Glucocerbrosidase Enhancing The Cells Lysosomal System
GBA is a gene that increases the risk of developing PD. The GBA protein works in the lysosome, the garbage disposal system of the cell, breaking down cellular products that can be harmful to the cell. Having two abnormal GBA genes causes Gauchers disease, which is characterized by the buildup of these cellular products. This results in fatigue, bone pain, easy bleeding and an enlarged spleen and liver. When a person inherits only one abnormal gene, he or she does not develop Gauchers disease however, they do incur a small increased risk of PD. Most people with one mutated GBA gene do not develop PD.
Enzyme replacement therapy, in which the GBA protein is given intravenously, is available as a treatment for Gauchers disease. This protein is too big to cross the blood-brain-barrier however, and so it does not enter the brain and does not treat any symptoms caused by the abnormal buildup of cellular components in the brain. The following strategies were developed in an attempt to compensate for the effects of the GBA mutation in the brain:
- Ambroxol, approved in Europe for respiratory illnesses, improves the function of GBA in neurons NCT02941822 and NCT02914366
- These small molecules can cross the blood-brain-barrier and help decrease the amount of accumulated cellular products in the brain:
Parkinsons Surveys Clinical Trials And Volunteer Opportunities
PAIRing Up If you are a person with Parkinsons or a care partner to someone with Parkinsons, you are invited to participate in an online survey to address neuropsychiatric concerns in Parkinsons. The survey aims to learn about the needs and priorities for clinical care, education, support, and research as related to neuropsychiatric symptoms. To learn more and participate, .
The University of Oulu, along with collaborators from Aalborg University, Fraunhofer University, the University of Manchester, the University of Glasgow, the University of Lisbon, and the University of Melbourne, is conducting a survey for people with Parkinsons and Parkinsons care partners about self-care. Complete the survey here to share your self-care strategies and techniques. You can also review ideas submitted by others and add them to your own self-care toolbox.
Looking for a once-in-a-lifetime adventure? Pass to Pass, a nonprofit dedicated to raising Parkinsons awareness while supporting hikers living with Parkinsons, offers multi-day hiking trips on the Pacific Crest Trail in both Washington and Oregon. Participants are being recruited now for these summer 2021 events. For more details and information, visit www.PasstoPass.org or contact Bill Meyer at 509-991-1212 or .
Park Test University of Rochester
Project Euphonia LSVT Global and Project Euphonia
Updates On Currently Approved Pd Treatments
Table 1 Approved dopaminergic drugs
Later, DA receptor agonists, such as those shown in Table , were developed either as monotherapies or combination therapies with L-DOPA for the treatment of PD. Five types of DA receptors, D1D5, exist in the brain. The D1 and D5 receptors are grouped together as D1-like receptors based on their stimulatory effects on adenylyl cyclase , and the D2, D3, and D4 receptors are classified as D2-like receptors due to their inhibition of cAMP activity. Many synthetic DA agonists, including pramipexole and apomorphine, activate D2-like receptors, and have a lower incidence of motor fluctuations and dyskinesia .
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Is Angiogenesis A Treatment And Potential Cure
Zhittya Genesis Medicine is developing a drug, fibroblast growth factor 1 , to possibly treat Parkinson’s disease by growing new blood vessels in the brains of individuals suffering from Parkinson’s. FGF-1 is a potent stimulator of angiogenesis and is capable of growing these new blood vessels in ischemic areas of the body, including the brain. Research has indicated that a lack of blood perfusion to dopamine producing neurons located in the substantia nigra region of the brain lead to a lack of dopamine and the classic symptoms of Parkinson’s.
In the past, FGF-1 has been able to grow new blood vessels in the human body. In a US FDA Phase IIA clinical trial, conducted at the University of Cincinnati, our drug was able to grow new blood vessels in the hearts of individuals with coronary artery disease, improving many of their symptoms.
