According to the speaker, there are three different kinds of therapies – symptomatic, disease-modifying, and neuroprotective. Currently, all approved therapies are only for symptomatic treatment; these therapies help improve symptoms – appearance and impact – without affecting the underlying cause of disease. Neuroprotective therapies aim to protect neurons. These therapies can’t be done by looking at a person clinically; neurons themselves must be studied.
In early May, the Parkinson and Movement Disorder (PMD) Alliance hosted neurologist Dr. Zoltan Mari to review disease modifying therapies in Parkinson’s disease (PD). Disease modifying therapies alter aspects of the disease in a lasting manner. Researchers want to find therapies that modify both motor and nonmotor aspects of PD.
Dr. Mari discussed some of the reasons that disease-modifying treatments have yet to be developed, such as lack of specific disease progression markers and poor clinical trail designs. Additionally, the heterogeneity of PD and our incomplete understanding of PD etio-pathogenesis hinder treatment development.
Dr. Mari mentioned possible disease-modifying therapies such as stem cell transplantation, genetic-based therapies for the LRRK2 gene, and immune-based therapies. He gave special attention to alpha-synuclein antibody therapies.
During the question-and-answer session, Dr. Mari was asked whether it has been proven that exercise is neuroprotective and slows disease progression. His reply is very interesting:
“The jury is still out on that. There are studies that have demonstrated some slowing of progression from exercise, but the reason why the jury is still out is because you cannot well develop a proper control and blinding for exercise based clinical trials. There’s also a question about mechanism. Part of the reason why people exercise better is because they are conditioning their musculoskeletal and nervous systems, and that’s why they have better scores, but it doesn’t really prove that you are neuroprotective. There haven’t been enough studies on what happens when you stop exercising, a ‘washout,’ because why would you want to do that, we don’t want to hurt you. Trials shouldn’t compromise standard clinical treatment so stopping exercise isn’t a good idea. We still advocate for exercise because it’s certainly a possibility.”
The webinar recording can be found on the PMD Alliance YouTube channel here.
Please see below for notes on the May 10th webinar.
– Joëlle Kuehn
“Update on (Parkinson’s) Disease Modifying Therapies” – Webinar notes
Speaker: Dr. Zoltan Mari, MD, director, Parkinson’s and Movement Disorder Program, Cleveland Clinic Center for Brain Health
Webinar Host: PMD Alliance
Webinar Date: May 10, 2021
Summary by Joëlle Kuehn, Stanford Parkinson’s Community Outreach
Symptomatic vs. “disease modifying” vs. neuroprotective
- All currently approved treatments for PD
- Help improve symptoms: the appearance and impact without affecting the underlying causes of disease
- Symptomatic and disease modifying efficacy may not be exclusionary of each other
- “Disease modifying” (not a synonym of “neuroprotective”)
- No known proven or approved neuroprotective or disease modifying treatments – only symptomatic at this point
- Disease modifying means altering any aspect of the disease in a lasting manner (ex. after removing the intervention)
- This may be through neuroprotection, but could be through a number of other mechanisms
- Endpoints capturing disease modifications technically more feasible than actual neuroprotection in human clinical trials
- However, showing disease modification may imply underlying neuroprotection depending on purported mechanism of action
- Want to find therapies that modify both motor and nonmotor
- Defined by apparent clinical progression over time, how bad you are 2,5, 10 years from now, etc. We don’t count neurons but we can look at clinical features to determine the severity of your PD.
- Neuroprotective means that defacto protected neurons themselves
- Difference is we hope that that is what happens but we don’t actually know that by looking at a person clinically
- To know that you have to look at the microscope and look at the neuron
- Preclinical studies for neuroprotectives can use neuroprotective because they can count neurons in a petri dish
Levodopa was the first drug that showed a dramatic clinical improvement of previously untreatable symptoms. It was the creation of the dopamine-centric classification of PD.
The targets that the drug would affect are not the same for everyone who meets the clinical diagnostic criteria for PD. Because of this, there are few drugs on the market, and there is a poor track record of drugs working for everyone, even if preclinical work is promising. It’s not an easy task because there are no natural occurrences of PD in animals so it is hard to test compounds to see if they protect neurons.
