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Human personalized autologous cell therapy for Parkinson’s Disease

Posted in Autologous Cell Therapy, Biological Engineering, Biological Networks, Biomarkers & Medical Diagnostics, Biotechnology, Cell Biology, Cell Biology, Signaling & Cell Circuits, Cell Processing System in Cell Therapy Process Development, cell-based therapy, Cerebrovascular and Neurodegenerative Diseases, Competition in regenerative stem cell science, Genomic Endocrinology, hNPCs, Innovations in Neurophysiology & Neuropsychology, Neurodegenerative Diseases, Neurohumoral Transmission, Neurological Diseases, Neuronal Circuits, Neuroscience, Parkinson's disease dyskinesia levodopa, Patient-centered Medicine, Personal Health Applications: Tech Innovations serves HealhCare, Personalized and Precision Medicine & Genomic Research, Signaling & Cell Circuits, stem cell biology and patient-specific, Stem Cells for Regenerative Medicine, tagged brain, dopamine, hiPSC, Parkinsons disease, Therapy on December 2, 2019| Leave a Comment »

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Parkinson’s Disease (PD), characterized by both motor and non-motor system pathology, is a common neurodegenerative disorder affecting about 1% of the population over age 60. Its prevalence presents an increasing social burden as the population ages. Since its introduction in the 1960’s, dopamine (DA)-replacement therapy (e.g., L-DOPA) has remained the gold standard treatment. While improving PD patients’ quality of life, the effects of treatment fade with disease progression and prolonged usage of these medications often (>80%) results in side effects including dyskinesias and motor fluctuations. Since the selective degeneration of A9 mDA neurons (mDANs) in the substantia nigra (SN) is a key pathological feature of the disease and is directly associated with the cardinal motor symptoms, dopaminergic cell transplantation has been proposed as a therapeutic strategy.

Researchers showed that mammalian fibroblasts can be converted into embryonic stem cell (ESC)-like induced pluripotent stem cells (iPSCs) by introducing four transcription factors i.e., Oct4, Sox2, Klf4, and c-Myc. This was then accomplished with human somatic cells, reprogramming them into human iPSCs (hiPSCs), offering the possibility of generating patient-specific stem cells. There are several major barriers to implementation of hiPSC-based cell therapy for PD. First, probably due to the limited understanding of the reprogramming process, wide variability exists between the differentiation potential of individual hiPSC lines. Second, the safety of hiPSC-based cell therapy has yet to be fully established. In particular, since any hiPSCs that remain undifferentiated or bear sub-clonal tumorigenic mutations have neoplastic potential, it is critical to eliminate completely such cells from a therapeutic product.

In the present study the researchers established human induced pluripotent stem cell (hiPSC)-based autologous cell therapy. Researchers reported a platform of core techniques for the production of mDA progenitors as a safe and effective therapeutic product. First, by combining metabolism-regulating microRNAs with reprogramming factors, a method was developed to more efficiently generate clinical grade iPSCs, as evidenced by genomic integrity and unbiased pluripotent potential. Second, a “spotting”-based in vitro differentiation methodology was established to generate functional and healthy mDA cells in a scalable manner. Third, a chemical method was developed that safely eliminates undifferentiated cells from the final product. Dopaminergic cells thus produced can express high levels of characteristic mDA markers, produce and secrete dopamine, and exhibit electrophysiological features typical of mDA cells. Transplantation of these cells into rodent models of PD robustly restored motor dysfunction and reinnervated host brain, while showing no evidence of tumor formation or redistribution of the implanted cells.

Together these results supported the promise of these techniques to provide clinically applicable personalized autologous cell therapy for PD. It was recognized by researchers that this methodology is likely to be more costly in dollars and manpower than techniques using off-the-shelf methods and allogenic cell lines. Nevertheless, the cost for autologous cell therapy may be expected to decrease steadily with technological refinement and automation. Given the significant advantages inherent in a cell source free of ethical concerns and with the potential to obviate the need for immunosuppression, with its attendant costs and dangers, it was proposed that this platform is suitable for the successful implementation of human personalized autologous cell therapy for PD.