FGF-1 has also shown excellent efficacy in treating Parkinson’s disease in Cynomolgus monkey models. After being injected with a neurotoxin that selectively destroys dopamine-producing neurons, the two groups of monkeys came down with the classic symptoms of Parkinson’s disease. After one group was administered FGF-1 and the other a placebo dose, the FGF-1 administered monkeys not only improved their motor scores almost to normal, but also increased their dopamine production and decreased their build up of alpha-synuclein plaque.
Latest News In Parkinson Disease: Treatment Progress Cognition Improvements And More
An overview of the latest news in Parkinson disease reported across MJH Life Sciences.
An overview of the latest news in Parkinson disease reported across MJH Life Sciences.
FDA Approves Investigational NDA for Ketamine in Levodopa-Induced Dykinesia
As the gold standard of treatment for PD, levodopa effectively reduces parkinsonian symptoms, although long-term use has been linked with several adverse events. Chief among these, frequency of OFF time and abnormal involuntary movements, known as levodopa-induced dyskinesia , have been shown to significantly impact quality of life and treatment efficacy.
There are no approved treatments to address LID however, an article by NeurologyLive® indicates there may be some progress in addressing this issue. Last week, the FDA approved PharmaTher Holdings investigational new drug application for ketamine, an N-methyl-D-aspartate receptor-modulating drug, in the treatment of LID in patients with PD.
A phase 2 clinical trial evaluating the safety, efficacy, and pharmacokinetics of ketamine compared with the active control treatment of midazolam is expected to begin patient enrollment in the third quarter of this year. Pending success, the manufacturer noted that it will seek an agreement with the FDA to proceed to a phase 3 clinical study next year.
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Search For Primary Endpoints Reflecting The Progression Of Parkinsons Disease In The Prodromal Stages
Taking together the discoveries on the genetic background of PD and the Braak staging hypothesis, new avenues for drug development and clinical testing have opened up. For clinical testingat least in the next few yearspotential disease-modifying compounds are and will be tested in the early stage of motor PD that is, very earlyde novo PD patients, who never received a symptomatic therapy will be recruited and should present with a unilateral asymmetric very mild motor symptomatology.
However, for true neuroprevention , parameters and biomarkers which reflect the progression of the alpha-synucleinopathy in the prodromal stage have to be discovered. In addition, such a parameter must be responsive to therapy, even in the prodromal stage, in order to qualify as a primary endpoint for pivotal registration trials. At present, such a parameter has not been identified. Respective research ranges from studies on biomarkers in the cerebrospinal fluid, peripheral blood, saliva, and sweat and in biopsies of the colonic enteric nervous system, the salivary gland, or the skin. Major efforts are placed into different imaging techniques with sophisticated magnetic resonance methods, nuclear medical ligands for the dopamine transporter single-positron emission computed tomography or fluoro-desoxyglucose positron emission tomography.
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Treatments In Phase Iii Trials
What we see in Phase III trials this year is a total of 22 treatments from five different therapeutic categories. Three treatments in Phase III are disease-modifying treatments that have the potential to alter the progression of Parkinsons disease. One is widely used in traditional Chinese medicine, one is a repurposed Alzheimers medication, and the other is a repurposed diabetes medication.
There are also 19 studies in Phase III addressing symptoms of Parkinsons. While the community waits for gains to be made with disease-modifying treatments, improvements in symptom relief are critical for maintaining the quality of life. more personalized treatment plans If the symptom management products in Phase III safely and successfully complete their trials, the medical community will have more tools available to support Parkinsons symptom management.
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Table 2 Therapy With Compounds Of Disease
| Compound |
|---|
| Oertel et al. 2016100Quik et al. 2008101Hong et al. 2009102 |
Modified from Oertel and Schulz17 .
The second approach relates to the groundbreaking genetic discoveries in PD. In fact, a dramatic shift in the strategy for developing a new PD therapy has taken place: pharmaceutical efforts now target alpha-synuclein protein synthesis, degradation , protein aggregation, and propagation in the nervous system. Finally, 20 years after the discovery of PARK1, the academic and pharmaceutical industrial scientific community can offer the first candidates with a potential for a disease-modifying effect in PD.
