, Atg7, Atg12, Map1lc3), proteasomal degradation (Uba1, Uba2, Uba3, Smurf1, Nedd8) and unfolded protein response (Edem1, Eif2a, Herpud1) by PCR array, to obtain mechanistic insight on the effect of the combined therapy on this MSA mouse model.

2. Lenalidomide reduces α-syn accumulation and microgliosis in the striatum of MBP1-hα-syn transgenic mice

During this first year we have also analyzed the effects of the immunomodulatory drug lenalidomide in the MBP1-hα-syn mouse model of MSA.  Non-tg and MBP1-hα-syn tg mice were treated with either vehicle or lenalidomide at 100 mg/kg for 4 weeks, as previously described (Valera et al., 2015).  Neuropathologically, we observed a reduction in the number of alpha-synucelein positive cells in striatum after lenalidomide treatment (Figure 1A, 1B), together with a normalization of the pro-inflammatory microglial phenotype as measured by Iba1 staining in the same brain region.  Our preliminary results suggest that the pro-inflammatory activation of microglia in MBP1-hα-syn tg animals might impair microglial functioning, and the reduction in this microglial activation induced by lenalidomide could lead to an improvement in the phagocytic activity of these cells towards extracellular alpha-synuclein.  We have previously observed a similar reduction in pro-inflammatory microglial activation by lenalidomide in a transgenic mouse model of PD (Valera et al., 2015).

3. A brain-targeted (ApoB), modified α-syn-degrading enzyme (neurosin) reduces α-syn accumulation in MBP1-hα-syn transgenic mice

Neurosin (kallikrein-6) is a serine protease capable of cleaving alpha-synuclein in the CNS, and we had previously shown that LV vector delivery of neurosin into the brain of a mouse model of Parkinson’s disease reduces the accumulation of alpha-synuclein and improves neuronal synaptic integrity (Spencer et al., 2013). Therefore, in this first year we have investigated the ability of a modified, systemically delivered neurosin to reduce the levels of alpha-synuclein in oligodendrocytes and reduce the cell-to-cell spread of alpha-synuclein to glial cells in the MBP1-hα-syn mouse model of MSA.  We engineered a viral vector that expresses a neurosin genetically modified for increased half-life (R80Q mutation) that also contains a the brain-targeting sequence ApoB for delivery into the CNS.  Peripheral administration of the LV-neurosin-ApoB to the MBP1-hα-syn tg model resulted in accumulation of neurosin-ApoB in the CNS, reduced accumulation of alpha-synuclein in oligodendrocytes and astrocytes, improved myelin sheath formation in the corpus callosum and behavioral improvements (Spencer et al., 2015).  These results validate the use of brain-targeted therapies aimed at reducing alpha-synuclein as potential therapeutic tools for MSA.

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

In multiple system atrophy (MSA) a protein called alpha-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 alpha-synuclein in MSA, so we believe that the breakdown of alpha-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 alpha-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 alpha-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 alpha-synuclein. As the first study to examine proteases in MSA we will improve understanding of alpha-synuclein breakdown and help to find new avenues for research and potential treatments.

Research update by Janice Holton (December 2015):

In multiple system atrophy (MSA) and similar diseases like Parkinson’s disease and dementia with Lewy bodies, we know that the sticky protein alpha-synuclein builds up in areas of the brain and is likely responsible for the damage which occurs in the brain.  However, our work and the work of others have shown that no extra alpha-synuclein is created in brains with these diseases compared to healthy brain.  We also know that in a healthy brain specialized enzymes break down any alpha-synuclein that builds up before it can be a problem.  For this reason, we believe that the alpha-synuclein which accumulates in the brains of people with MSA is not being properly cleared out.  This is why the aim of this study is to analyze whether these enzymes are working in MSA brains and see if we can improve their efficiency in a cell culture system.