References:

https://www.jci.org/articles/view/130767/pdf?elqTrackId=2fd7d0edee744f9cb6d70a686d7b273b

https://www.ncbi.nlm.nih.gov/pubmed/31714896

https://www.ncbi.nlm.nih.gov/pubmed/23666606

https://www.ncbi.nlm.nih.gov/pubmed/27343168

https://www.ncbi.nlm.nih.gov/pubmed/21495962

https://www.ncbi.nlm.nih.gov/pubmed/28083784

https://www.ncbi.nlm.nih.gov/pubmed/20336395

https://www.ncbi.nlm.nih.gov/pubmed/28585381

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Ability of gut microbiota to influence the bioavailability of levodopa in Parkinson’s disease – The presence of more bacteria producing the tyrosine decarboxylase (TDC) enzyme means less levodopa in the bloodstream

Posted in Biochemical pathways, Enzymes and isoenzymes, Metabolomics, Neurodegenerative Diseases, Neurological Diseases, Parkinson's disease dyskinesia levodopa, Pharmacodynamics and Pharmacokinetics, Pharmacologic toxicities, tyrosine decarboxylases on January 23, 2019| Leave a Comment »

Ability of gut microbiota to influence the bioavailability of levodopa in Parkinson’s disease – The presence of more bacteria producing the tyrosine decarboxylase (TDC) enzyme means less levodopa in the bloodstream

Reporter: Aviva Lev-Ari, PhD, RN

Decarboxylase enzymes can convert levodopa into dopamine. In contrast to levodopa, dopamine cannot cross the blood-brain barrier, so patients are also given a decarboxylase inhibitor. “But the levels of levodopa that will reach the brain vary strongly among Parkinson’s disease patients.

The bacterial tyrosine decarboxylase enzyme, which normally converts tyrosine into tyramine, but was found to also convert levodopa into dopamine. “We then determined that the source of this decarboxylase was Enterococcus bacteria.” The researchers also showed that the conversion of levodopa was not inhibited by a high concentration of the amino acid tyrosine, the main substrate of the bacterial tyrosine decarboxylase enzyme.

Carbidopa is over 10,000 times more potent in inhibiting the human decarboxylase,

the higher abundance of bacterial enzyme in the small intestines of rats reduced levels of levodopa in the bloodstream,

positive correlation between disease duration and levels of bacterial tyrosine decarboxylase.

Some Parkinson’s disease patients develop an overgrowth of small intestinal bacteria including Enterococci due to frequent uptake of proton pump inhibitors, which they use to treat gastrointestinal symptoms associated with the disease.

Altogether, these factors result in a vicious circle leading to an increased levodopa/decarboxylase inhibitor dosage requirement in a subset of patients.El Aidy concludes that

the presence of the bacterial tyrosine decarboxylase enzyme can explain why some patients need more frequent dosages of levodopa to treat their motor fluctuations. “This is considered to be a problem for Parkinson’s disease patients, because a higher dose will result in dyskinesia, one of the major side effects of levodopa treatment.“

SOURCE

https://www.rdmag.com/news/2019/01/how-gut-bacteria-affect-treatment-parkinsons-disease?type=cta&et_cid=6585419&et_rid=461755519&linkid=Mobius_Link

Article | OPEN | Published: 18 January 2019

Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease

Sebastiaan P. van Kessel,

Alexandra K. Frye,

Ahmed O. El-Gendy,

Maria Castejon,

Ali Keshavarzian,

Gertjan van Dijk &

Sahar El Aidy

Nature Communications volume 10, Article number: 310 (2019) | Download Citation

Abstract

Human gut microbiota senses its environment and responds by releasing metabolites, some of which are key regulators of human health and disease. In this study, we characterize gut-associated bacteria in their ability to decarboxylate levodopa to dopamine via tyrosine decarboxylases. Bacterial tyrosine decarboxylases efficiently convert levodopa to dopamine, even in the presence of tyrosine, a competitive substrate, or inhibitors of human decarboxylase. In situ levels of levodopa are compromised by high abundance of gut bacterial tyrosine decarboxylase in patients with Parkinson’s disease. Finally, the higher relative abundance of bacterial tyrosine decarboxylases at the site of levodopa absorption, proximal small intestine, had a significant impact on levels of levodopa in the plasma of rats. Our results highlight the role of microbial metabolism in drug availability, and specifically, that abundance of bacterial tyrosine decarboxylase in the proximal small intestine can explain the increased dosage regimen of levodopa treatment in Parkinson’s disease patients.

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Identifying Another Piece in the Parkinson’s Disease Pathology Puzzle

Posted in Biomarkers & Medical Diagnostics, Innovations in Neurophysiology & Neuropsychology, Nervous System Function, Neurodegenerative Diseases, Neurohumoral Transmission, Parkinson's disease dyskinesia levodopa, tagged Conditions and Diseases on February 2, 2016| Leave a Comment »

