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Additionally, Lewy bodies, abnormal accumulations of the protein α-synuclein, are found in the substantia nigra neurons of PD patients. Researchers are still trying to understand the role of α-synuclein and how this protein may influence PD and Lewy body dementia (LBD). LBD encompasses the two related clinical diagnoses of PD dementia and dementia with Lewy bodies (6). Some research efforts have been focused on blocking the formation of α-synuclein to slow the progression of PD. α-Synuclein exists in several structural forms and researchers have identified that the β-sheet oligomer form of α-synuclein produces a significant loss of dopamine neurons in the substantia nigra. Reducing the formation and propagation of the β-sheet oligomers could be a new route for therapeutic intervention (7).
PD patients also have a loss of nerve endings that produce norepinephrine, an important chemical messenger that controls automatic body functions such as blood pressure. This loss results in some of the non-movement related symptoms of PD such as fatigue and irregular blood pressure (2).
Current drugs for PD improve symptoms but they do not slow or stop disease progression. By the time that patients start experiencing PD symptoms, substantia nigra neurons are already impaired or lost. Researchers are working towards developing new treatments for PD and identifying biomarkers of the disease that may provide opportunity for early diagnosis.
Peptides and Proteins in PD Research
Glial cell line-derived neurotrophic factor (GDNF) is a potential treatment for PD. In preclinical studies with an animal model of PD, a single injection of microencapsulated GDNF achieved sustained GDNF levels within the brain and provided improved motor function and dopaminergic function restoration (8).
Due to interactions between the neurotensin and dopamine systems, neurotensin, a 13 amino acid peptide, is of interest for PD research but clinical use of neurotensin has been limited due to its rapid degradation. Recently, neurotensin (8-13) analogs have been designed to limit degradation and researchers have investigated their possible neuroprotective effects on an experimental model of PD in rats induced with 6-hydroxydopamine (6-OHDA) treatment to produce striatal lesions. In the study, the neurotensin fragment analogs were found to penetrate the blood-brain barrier and treatment with the neurotensin analogs improved the memory of lesioned animals. Also, dopamine content in the brain of neurotensin analog treated rats increased (9).
There has been increasing interest in GLP-1 receptor agonists such as exenatide, liraglutide and lixisenatide as potential disease modifying agents in PD. GLP-1 receptors have been found throughout the brain. Systemic insulin resistance is thought to be associated with the onset of PD. Patients with PD usually have impaired glucose tolerance that can induce brain insulin resistance which is implicated in the neurodegenerative process. In preclinical models of PD, exenatide and other approved GLP-1 receptor agonists have demonstrated neuroprotective effects. Recently, a randomized, double-blind, placebo-controlled clinical study of exenatide in the treatment of PD, showed that patients using exenatide displayed better motor function compared to the placebo group (10). Additional clinical trials are underway to evaluate GLP-1 receptor agonists in patients with PD.
Orexins, neuropeptides produced by neurons in the lateral hypothalamus and perifornical area, are also suspected to be involved in PD. The orexin system plays a role in motor control as well as regulating other vital body functions such as feeding and sleep. Research has shown that PD patients have a loss of orexinergic neurons and the level of orexins in plasma and cerebrospinal fluids is decreased. In a study of orexin-A treatment on MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse model of PD, orexin-A significantly protected the dopaminergic neurons in the substantia nigra and improved motor and cognitive impairments that were induced by MPTP (11).
Current PD Treatments
There are several types of drugs available to treat the symptoms of PD (Table 1).
|Type of Treatment||Generic Drug Names|
|Dopamine precursor||levodopa (L-dopa)|
|Dopamine agonists||apomorphine, rotigotine, pramipexole, ropinirole|
|MAO-B (monoamine oxidase B) inhibitors||rasagiline, selegeline, safinamide|
|COMT (catechol-O-methyl transferase) inhibitors||entacapone, tolcapone|
|Mixed mechanisms, including NMDA (N-methyl-D-aspartate) antagonism||amantadine|
Levodopa is the primary treatment for PD and levodopa is often prescribed with carbidopa. Levodopa helps the nerve cells make dopamine. Carbidopa serves to prevent or reduce the undesirable side effects of levodopa such as nausea and vomiting (2). While levodopa attenuates the symptoms of PD, it does not halt the progressive degeneration of dopaminergic neurons.