Three different principles of therapeutic action are addressed: active or passive immunotherapy, modulation of alpha-synuclein aggregation, and enhancement of autophagy of alpha-synuclein .
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New Medications For Off Time
A number of new medications approved recently are designed to reduce OFF time. These medications fall into two major categories:
- Medications that lengthen the effect of a carbidopa/levodopa dose
- Medications that are used as needed if medication effects wear off
Well give specific examples below. In general, new medications that extend the length of a carbidopa/levodopa dose are used if OFF time is somewhat predictable and occurs prior to next dose. New medications that are used as needed are most beneficial when OFF time is not predictable.
New medications that lengthen the effect of a dose of carbidopa/levodopa
- Istradefylline is an adenosine A2A receptor antagonist which was approved in the US in 2019 as an add-on therapy to levodopa for treatment of OFF time in PD. Unlike many of the other medications, it has a novel mechanism of action and is the first medication in its class to be approved for PD. It acts on the adenosine receptor, which modulates the dopaminergic system, but is not directly dopaminergic. The drug was developed in Japan and underwent clinical trials both in Japan and in the US.
- Opicapone is a catechol-O-methyltransferase inhibitor that is taken once a day. It was approved in the US in 2020 as an add-on therapy to levodopa for motor fluctuations.
New formulations of levodopa designed to be used as needed if medication effects wear off
Other medications used as needed if medication effects wear off
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Levodopa In The Treatment Of Parkinsons Disease: Current Status And New Developments
Article type: Review Article
Authors: Salat, David | Tolosa, Eduardo
Affiliations: Universitat Autònoma de Barcelona, Barcelona, Spain | Parkinsons Disease and Movement Disorders Unit, Neurology Service, Hospital ClÃnic, University of Barcelona Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Barcelona, Spain
Note: Correspondence to: Eduardo Tolosa MD, FRCP, Neurology Service, Hospital Clinic, University of Barcelona, Villarroel 170, Barcelona 080036, Spain. Tel.: +34 93 227 57 85 Fax: +34 93 227 57 83 E-mail:
Keywords: Levodopa/carbidopa, Parkinsons disease, wearing-off, dyskinesia, entacapone
DOI: 10.3233/JPD-130186
Journal: Journal of Parkinsons Disease, vol. 3, no. 3, pp. 255-269, 2013
Abstract
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Treatments In Phase Ii Trials
Another strategy in the therapeutic research space is drug repurposing. This is when an existing medication for one condition is repurposed to treat an entirely different condition. Working with repurposed medications comes with many advantages including understanding its general safety. Repurposing an existing medication, rather than starting from scratch, typically requires fewer tests for safety as the drug has already met these requirements. This can reduce costs and speed up the process through the clinical trial pipeline. It can also lead to faster approvals, getting much-needed treatments into the hands of people with Parkinsons as soon as possible. There are a total of 74 therapies in Phase II trials and 44% are repurposed medications.
One exciting takeaway from Phase II trials this year is the progress made with stem cell therapies. While there are nine stem cell therapies being explored in Phase I, two stem cell therapies graduated to Phase II trials this year! Moving into Phase II means these treatments are being administered to a larger group of people to monitor their effectiveness and further evaluate their safety.
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Updates On The Clinical Progress Of Dopaminergic Pd Treatments
Despite the intensive efforts in PD research and development, there are clear unmet medical needs for the development of additional dopaminergic treatment options to improve current DA-centered treatment. Most currently used dopaminergic drugs selectively activate D2-like DA receptors , but no D1-like selective agonists have been successfully approved even though the D1 receptor is a known target for PD treatment. Recently, important progress has been made in the clinical development of D1 selective agonists and allosteric modulators. All active dopaminergics since 2012 on the clinical trial website are summarized in Fig. and Table .
Fig. 2
Common Scale Of Motor Symptom Severity May Have Flaws: Study
A commonly used measure of how motor symptoms are affecting daily life could also for people in early stages of Parkinsons disease be taking into account the contribution of their non-motor symptoms, a study suggests. This is a likely reason for the discrepancies seen in evaluations made by patients
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Clinical Implications Of Intanapraced
In addition to LRRK2G2019S mice, itanapraced also prevented the loss of dopamine neurons in a chemically induced model of Parkinsons disease.