Why the failures in trials for disease modification?
- The model and underpinning of decades of clinical testing (for symptomatic / dopaminergic therapies) not applicable for disease modification. Especially in patient selection.
- Animal models are imperfect: toxin-based models may be useful for disease state (pathology) but not etiology.
- PD doesn’t occur in any known animal, so it isn’t possible to do it naturally
- In the 1970’s, there were the MPTP cases:
- MPTP targets the dopamine neurons and destroys them, causing young people to show symptoms of PD.
- MPTP was seen as the ultimate savior for PD because they can now create animal models by injecting animals with MPTP to have them exhibit symptoms of PD
- Can inject in one half and can make animal parkinsonic on one side but have the other as a control
- This is great for finding symptomatic treatments because you destroy the dopamine network entirely and can test dopaminergic drugs as to how well they worked
- They are also misleading and useless when we are trying to find the causing factors, or etiology, initial cause of PD because the destroying is artificially done
- Timing issues (can perfect control in animal experiments – not so much in real life). Can’t control people in every aspect of their lives and environment
- Lack of sensitive / specific disease progression markers – no good endpoint / poor clinical trial designs
- Heterogeneity of PD – it is a syndrome not a specific disease – particularly relevant in disease modification
- Our incomplete understanding of PD etio-pathogenesis
- Singled out targets may be insufficient to carry significant impact on overall disease, which is multifactorial
Many biological systems involved in PD
- Calcium homeostasis
- Synaptic pathobiology
- a-Synuclein misfolding
- Mitochondrial dysfunction
- Failure of protein degradation systems
- Unknown pathways
Potential targets of disease modification
- Transplantation therapies – stem cells
- Popular topic, but it is abused worldwide to defraud patients
- There is an apparent acquisition of synuclein pathology in the graft
- LRRK2 gene – genetic based therapies
- Immune based therapies [using alpha-synuclein (a-Syn) antibodies]
- Small molecule therapies / (a-Syn) aggregation inhibition
- C-Abl inhibition
- Microglia / neuroinflammation (HMGB1) / apoptosis. GLP1 agonists
- Immunotherapies in PD rely on 3 basic strategies
- Generation of antibodies against a-Syn (primarily for removal of a-syn aggregates)
- The induction of a particular T cell response to modulate the neuroinflammatory response
- “Cool down” microglia and thus the neuroinflammatory response (ex. GLP1 agonist peptides)
Some controversies of PD and neuroprotection
- There is a profound lack of translation from basic science success to clinical trial results
- Is levodopa potentially toxic?
- Is it proven that MAO-B inhibitors are neuroprotective?
- No because even if disease modification is shown, that is not equivalent with neuroprotection
- There was a trial called ADAGIO on this which was inconclusive
- “Conditioning” confound of symptomatic agents tested in the context of disease modification
Question & Answer:
Question: What can you say to siblings where one was an early onset and another was a typical onset?
Answer: With different genetic mixes (they aren’t identical twins), it is possible that the person who had the later onset was a different type, it could be sporadic, whereas the early onset could carry the mutation. It’s possible that the typical onset which was sporadic didn’t have 2 copies of the mutation whereas the early onset did. It’s also possible that certain risk genes can manifest in different ways.
Question: Regarding neuroprotection, hasn’t it already been proven that particular types of exercises slow progression?
Answer: The jury is still out on that. There are studies that have demonstrated some slowing of progression from exercise, but the reason why the jury is still out is because you cannot well develop a proper control and blinding for exercise based clinical trials. There’s also a question about mechanism. Part of the reason why people exercise better is because they are conditioning their musculoskeletal and nervous systems, and that’s why they have better scores, but it doesn’t really prove that you are neuroprotective. There haven’t been enough studies on what happens when you stop exercising, a “washout”, because why would you want to do that, we don’t want to hurt you. Trials shouldnt compromise standard clinical treatment so stopping exercise isn’t a good idea. We still advocate for exercise because it’s certainly a possibility.