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Therapies for non-motor symptoms of PD in clinical trials

The pipeline for Parkinson’s disease (PD) medications is extremely crowded these days, with multiple medications at various stages of research and development. Currently most of the approved medications for PD address the motor symptoms of PD – tremor, slowness, stiffness, and walking difficulties. Medications are also available to help people overcome OFF time or improve dyskinesias.
Clinical Trials for Non-Motor Symptoms of PD
One of the major unmet needs in PD treatment is therapies for non-motor symptoms  (such as cognitive issues, psychosis, constipation and others) as these can have a significant effect on daily quality of life for both the person living with PD and their care partner. Therefore, it is particularly exciting to witness compounds being studied in clinical trials for these symptoms. Many of the currently active clinical trials for non-motor symptoms involve studying medications that are already approved for other diseases or uses, in hopes of determining if the medication also works for a particular symptom in the context of PD. Although these trials are crucial, this blog will focus on clinical trials of newly developed compounds aimed to specifically treat non-motor symptoms in PD.
If you are interested in getting involved in a clinical trial, Clinicaltrials.gov is a website that you should know about. It is a database of all clinical trials for all diseases worldwide. When a clinical trial is registered with the site, it is assigned a unique number called the National Clinical Trial (NCT) number. I will be referring to these numbers as I outline the clinical trials that are being conducted for newly developed compounds for non-motor symptoms of Parkinson’s disease so that you can learn more about them if you’re interested in participating in the trial.
Treating Non-Motor Symptoms of Parkinson’s Disease
 Cognition
Treatment of cognitive difficulties in PD is a major unmet need. There is only one medication approved for PD dementia, called rivastigmine, and its effects are mild. Research efforts are focused on trying to develop new therapies to improve this symptom.

SAGE-718 is an NMDA receptor positive allosteric modulator, a molecule that enhances the activity of the NMDA receptor. It is currently being studied in a Phase 2 open label trial (meaning that everyone receives the active compound and no one receives a placebo) for people with PD and mild cognitive impairment (NCT04476017). In order to be considered for the trial, participants must have a Montreal cognitive assessment (MoCA) of 20-25 (a range of scores meant to target people with mild cognitive impairment.)

This molecule has previously been tested in Phase I clinical trials, in both healthy people and people with Huntington’s disease (HD). Healthy people were given a molecule that blocks the NMDA receptor before administration of SAGE-718 or placebo. Those receiving SAGE-718 showed a statistically significant improvement of measures of working memory and complex problem solving. The molecule was also tested in six people with HD, a neurodegenerative condition that often results in dementia and although is very distinct from PD, does share some of its features. This study was open label (no placebo group). Participants

Where are they now? APDA’s research success

Q&A with APDA research grant recipients
 
Since 1961, APDA has been a funding partner in many major scientific breakthroughs and has awarded more than $49 million in research grants to date.
APDA funds individual research grants and fellowships to scientists performing innovative Parkinson’s disease (PD) research. Grants are awarded through a competitive application process and

reviewed by APDA’s Scientific Advisory Board (SAB). The SAB is comprised of scientists with a wide array of backgrounds and expertise in all areas relevant to Parkinson’s disease research.
One of our goals is to bring the best new talent to the field of PD research and help encourage a passionate pursuit for answers. As such, after APDA awards a grant and the project is undertaken, we hope that the story does not end there. The funding of one project can lead to additional hypotheses to test and additional research funding from other funding sources such as the National Institutes of Health (NIH). Each step brings the PD research community closer to new treatments and eventually, a cure.
Learn how to apply for research funding
Today, we highlight three researchers who were awarded past APDA grants. We asked them about the work that was funded at the time and what has happened in their research and careers since. We hope you are inspired by their passion for their work, and encouraged by the impact APDA funding has had on their research trajectory.

Mian Cao, PhD, grant recipient in 2013:
You received a grant from APDA in 2013. Can you give us a brief summary of the results of that project and its potential implications for the PD community?
In our APDA supported project, we investigated Parkin, a protein which is mutated in some forms of familial PD. We examined the role of Parkin at the synapse, the junction between two nerve cells, and particularly its role in endocytosis at the synapse, the process by which cellular material gets internalized into the cell. We found that Parkin is abnormally increased in mice defective in endocytosis and that Parkin directly interacts with particular proteins important in endocytosis, endophilin and SJ1. Our findings suggested the potential function of Parkin in regulating endocytic trafficking at synapses. Understanding what Parkin does in the cell under normal circumstances can help us understand what goes wrong to cause PD when Parkin is mutated.
What has been the general trajectory of your research and your career since 2013?
When I received the APDA award in 2013, I was a postdoc fellow in Dr. Pietro De Camilli’s lab at Yale. After that, I advanced to become an Associate Research scientist in Dr. De Camilli’s lab. In 2019, I moved to Singapore and started my own lab at Duke-NUS Medical School as an Assistant Professor.
Did your APDA grant help shape the next steps of your research? If so, how?
This APDA project was the first one I spearheaded on my own during my postdoc training. Since then, I continued to focus on PD research and have had continued success in discovering the disturbances in endocytosis related to