This suggests that itanapraced may have the potential for the treatment of cases of Parkinsons disease besides those involving the LRRK2G2019S mutation.
Our study is the first to connect AICD/APP and LRRK2, the important molecules in Alzheimers disease and Parkinsons disease , respectively, on a common pathway and identified a new treatment target of AICD for PD. Pathological markers in LRRK2-mutant PD models were reduced by targeting the AICD with itanapraced, a small-molecule inhibitor that is currently in trials to treat Alzheimers disease, Dr. Li said.
Our findings reveal that LRRK2 and the AICD are reciprocally linked and that itanapraced may be therapeutically beneficial in PD.
Prof. Louis Tan, a senior consultant neurologist and director at National Neuroscience Institute, told MNT:
This important discovery opens the way to finding a common therapeutic target for both Parkinsons disease and Alzheimers disease, the two most common neurodegenerative diseases globally. This novel drug has the potential to improve and preserve the function and quality of life for those afflicted with these diseases.
What The Experiments Showed
Initially, the researchers tested the nanobody on mouse brain tissue in vitro. They found that PFFNB2 could bind to aggregates of alpha-synuclein, but could not prevent the formation of clumps.
Further experiments revealed that the nanobody could bind to and disrupt fibrils of alpha-synuclein that had already formed, destabilizing the misshapen proteins.
The researchers then tested this in live mice and found that the nanobody prevented alpha-synuclein from spreading to the cortex of the brain. The cortex is the largest part of the brain and is responsible for most higher brain functions.
Dr. Petrossian explained for MNT that he results showed that they were able to specifically target the preformed fibrils of alpha-synuclein in cell and mouse models, that they were able to reduce the clumping of alpha-synuclein in cell models, and they were able to reduce alpha-synuclein pathology in mouse models.
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Amneal Tests A New Formulation
AmnealPharmaceuticals plans to report Phase III safety results for IPX-203, a reformulation of the common generic PD treatment combination of carbidopa and levodopa that could reduce symptom fluctuations. The company said the Phase III, open-label extension study will have results available by the end of the second quarter of 2022.
CD/LD can lead to troughs and spikes of plasma levels that generate side-effects like dyskinesia, Kordower explains. A new extended-release version of CD/LD could smooth out these drops, he notes.
If approved, IPX-203 will join several other marketed reformulations of CD/LD. Amneals own extended-release capsule Rytary, Schwarz Pharmas orally disintegrating tablet Parcopa, and AbbVie’s enteral suspension Duopa all have FDA approval in PD. A GlobalData consensus forecasts pegs peak IPX-203 sales at $127 million in 2028.
In a separate, placebo-controlled Phase III trial , IPX-203 resulted in 0.53 more hours of ON time than immediate-release CD/LD after seven weeks . Earlier, a six-week Phase II trial of IPX-203 reported no serious treatment-emergent adverse events among the 26 patients enrolled. Experts say the long-term safety data will be key in determining IPX-203s place among CD/LD formulations.
The Parkinsons Disease Medication Pipeline
The pipeline for Parkinsons disease medications is extremely crowded these days, with multiple medications at various stages of research development. This is very exciting news for the PD community and is a perfect example of the hope in progress part of our organizations motto. It is thrilling to see the research that is underway, especially the potential treatments that have already made it to the clinical trial phase of development. However, this progress brings with it the welcome challenge of keeping track of all the potential compounds that are in research development! Recently, a review was published in the Journal of Parkinsons Disease which cataloged the 145 compounds that are currently being studied in humans via clinical trials for PD. This is a staggering number and is even more exceptional when you consider the many more compounds that are not quite yet ready for human trials, but are currently being studied in the laboratory in test tubes, cell culture or animal models of PD. The number also does not account for compounds that have been studied in small clinical trials, garnered promising data, and will be studied in larger clinical trials in the near future but are not being tested in clinical trials right now.
Some background on the review
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