In late February 2021, the American Parkinson Disease Association (APDA) hosted four of its APDA-funded researchers to provide an update on what their labs have been working on. In the “APDA Virtual Research Roundtable,” Dr. Vikram Khurana discussed his lab’s research in stem cells; Dr. Karen Nuytemans discussed identifying genetic factors that influence development of PD in hispanic populations; Dr. Brian Daniels explained his research of the role of inflammation and genetics in PD, and Dr. Bonnie Wong described her research into the effectiveness of telehealth visits during COVID and beyond. The researchers answered questions from the listeners.
The webinar can be found on the APDA’s YouTube channel.
Please see below for notes on the February 24th roundtable.
– Joëlle Kuehn
“APDA Virtual Research Roundtable” – Webinar Notes
Host: American Parkinson Disease Association (APDA)
Webinar Date: February 24, 2021
Summary by Joëlle Kuehn, Stanford Parkinson’s Community Outreach
The four researchers and the titles of their talks were:
- Vikram Khurana, MD, PhD, Brigham and Women’s Hospital, and Stem Cell Institute at Harvard Medical School, “Alpha synuclein mutations and their role in PD – using stem cell technology”
- Karen Nuytemans, PhD – University of Miami Miller school of Medicine – “Genetic factors that influence development of PD in hispanic populations”
- Brian Daniels, PhD – Rutgers University- “Goal of inflammation in PD: Investigating roles for inflammatory astrocytes in PD”
- Bonnie Wong, PhD – Boston University – “Telehealth in treating depression and cognitive impairment in PD”
David Standaert, MD, PhD, Chairman of the APDA Scientific Advisory Board took part in the Q&A but did not present.
Session 1: Vikram Khurana, MD, PhD
His Lab: An important challenge for PD when we think about therapy is that PD may be different from patient to patient. No one-size-fits-all. They use tech in stem cell biology to take insights from stem cells from patients to develop gene therapies that are specific to patients and patient subtypes
“Pluripotent” stem cells and mini brains can be generated from patients:
- Take a skin biopsy, take the skin cells, convert those into IPS cells (induced pluripotent stem cells), make neurons from them, and then use them to discover pathologies and ultimately identify biomarkers, genetic risk factors, and test therapies in brain cells
- Direct window into the pathology and biology of the disease while the patients are alive
- Until this tech came around – you could only see it after the person passed away and the postmortem brain is investigated
- If we know there are mutations that patients cary, can use genome editing to correct the mutations so we can compare neurons with mutation and with mutation corrected to be sure we are studying the right kind of technology
- Have used this method to:
- Identify potential PD therapies (that are now in Phase 1 clinical trials)
- Begin “n of 1” antisense gene therapy development for children with aggressive early-onset parkinsonism
Finding Genetic Targets in PD:
- Finding targets during late onset disease is more difficult because we don’t fully know what drives the disease process in each stage in each patient
- No matter the cause, know that the disease in every patient is always aggregated with a specific protein alpha-synuclein
- Involved in transport of other proteins around the cell nada release of brain molecules neurotransmitters do neurons can signal one to the other
- In PD, no matter the cause, the protein changes its form and aggregates to an abnormal form that is related to the disease
- Is the underlying pathology of PD
The lab creates a cellular roadmap of alpha-synuclein and sees what connections it has to other proteins in the cell. Roadmap guides researchers to genes that are responsible for PD in specific patients and then tests the hypothesis (hypothesis being that they believe the genes are important) in stem cells made from those patients.
APDA’s funding specifically helps with finding which proteins are involved and how they are connected to alpha-synuclein. They specifically are researching mRNA binding proteins that are involved in translating DNA messages to generate proteins – discovered they directly interact with alpha-synuclein. It was previously unknown that they are involved in the process. Implications for new functions in the proteins and new ways to understand how the disease is caused.
Session 2: Karen Nuytemans, PhD
Importance of Genetics in PD
Though the vast majority of PD is late onset, there is sporadic family history (15%) and 10% of those is early onset. Even in late onset PD cases there are genetic variances that increase risk for PD. ID of genetic factors help in diagnosis and prognosis of PD, and developing an understanding of biological mechanisms (which are important for the development of treatments).