Parkinson’s Partners: Introducing Medical Students to Parkinson’s disease

As all of you know very well, Parkinson’s disease (PD) is a complex disorder that affects so many parts of a person’s life. In order for physicians to fully understand the impact the disease has on people with PD, it is not enough to learn the science and medicine of the condition. But how is it possible to teach a physician what it feels like to have PD?
One program that attempts to do just that, was pioneered at University of Louisville School of Medicine in Louisville, KY and adapted at Boston University (BU) School of Medicine. Parkinson’s Partners is a program in which first year medical students are paired with people with PD for a semester full of activities.
The goal of the program is to expose physicians-in-training to the “person behind the disease”, while engaging in activities that are therapeutic for people with PD. APDA has a long-standing and strong partnership with BU and we’re proud of their commitment to the PD community.
About Parkinson’s Partners
At BU, student leaders guided by the BU Movement Disorders faculty, recruit first year students who have not yet had clinical experience, and pair them up with PD patients of the BU Movement Disorders clinic. The student leaders plan and implement regular activities throughout the year that allow the student and the person with PD to form a mutually beneficial relationship. Since its inception in 2017, the students and faculty have also collected data and information on the program and on lessons learned.
BU School of Medicine has many close ties with APDA. One of APDA’s Information and Referral Centers is housed at BU, which worked in tandem with APDA’s Massachusetts Chapter. BU also houses an APDA Center for Advanced Research.
The Medical Director of BU’s Parkinsons disease and Movement Disorders center is Dr. Marie-Helene Saint-Hilaire, who is a long-standing member of APDA’s Scientific Advisory Board. BU also houses APDA’s National Rehabilitation Resource Center. APDA is therefore particularly proud of the Parkinson’s Partners BU initiative.
I spoke with Taylor Francoeur and Max Rosenthaler, two current 4th year medical students at BU who started the program in 2017, as well as Dr. Katelyn Bird, Assistant Professor of Neurology and Movement Disorders physician at BU who is the faculty advisor for the program. They shared their thoughts about the inception of the program and its value to the students of BU and to people with PD. Note: Some answers have been combined and edited for clarity.
How did you come up with the idea for Parkinson’s Partners?
Taylor and Max: We came up with this idea with help of Dr. Saint-Hilaire, one of the Movement Disorders faculty members at Boston University Medical Center. She asked if any students would be interested in developing a student partnership program for PD patients. She had heard of a program that was started at the University of Louisville and knew of the benefits it might provide for the PD population. We worked with her and Dr. Stephanie Bissonnette (who was a Movement Disorders fellow at the time and is now

Where are they now? APDA’s research success

Q&A with APDA research grant recipients
 
Since 1961, APDA has been a funding partner in many major scientific breakthroughs and has awarded more than $49 million in research grants to date.
APDA funds individual research grants and fellowships to scientists performing innovative Parkinson’s disease (PD) research. Grants are awarded through a competitive application process and

reviewed by APDA’s Scientific Advisory Board (SAB). The SAB is comprised of scientists with a wide array of backgrounds and expertise in all areas relevant to Parkinson’s disease research.
One of our goals is to bring the best new talent to the field of PD research and help encourage a passionate pursuit for answers. As such, after APDA awards a grant and the project is undertaken, we hope that the story does not end there. The funding of one project can lead to additional hypotheses to test and additional research funding from other funding sources such as the National Institutes of Health (NIH). Each step brings the PD research community closer to new treatments and eventually, a cure.
Learn how to apply for research funding
Today, we highlight three researchers who were awarded past APDA grants. We asked them about the work that was funded at the time and what has happened in their research and careers since. We hope you are inspired by their passion for their work, and encouraged by the impact APDA funding has had on their research trajectory.