We are happy to say that we are on schedule with regards to the time line which we outlined in the original grant proposal.  To date we have sampled tissue from six brain regions from twenty non-diseased and twenty MSA brains as well as two cases which have a G51D mutation and one case with an A53E mutation of the SNCA alpha-synuclein gene.  Samples have been sent to Prof Seth Love’s group in Bristol where they are currently training a new research technician to perform assay which will allow us to determine whether these enzymes are working at the sample efficiency in MSA as in non-diseased brain.  Meanwhile at the Queen Square Brain Bank I have been analyzing the quantity of the enzymes in the same brain regions compared to non-diseased control.  I have also been preparing samples of paraffin embedded MSA and non-diseased brain tissue to mount on to glass slides and to stain for enzymes and alpha-synuclein.  These samples will be viewed using a specialized fluorescent microscope and we will be able to see whether the enzymes are in the right location to target alpha-synuclein and perform effectively.

Finally we are currently growing and maturing oligodendrocyte cells which we will use in the New Year to test whether we can fine tune the level of enzymes so that we can improve the breakdown of any type of alpha-synuclein we choose to introduce to the cell dish, be it normal alpha-synuclein or the more complex G51D mutant alpha-synuclein.

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

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.

Research update by Henry Houlden (December 2015):

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 multiple system atrophy (MSA).  For that we need to analyze blood samples and tissue from specific regions of the brain of individuals with and without the disease.

We have already collected blood samples from approximately 20 individuals, and are continuing the collection of volunteer individuals at our MSA specialized clinic at the National Hospital for Neurology and Neurosurgery (NHNN, London, UK).

Because the brain tissue we had collected previously was not of enough quality for the analyses we need to do, we have requested and awaiting additional brain tissue from Queen Square Brain Bank (London, UK).

To obtain more reliable results, we need to analyze in the lab the samples from all individuals at the same time. Therefore the main experiments in the lab will only start by early 2016.

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

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.

Research update by Wassilios Meissner (December 2015):

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 findings in postmortem brain tissue of MSA patients confirm insulin resistance compared to healthy controls.

The preclinical study assessing the effects of exendin-4 on motor symptoms and surrogate markers of neurodegeneration in MSA mice is ongoing.  First preliminary results are encouraging and suggest a positive effect of high-dose exendin-4 treatment in MSA mice.

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

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 TX)

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.

Research update by Ruth Perez (December 2015):

We established a Material Transfer Agreement with Dr. Virginia Lee at the University of Pennsylvania to obtain her CNPase promotor MSA mice to establish a breeding colony in El Paso.  Due to unforeseen problems with her live mice, we had to make arrangements to re-derive the CNPase mice at the Jackson Laboratories.  This began in November and we were recently notified that mice have been born.  Mice will be genotyped prior to shipping to us by the end of February.

In the meantime, we have been evaluating FTY720/Fingolimod/Gilenya in cell models and have obtained data for a paper that is currently in preparation.  The data in cells show that FTY720 is turning on neurotrophic factor expression and has the capacity to reverse pathology induced by toxic alpha-synuclein   accumulation in oligodendroglia cells (OLGs).  This suggests that a novel protective property for MSA could occur by stimulating neurotrophic factor expression in OLGs by using FTY720.  These findings further encourage us to evaluate the potential benefits of the drug in vivo in the CNPase mice to begin soon.

We have also been working with Dr. Jeffrey Arterburn to create new versions of the drug for further analysis, and recently received a shipment of drug from him.

Funding has been used to cover the cost of reagents, supplies, salaries and mice. As we proceed with the newly re-derived MSA mice, we will require additional funding.

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

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.

Research update by Armin Giese (December 2015):