Identifying Another Piece in the Parkinson’s Disease Pathology Puzzle

Curator: Evelina Cohn, PhD

Press release on January 29,2016

International Consortium Identifies and Validates Cellular Role of Priority Parkinson’s Disease Drug Target, LRRK2 Kinase
An international public-private consortium MARTINSRIED, GERMANY; DUNDEE, UNITED KINGDOM; NEW YORK, has identified and validated a cellular role of a primary Parkinson’s disease drug target, LRRK2 kinase. This finding was published in the online open access eLife journal (http://dx.doi.org/10.7554/eLife.12813), illuminates a novel route for therapeutic development and intervention.
A team of investigators from the Max Plank Institute of Biochemistry, The University of Dundee, the Michael J. Fox Foundation for Parkinson’s Research (MJFF), GlaxoSmithKline and MSD contributed to systematic testing to determine that LRRK2 kinase regulates cellular trafficking by deactivating certain Rab proteins.
It is known that LRRK2 gene are the greatest known genetic contributor to Parkinson’s disease. Pharmaceutical Companies are developing LRRK2 kinase inhibitors to correct the effect of those mutations and treat Parkinson’s disease. The new breakthrough finding that links Mutant LRRK2 to inappropriate deactivation of Rab function opens the doors to more than 20 years of accumulated knowledge of the roles of Rab proteins to improve the understanding of LRRK2 dysfunction in the Parkinson’s disease process
“The pathological cascade leading to brain diseases such as Parkinson’s likely includes many cellular players,” said Matthias Mann, PhD, Director of the Department of Proteomics and Signal Transduction at the Max Planck Institute of Biochemistry. “The identification of this LRRK2 substrate gives us a central piece in this puzzle and another potential place to intervene in the disease process.”
Marco Baptista, PhD, MJFF Senior Associate Director of Research Programs, said, “Identification of Rab proteins as a LRRK2 substrate presents a tool to measure the impact of these inhibitors not only on LRRK2 levels but also on LRRK2 function. This critical component will advance development of these therapies to slow or stop Parkinson’s disease, patients’ greatest unmet need.”
This MJFF-led consortium used a combination of tools in the discovery, including a knock-in mouse model of the most common LRRK2 mutation strongly associated with Parkinson’s (created by GSK), a second knock-in LRRK2 mouse model generated by MJFF, LRRK2 kinase inhibitors from GSK and Merck, and state-of-the-art mass spectrometry. These tools — and the collaborative spirit that united the partners — were necessary to make this finding.
“This unique model of collaboration and our systematic approach across laboratories using advanced technologies and layers of confirmation provide a firm foundation from which to continue this line of investigation and further refine our understanding of the LRRK2 Rab relationship,” said Dario Alessi, PhD, Director of the Protein Phosphorylation and Ubiquitylation Unit at the University of Dundee.
With additional MJFF funding, this research group now is working to further characterize the Rab proteins modified by LRRK2 and to understand how an imbalance in cellular trafficking leads to the degeneration of neurons seen in Parkinson’s disease.
More information about LRRK2 in this Youtube Video:

About the Max Planck Institute of Biochemistry
The Max Planck Institute of Biochemistry (MPIB) belongs to the Max Planck Society, an independent, non-profit research organization dedicated to top level basic research. As one of the largest Institutes of the Max Planck Society, 850 employees from 45 nations work here in the field of life sciences. In currently eight departments and about 25 research groups, the scientists contribute to the newest findings in the areas of biochemistry, cell biology, structural biology, biophysics and molecular science. The MPIB in Munich-Martinsried is part of the local life-science-campus where two Max Planck Institutes, a Helmholtz Center, the Gene-Center, several bio-medical faculties of two Munich universities and several biotech-companies are located in close proximity. http://www.biochem.mpg.de

About the University of Dundee
The University of Dundee is the top ranked University in the UK for biological sciences, according to the 2014 Research Excellence Framework. Dundee is internationally recognised for the quality of its teaching and research and has a core mission to transform lives across society. More than 17,000 students are enrolled at Dundee, helping make the city Scotland’s most student-friendly. The University is the central hub for a multi-million pound biotechnology sector in the east of Scotland, which now accounts for 16% of the local economy. http://www.dundee.ac.uk

About The Michael J. Fox Foundation for Parkinson’s Research
As the world’s largest nonprofit funder of Parkinson’s research, The Michael J. Fox Foundation is dedicated to accelerating a cure for Parkinson’s disease and improved therapies for those living with the condition today. The Foundation pursues its goals through an aggressively funded, highly targeted research program coupled with active global engagement of scientists, Parkinson’s patients, business leaders, clinical trial participants, donors and volunteers. In addition to funding more than $525 million in research to date, the Foundation has fundamentally altered the trajectory of progress toward a cure. Operating at the hub of worldwide Parkinson’s research, the Foundation forges groundbreaking collaborations with industry leaders, academic scientists and government research funders; increases the flow of participants into Parkinson’s disease clinical trials with its online tool, Fox Trial Finder; promotes Parkinson’s awareness through high-profile advocacy, events and outreach; and coordinates the grassroots involvement of thousands of Team Fox members around the world.

Source: Michael J Fox Foundation
https://www.michaeljfox.org/foundation/publication-detail.html?id=598&category=7&et_cid=466921&et_rid