Current Status of PD Genetics:
- Have found some genes related to PD
- Close to causal genes (these genes cause PD or risk of PD)
- Only explain 10% of PD – still a lot to be identified
- Genes are involved in protein clearance and mitochondrial function
Disparity in Genetics:
- Vast majority of genetic (and other biomedical research) data comes from studies in European and Asian descent populations – vast majority is European
- No or little information on other ancestries
- The gap in knowledge creates a health disparity, with an inequality on treatment information and diagnostic tools
- Her lab looks into Genetics in Admixed Populations – coming from many different ancestries
- Hispanics have contributions from European, African and Amerindian ancestry
- The percentage of contributions varies vastly across different hispanic nationalities and groups
Current work in Hispanic PD:
- Enroll ~250 Hispanic PD patients in genetic research
- Most are of Carribean descent
- Screen for known PD genes (identified in Europeans) and identify novel variants or new genes
- In dataset of 90 Hispanic individuals (of which 80% are Caribbean)
- They were screened for known variants in certain genes
- One gene (LRRK2 G2019S) was found in 5 individuals, who have a European background
- (GBA) variants was found in 6 individuals, who also have a european background
- Also found novel variants
- LRRK2 D734N on African background; novel and is predicted to be important for function and unique to Puerto Rico
- LRRK2 P1480L – Amerindian background; predicted important for function
- GBA S310G mutation on Amerindian or European background; predicted to be pathogenic for PD before as it has been seen on east asian patients of east asian background
- The variant has risen on asian background as well as Amerindian or European background
Take away / Future Prospects:
- Important to include all populations and all ancestries not only for their own benefit, but for the purpose of improving diagnosis and being involved in development of future treatment
- Also important for overall knowledge of PD and it’s biology
- Specifically interested in admixed populations because can inform on genetics in many populations with same ancestral backgrounds
- Collaboration with Dr. Mata (of LARGE-PD consortium) to complement both studies (his continental and Dr. Nuytemans caribbean hispanics studies)
Session 3: Brian Daniels, PhD
Astrocytes are key brain cell type:
- Most abundant type of cell in the brain (more than neurons)
- Many diverse functions – supporting neurons through metabolic support, regulating neurotransmitter at the level of the synapse
- Important for regulating neurologic functions of brain
- Also regulate immunologic functions (inflammation)
- Through blood vessels in brain
- Regulates how immune system can interact with brain
- Serve both protective and harmful functions in disease
- His lab focuses on promoting beneficial aspects of astrocytes and turn down harmful activities that they may be able to exert in disease
RIPK3 – helps balance protective and harmful functions
- Protein associated with inflammation and programmed cell death
- In PD the molecule is expressed higher in mid-brain with patients with PD
- Have twice as much
- Don’t know why it is there and what is doing
- Big question: Does RIPK3 activity in astrocytes promote the pathogenesis of PD?
Their research tools:
- Molecular genetic tools (RIPK3 deletion) – delete the RIPK3 and see what happens
- Pharmacological RIPK3 inhibitors to see responses to that
- Use human astrocyte cultures and mouse models of PD
- In mouse models – if they delete astrocytic RIPK3, the PD mouse dopamine results looks likes a normal mouse’s result
Session 4: Bonnie Wong, PhD
Study: videoconference cognitive-behavioral therapy for depression in PD: Effect on non-motor symptoms
Mood and anxiety disorders in PD:
- Depression and anxiety are prevalent non-motor symptoms of PD
- Clinical level depression affects 40-50% of individuals with PD
- Clinical level anxiety affects 40% of individuals with PD
- Presence of depression and anxiety symptoms in PDis due to both biological and psychosocial factors
- Biological: downstream effect of PD neuropathology
- Psychosocial: diagnosis and progression of PD, disease-specific stigma
- Depression and anxiety can worsen both motor and cognitive symptoms that go along with PD
- Medication is one way the mood symptoms can be addressed but there is side effects so alternatives are desirable
- It also adds even more to their regiment of medications and can cause complication
- If don’t want medications, think of psychotherapy – especially Cognitive Behavioral Therapy (CBT)
Cognitive behavioral therapy (CBT)
- Kind of psychotherapy
- Evidence-based treatment effective for a wide range of mood and anxiety disorders in older adults
- Has been shown effective in treating depression and anxiety in PD
- Involves strategies that help the individual think flexibly, regulate emotions, constructively approach difficult situations, increase activity, and engage in healthy interpersonal communication
There are barriers to the treatment…
- Motor symptoms – mobility issues preventing one from going out into the community and accessing resources
- Scheduling conflicts such as work
- transportation/location – too far away, not accessible
- Care partner burden – an additional treatment/appointment they need to transport them too and add to their schedule
- Stigma about therapy
- medical/health/social complications – COVID significantly limited access to therapeutic interventions and treatment
Want to make it more accessible… one way is trying to do CBT by Telehealth
- Goals of CBT by Telehealth protocol study is to examine the feasibility, acceptability, and efficacy of CBT by video
- Does it work, is it sustainable, as effective as in person…
- Primary outcomes want to see: will show an objective improvement in mood, sustained over time
- Secondary outcomes: if they do show an improvement in their mood, does it also result in improvement in cognition, anxiety, apathy, sleep, quality of life, daily function
How they did the study:
- Assessed the person’s mood and cognitive function before the treatment
- Treatment sessions of CBT by video
- 12 weekly sessions
- Post-treatment assessment of mood and cognitive function
- 6-week assessment after the treatment to assess mood and cognitive function
Study is still ongoing… but preliminary results:
- 5 have completed entire protocol (7 more are near completion or still in treatment)
- All are no longer meeting the criteria for MDD (major depression)
- All reported a reduction in symptoms (depression, anxiety, apathy)
- 4 reported improvements in quality of life
- 2 reported improvements in sleep
- Modest improvements in aspects of memory and attention
Potential mechanisms for improvement:
- Reduction in beliefs about unacceptability of experiencing or expressing negative emotions
- Reduction in experiential avoidance (avoidance or tendency to avoid)
- Reduction in use of expressive suppression to regulate emotions
- Regulate emotions with cognitive reappraisal
Conclusions & Future Directions:
- CBT for treatment of depression by telehealth is a viable option for PD patients
- CBT telehealth for anxiety disorders, sleep problems and pain management in the future
- CBT for managing cognitive symptoms in the future
Question & Answer:
Question: Why is PD research so difficult and taking so long when something like COVID has reached treatment options much quicker?