With financial support of the MSA coalition grant, we were able to purchase the necessary hardware, a BMG FLUOstar Omega multiwell plate reader, for establishing qRT-QuIC for the detection of alpha-synuclein aggregation.  Primary instrument settings were adjusted and quality controls were carefully performed. Recombinant monomeric alpha-synuclein, which is used as a substrate for the seeding reaction, was purified and fibrils, to be used as recombinant seeds were generated according to our standard protocol.  We tested different combinations of conditions regarding buffer composition, pH of the reaction, and incubation temperature.  We checked for potential differences using sonicated or non-sonicated as well as centrifuged or non-centrifuged seeds.  Furthermore we checked, whether different badges of purified substrate lead to different characteristics of the aggregation process.  Based on the results of our analyses, we assume the assay conditions regarding especially its sensitivity to be adequately sufficient for now to move on to analyzing CSF samples.  In a first step, the influence of the CSF matrix per se (e. g. blood contamination, cells, other proteins, electrolytes) as well as conditions of sample processing and storage have to be characterized by adding in vitro formed seeds to CSF samples of control patients without neurodegenerative disease (`spiked´ CSF). Subsequently, we will proceed to CSF samples from patients with synucleinopathies and further optimize the assay.  The final adaptation of the qRT-QuIC assay for alpha-synuclein seeds will be the result of mutual optimization steps of the assay using purely in vitro components, spiked CSF matrix as well as CSF samples from patients with synucleinopathies.  Once we could determine the optimal conditions for the seeding reaction of CSF-derived alpha-synuclein seeds, the assay is to be validated by testing adequate numbers of CSF samples of patients and healthy controls.  The final aim will be to further standardize and automatize qRT-QuIC for the application in clinical routine diagnostics.

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

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 alpha-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 alpha-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.

Research Update by Nadia Stefanova (November 2015): 

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder that currently lacks efficient therapy.  We are testing a novel drug candidate that blocks formation of toxic alpha-synuclein aggregates, which are believed to have a causative role in the pathogenesis of MSA.  The drug has shown promising results in pre-clinical models of Alzheimer’s and Parkinson’s disease.  As a necessary step towards human clinical trials, we now test the drug in a pre-clinical model of MSA.

The project has the goal to test the ability of the new drug CLR01 to prevent and/or reverse the formation of the alpha-synuclein aggregates that are believed to play a major role in the disease process of MSA.

MSA transgenic mice that have alpha-synuclein aggregates in oligodendrocytes and replicate the pathological hallmark of the human disease were used.  The MSA mice were divided into treatment groups as follows: group one, receiving vehicle; group two, receiving the drug CLR01 at low concentration; and group three, receiving the drug CLR01 at high concentration over a period of one month.  To ensure that the drug reached the CNS, it was delivered by an intracerebroventricular catheter.

Our first results indicate that the treatment with the drug CLR01 is not related to indicative of toxicity, i.e. body weight dynamics and survival in the three groups did not differ when monitored during the in vivo observation period.  Behavioral analysis at the end of the treatment period indicated significant functional improvement in a dose-dependent manner in MSA mice that received CLR01 therapy back to levels of healthy mice lacking alpha-synuclein aggregates in oligodendrocytes.

Currently we are performing neuropathological and biochemical analysis of the brains to define the pathological substrate of the observed functional improvement.

Based on our interim data we have identified a promising therapeutic strategy to provide functional amelioration in MSA mice.  Importantly, the beneficial effect of CLR01 therapy was achieved in MSA mice with a clear phenotypic dysfunction, which corresponds to a stage of clinically overt disease in patients.  Therefore the results suggest that CLR01 treatment may be efficient to provide disease modification in MSA patients even when initiated after the clinical onset of symptoms.

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

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:

“Spreading of α-synuclein pathology in multiple system atrophy”: Johannes Brettschneider (University of Ulm, Germany) and John Trojanowski (University of Pennsylvania PA) – Joint Grant with CurePSP

The main neuropathological findings in multiple system atrophy (MSA) are aggregates of the protein alpha-synuclein in oligodendrocytes, the cells that produce the insulating myelin sheath surrounding axons or nerve fibers known as oligodendrocytes and also in specific nerve cells of the central nervous system (CNS).  Similar aggregates of alpha-synuclein have been observed in other neurodegenerative synucleinopathies, including sporadic Parkinson’s disease and dementia with Lewy bodies, and the progressive regional spreading of such protein aggregates from a focal onset to widespread areas of the CNS is now considered a key aspect characterizing the pathology of many neurodegenerative diseases.  To date, however, there are no studies that have attempted to determine if a regional spreading of alpha-synuclein aggregates might also underlie disease progression in MSA.  Furthermore, it is unclear what characterizes the cells that are vulnerable and those that are resistant to alpha-synuclein pathology in MSA, and what determines pathways of disease progression.  We aim to analyze neuropathological evidence for a potential spreading of alpha-synuclein pathology in a cohort of n=60 clinically well-characterized autopsy cases of MSA from patients studied clinically during life.  We will analyze neuroanatomical characteristics of cells that are vulnerable and resistant to alpha-synuclein pathology, and we shall determine pathways by which alpha-synuclein pathology could propagate.  In so doing, we can lay the essential groundwork for strategies aiming to prevent the propagation of alpha-synuclein in MSA, which would constitute a fundamentally novel approach to its treatment.  For the development of potential therapeutic agents, for example using immune therapy, insights into propagation pathways, potential mechanisms of dissemination, and determinants of vulnerability of specific cellular types to alpha-synuclein propagation are essential.