Mian Cao, PhD, grant recipient in 2013:
You received a grant from APDA in 2013. Can you give us a brief summary of the results of that project and its potential implications for the PD community?
In our APDA supported project, we investigated Parkin, a protein which is mutated in some forms of familial PD. We examined the role of Parkin at the synapse, the junction between two nerve cells, and particularly its role in endocytosis at the synapse, the process by which cellular material gets internalized into the cell. We found that Parkin is abnormally increased in mice defective in endocytosis and that Parkin directly interacts with particular proteins important in endocytosis, endophilin and SJ1. Our findings suggested the potential function of Parkin in regulating endocytic trafficking at synapses. Understanding what Parkin does in the cell under normal circumstances can help us understand what goes wrong to cause PD when Parkin is mutated.
What has been the general trajectory of your research and your career since 2013?
When I received the APDA award in 2013, I was a postdoc fellow in Dr. Pietro De Camilli’s lab at Yale. After that, I advanced to become an Associate Research scientist in Dr. De Camilli’s lab. In 2019, I moved to Singapore and started my own lab at Duke-NUS Medical School as an Assistant Professor.
Did your APDA grant help shape the next steps of your research? If so, how?
This APDA project was the first one I spearheaded on my own during my postdoc training. Since then, I continued to focus on PD research and have had continued success in discovering the disturbances in endocytosis related to

Is a vaccine for Parkinson’s disease possible?

As the world awaits an effective vaccine for SARS-CoV2 (the virus that causes COVID-19), vaccines and vaccination are at the front and center of the news and in our minds.
A vaccine is a substance that is introduced into the body in order to stimulate the immune system to provide protection against a particular disease.
Did you know that many pharmaceutical companies are working on vaccinations as a treatment for Parkinson’s disease (PD)?  It is important to note that while a vaccine is not imminent, each clinical trial and study that is underway is teaching us something new and important that will hopefully get us closer to a successful outcome. Even the projects that fail offer us substantial learnings that can be applied to future research efforts in this area.
People with PD have protein deposits in their brain (Lewy bodies) which are composed of accumulated α-synuclein. Preventing alpha-synuclein aggregation and dissolving pre-formed aggregates (or clumps) may be an effective strategy for treating PD.
Two related strategies have been devised in order to protect against this accumulation:

Introduction of antibodies to alpha-synuclein into the body, also known as passive immunity
Introduction of a molecule that induces the body to produce its own antibodies against alpha-synuclein, also known as active immunity

The theory is that in both scenarios, the antibodies to alpha-synuclein (either introduced directly or created by the body) would bind to clumped alpha-synuclein and aid in their removal. Let’s look at these scenarios in more depth.
Alpha-synuclein antibodies (passive immunity)
There are multiple research efforts underway to create and test antibodies against alpha-synuclein.
The prasinezumab antibody
This antibody was studied in a Phase 2 trial called PASADENA, with 316 participants, all with newly diagnosed PD who had mild symptoms and were not on any medication for PD. The trial was double-blinded and placebo controlled which means some people received the drug and some did not, and neither the participants nor the researchers knew which group anyone was in.
This trial has been completed and the data has been analyzed. As happens sometimes in research, it unfortunately did not meet its primary endpoint (the original goal which was stated at the outset as the definition of success of the trial). The primary end point for the trial was an improvement over the course of the year in the total Movement Disorder Society-United Parkinson’s Disease Rating Scale (MDS-UPDRS). This scale has four parts. The first two are filled in by the patient or care partner and assess the motor and non-motor symptoms of PD from the patient’s perspective. The third part is a scale that reflects the motor examination performed by the clinician during the office visit. Part four captures historical and objective information about motor fluctuations and dyskinesias. The trial did not show any difference in the total MDS-UPDRS after one year between those receiving the antibody and those who did not.
It did, however, succeed in meeting some of its secondary endpoints (outcomes that were also determined at the start of the trial, but thought to be of lesser significance than the