In addition to prescription drugs, patients benefit from physical, occupational and speech therapy to help manage PD symptoms. In some cases, deep brain stimulation (DBS) is used to help stop movement-related symptoms of PD (2).
PD is a common neurodegenerative disease and there is a critical need for treatments to slow or stop the progression of PD. GLP-1 analogs and other peptides show promise as novel treatments for PD.
1) Statistics. Parkinson’s Foundation 2019.
2) Parkinson’s Disease. National Institute on Aging 2017.
3) P.Bansode, C.Vaishnavi ,A.P.Nikalje, A brief review on Parkinson’s disease. EC Pharmacology and Toxicology 2018, 6.7, 509-527.
4) Types of Parkinsonisms. Parkinson’s Foundation 2019.
5) P.Maiti, J. Manna, G.L.Dunbar, Current understanding of the molecular mechanisms in Parkinson’s disease: Targets for potential treatments, Translational Neurodegeneration 2017, 6, 28.
6) What is LBD? Lewy Body Dementia Association 2019.
7) J.M.Froula et al, Defining α-synuclein species responsible for Parkinson disease phenotypes in mice, Journal of Biological Chemistry 2019.
8) E.Garbayo et al, Brain delivery of microencapsulated GDNF induces functional and structural recovery in parkinsonian monkeys, Biomaterials 2016, 110, 11-23.
9) M.Lazarova, et al, Preventive effect of two new neurotensin analogues on Parkinson’s disease rat model, Journal of Molecular Neuroscience 2018, 66, 552-560.
10) D.Athuada et al, Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial, The Lancet 2017, 390, 1664-1675.
11) M.F. Liu et al, Orexin-A exerts neuroprotective effects via OX1R in Parkinson’s disease, Frontiers in Neuroscience 2019, 12, 835.
|Product Name||Generic Name||Pipeline Indication(s)||Phase for PD Indication||Companies|
|Saxenda, Victoza||liraglutide||Parkinson's Disease; Smoking Cessation; Binge Eating Disorder||II||Novo Nordisk AS|
|Lixisenatide||lixisenatide||Parkinson's Disease; Type 1 Diabetes||II||Sanofi|
|GM-6||--||Alzheimer's Disease, Multiple Sclerosis, Parkinson's Disease, Acute Ischemic Stroke, Huntington Disease, Amyotrophic Lateral Sclerosis||II||Genervon Biopharmaceuticals LLC|
|PT-320||exenatide||Parkinson's Disease, Drug-Induced Dyskinesia||II||Peptron Inc|
|NLY-001||--||Alzheimer's Disease; Parkinson's Disease||I||Neuraly Inc|
What is your official job title at Bachem?
I am a Project Manager.
How long have you been with Bachem? Where did you work before Bachem?
I have been with Bachem for over 5 years now. I first worked in R&D as a Project Chemist and later as a Group Leader and joined the Project Management team just recently. Before my time at Bachem, I did my PhD in polymer & organic chemistry at the University of Fribourg.
Briefly, what do you do at Bachem?
I lead and manage NCE projects in collaboration with an individual project team both at Bachem and on the customer’s side.
What do you like to do outside of work?
Being with friends and family. I like doing sports such as yoga, running and skiing. I also enjoy cooking very much, especially while listening to some good music and I love going to concerts.
What makes a perfect day for you?
Trying or creating something new, meeting with people, having a good laugh, being outside, finding a few moments for myself.
What do you like most about your job?
I like the complexity and versatility – not only in respect to the various tasks and projects, but also to the many different people I work with. Each day I learn something new, about team work, about peptides, about the pharmaceutical industry and in the end also about myself.
What do you do for fun?
Thank you very much Maren.
Interesting news about peptides in basic research and pharmaceutical development:
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