Research Update by Johannes Brettschneider (December 2014): 

We aim to establish a sequential order in which aggregates consisting of the protein alpha-synuclein spread within the nervous system of patients with multiple system atrophy (MSA).  Such a staging will be valuable not only for neuropathologists, but also to monitor disease progression in living patients once imaging markers of alpha-synuclein – which are currently developed by our group and others – become available. Then, the knowledge of the sequential order in which different areas of the brain are affected by alpha-synuclein pathology could help to determine the effectiveness of new therapeutic agents in clinical trials. To achieve that aim, we are currently analyzing a clinically well-defined cohort of 47 autopsy cases with MSA.  We use special neuropathological techniques that allow a detailed analysis of anatomical structures that are involved by this alpha-synuclein pathology.  We correlate our findings to detailed clinical data that is available from a comprehensive database at our center. In a first step, we focus on pathological changes in the cerebellum (a part of the brain important for movement coordination) and its connections in the brainstem and spinal cord, which show characteristic changes in MSA due to alpha-synuclein aggregation and neuronal loss.

“Selective Cell Vulnerability in MSA: Insights from cases with associated Lewy Body Disease”: Eduardo Benarroch, M.D. (Mayo Clinic Rochester MN) – Joint Grant with CurePSP

Despite extensive research, the cause of neuronal loss in multiple system atrophy (MSA) remains elusive.  ln particular, there is yet no clear explanation for the mechanism that causes the abnormal accumulation of the protein o-synuclein in the oligodendrocytes (the cells that produce the myelin around the axons of neurons in the central nervous system), called glial cytoplasmic inclusions (GCls) and the impact that this has in survival of the neurons.  This is particularly relevant in areas of the central nervous system that control vital functions such as blood pressure and breathing, which are frequently affected and cause disability and risk of death in MSA patients.  These abnormalities are more severe than in Parkinson’s disease and other so-called Lewy body disorders (LBD), in which alpha-synuclein accumulates in neurons instead of oligodendrocytes.  Our laboratory has the unique opportunity to address these questions, as we have availability of brains obtained at autopsy from patients with clinical diagnosis of either MSA or DLB but that show the pathological changes seen in both conditions.  The study of these cases may help to understand why neurons controlling vital functions are so much more vulnerable in MSA than in LBD.  One potentially important question is how the different types of cells in the central nervous system handle iron in these two types of disorders, as iron is potentially toxic to both oligodendrocytes and neurons.  Approaches aimed to reduce abnormal iron accumulation may protect cells in vital brain areas from damage in MSA.  Our laboratory has all the technical capabilities and expertise to undertake these studies. We expect to obtain enough preliminary information to apply for a NIH grant to further investigate this important issue.

 “Global MSA Registry & Study Group”: Florian Krismer, M.D. (Innsbruck Medical University, Austria) and Lucy Norcliffe-Kaufmann, Ph.D. (New York University NY)

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.

Update (April 2015): A published paper from this project is now available

“Multiple System Atrophy: The case for an international collaborative effort”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497581/

“Stem cell-based Therapeutics Platform for MSA”: Vikram Khurana, M.D, Ph.D. (Massachusetts General Hospital MA)

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 by Vikram Khurana (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 MN)

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 CA)

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.

Research Update (2015): A published paper from project is now available.

“A brain-targeted, modified neurosin (kallikrein-6) reduces α-synuclein accumulation in a mouse model of multiple system atrophy”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580347/

“Biomarker Development in MSA”: Roy Freeman, M.D. (Beth Israel Deaconess Medical Center MA)

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.