Highlights From The Movement Disorders Society Virtual Congress 2020

Every year the International Parkinson and Movement Disorder Society (MDS) holds a conference and every year APDA is there, learning about the newest research and sharing our resources with the wider PD community. The MDS Congress is the preeminent gathering of medical professionals from around the world who are dedicated to Parkinson’s disease (PD) and other movement disorders.  So much fascinating information is shared at the Congress that each year we report back to our readers about what we have learned. You can read our recaps from 2018 and 2019 to learn more.
This year the world has been turned upside down due to the COVID-19 pandemic, and an international conference that typically brings together thousands of people from dozens of countries around the world, was not possible. And much like many other in-person gatherings, this one went virtual.  It was a great accomplishment to conduct such a massive meeting on a virtual platform, and it was very exciting to be a participant in that inaugural event.
The event consisted of scientific talks as well as abstracts, or brief reports of new research.
Highlights from the Research Presented
Here are my highlights from the research abstracts presented at the first-ever MDS Virtual Congress 2020 along with a comment about why each project is important. It was interesting to see several COVID-19-related research projects presented.
Neurological manifestations of COVID-19 in Parkinson’s disease (Agarwal, P. et al)
The abstract reported neurologic manifestations in seven patients with Parkinson’s disease (PD) and COVID-19. Among this cohort, it was common to present with neurologic symptoms such as increased confusion. One patient presented with falls and worsening of tremor, which was initially attributed to progression of PD. Two of the patients died and five recovered to their baseline.
Take home message: It is important to recognize neurological manifestations of COVID-19 in PD patients in order to correctly identify and treat COVID-19 in this population. (Learn more about research related to the intersection of PD and COVID-19.)
Utility of deep brain stimulation remote programming for Parkinson’s disease during the COVID-19 outbreak (Zhang C. et al)
SceneRay, a medical device company based in China developed a deep brain stimulation (DBS) system that enables remote programming. The system allows the physician to change the DBS parameters of an individual’s device from a remote location. This technology is not available yet in the US. This abstract described the experience of practitioners using this technology in six centers in China both before and during the COVID-19 pandemic.
Take home message: Physician adjustment of DBS parameters remotely is available in some parts of the world (and hopefully will be available in the US in the future). Because of its convenience, it can be very helpful for patients who might have trouble getting to the doctor in person, especially during the COVID-19 pandemic.
UCB0599 transition to the clinic: An orally available brain-penetrant inhibitor of alpha-synuclein misfolding in Phase I development for Parkinson’s disease (Smit JW at al)
As explained in a recent blog, targeting of misfolded alpha-synuclein is one of the prime targets for

APDA Announces Funding For 2020-2021 Research Grants

New, Innovative Parkinson’s disease Research Being Funded by APDA
For people impacted by Parkinson’s disease (PD) the search for answers – the causes, a cure, better treatments – may seem elusive, too slow, frustrating. But all of us at APDA will not give up our pursuit, and rather than be deterred, we are inspired, energized and hopeful about the progress that has been made. And we are particularly optimistic when we see the exciting new work being done by some of the brightest minds in PD and we are extremely proud to support these researchers with funding through our grant process.
Today, APDA announced our research grantees for the year ahead. Our grant recipients are working tirelessly to understand the complexities of PD in an effort to develop new treatments and eventually, a cure, and we are honored to support their work. This year APDA awarded $1.4 million in grants that will support a wide range of fascinating research. This year, we also awarded the first-ever APDA Diversity in
APDA Scientific Advisory Board Members
Parkinson’s Disease Research grant to help address the issues and disparities regarding PD in underserved populations – more info about this new grant below.
The APDA Scientific Advisory Board thoroughly vetted each application and chose these grantees very carefully. While the science can seem complicated and the medical jargon confusing, rest assured that this work is not only significant, but exciting as well. Below, I present the research proposals to you and point out why they are important.
Post-doctoral Fellowships
Post-doctoral fellowships are awarded to support post-doctoral scientists whose research holds promise to provide new insights into our understanding of PD.
April Darling, PhD
University of Pennsylvania School of Medicine
Engineering therapeutic TRIM11 disaggregases
Major question to be answered: Can we create a molecule that efficiently prevents and dissolves aggregates of alpha-synuclein?
Why is this important? Such a molecule could serve as a new therapy for PD.
People with PD have protein deposits in their brain (Lewy bodies) which are composed of accumulated α-synuclein. Preventing α-synuclein aggregation and dissolving pre-formed aggregates may be an effective strategy for treating PD. A class of proteins known as protein disaggregases have the ability to dissolve protein aggregates. One recently identified disaggregase is TRIM11. This project aims to find the most effective variant of TRIM11 at dissolving aggregates and preventing clumping of α-synuclein.
 
Judit Pallos, Ph.D.
Oregon Health and Science University
Mechanisms of LRRK2-induced neurodegeneration
Major question to be answered: How does the protein Prospero, which is known to be involved in outgrowth of nerve cell projections, contribute to nerve cell death in an animal model of PD?
Why is this important? This work will further our understanding of why nerve cell death occurs in PD which may identify new targets for therapy,
Degeneration of the axon (the long projection of the nerve cell that extends out from the cell body to communicate with other nerve cells) is observed in the cells of people with PD as well as in animal models of the disease. Here, the role of the protein Prospero, known to control neuronal outgrowth, will be explored