Answer (Dr. David Standaert): There’s two reasons. PD is a challenging problem, it is a brain disease and has a very long course – it begins many years before the symptoms appear. Understanding how to slow and alter that is a complex task. The second reason is the investment made in COVID research is a world wide emergency with billions of dollars being spent in the last year on the vaccine. Much less than a billion dollars has ever been spent on any year on PD research.
Question: If all goes well, how long will trials start in people for RIPK2?
Answer (Dr. Daniels): My research is preclinical, but our preliminary findings need to go through basic research to establish proof of principle. The findings so far are promising but there are a lot of variables that go into determining which types of drug go from a basic lab like mine and get picked up to enter clinical trials in the pharma industry or hospital settings. In our case it may not be as long because there are drugs that target a similar molecule (RIP1) that are already in Phase 2 clinical trials, although not for PD. It’ll probably be some small number of years, but it is determined by if a pharmaceutical company decides if it is an avenue worth pursuing.
Question: If you are looking for a telehealth CBT practitioner, how do you find one?
Answer (Dr. Wong): Thanks to the pandemic, they have become more common and insurance providers are more supportive of it, which is often an impediment for finding a therapist. If you have providers who are part of a movement disorder clinic, they will have many kinds of clinicians who may have the correct background to provide that kind of therapy. It isn’t something many people specialize in, but thanks to telehealth you can now see someone who isn’t in your area.
Question: What is usually the timeline from an idea in a clinic to medication in a bottle?
Answer (Dr. Standaert): It varies on the kind of treatment. A completely new drug that has never been tested in humans has to pass through a lot of safety testing to ensure it is safe for humans, it would be 6-7 years at the fastest, sometimes 10 years. Sometimes existing drugs developed for other reasons can go through drug repurposing trials to see if they can help Parkinson’s, and will be faster. It takes a long time because of safety, if a drug has never been in a person before we want as much evidence as we can have to make sure it is safe for humans before we give it to anyone.
Question: Can Terazosin work with PD?
Answer (Dr. Khurana): It is used for urinary function, but there are interesting observational studies for PD noting that certain classes of drugs (like asthma, urinary function) are conferring decreased risk over time for PD. It needs to be revisited, but it is better for these agents to be tested specifically for PD in a case controlled design study.
Question: Is there any evidence that reducing inflammation through other means (prednisone or other anti-inflammatory therapies) reduces PD symptoms and how do such findings tie into your research?
Answer (Dr. Daniels): There is tremendous pre-clinical evidence for this, this is an exploding area of research. Some clinical trials I know of have shown that targeting some very specific parts of the inflammatory response can help prevent the death of dopamine neurons and stall the progression of PD. At the moment, to my knowledge, there aren’t any FDA approved therapies that are specific anti-inflammatories that are indicated for use in PD, but this is a very active area of research.
Question: Direct to consumer marketing of genetic products such as 23andme says that it tests for genetic markers of PD, do you recommend people with PD to test themselves in this way?
Answer (Dr. Nuytemans): I applaud any kind of genetic research, but the work that 23andme is doing does come with caveats. The work they’re doing is looking more at ancestry, which is a part of my work as well, and its great but in terms of actual genetic predisposition and the health issues that they’re studying, I would be very careful, the data they are supplying is very insufficient both in number of variants (ex – for PD they only test for 2 variants of PD out of the hundreds that we know of), and is slightly insufficient in providing enough information as to what it means (if it says increases risk by 5x, it doesn’t provide 5x of what amount… and 5x less than 1% is still a less than 5% risk and is a low percentage). If you want to do genetic testing talk to your doctor before and review the results with the doctor.
Question: Now that COVID has opened our eyes to telehealth, what do you think will happen to telehealth when COVID is over?
Answer (Dr. Wong): I think we will have even more options for telehealth than before and that it’ll continue. We’ve proven over the past year that this is a medium that does work. It isn’t perfect and doesn’t give us the same connections we would normally have in person but it’s a great alternative. It’s also great for patients because it reduces wait times in the waiting room, and the burden of travel and living in a place where parking is bad. I think having set up the infrastructure now in hospitals and at home will allow this to continue and may also increase the frequency of contact between a patient and their providers.