Ipscs As Disease Model For Parkinsons Disease
The contribution of pharmacogenomics has been heightened through the use of patient-specific iPSC lines and genetic engineering technology to manipulate them. Ever since Yamanakas discovery in 2007 that a handful of transcription factors can reprogram cellular differentiation, iPSCs have been utilized extensively in the study of neurodegenerative disease to direct patient-specific cell fate . While still limited in scope, iPSCs are currently the most robust and phenotypically similar model for PD . Mutations of consequence can now be captured in iPSC lines and directed by small molecules to a DAn fate in PD modelsall within a dish. Displayed openly, the real-time cellular effects of mutation can be physically observed and studied in tandem with control lines to limit genetic background effects of the affected individual similarly, effects of oxidative stress common to PD can also be quantified with broad clinical applications for drug screening without human side-effects. Not surprisingly, it remains difficult to physically confirm the mechanisms of neurodegeneration and neuroprotection implicated by iPSC research as patients neurons are hidden deep within the brain. These effects similarly cannot be perfectly translated into the cellular environment of PD due to some epigenetic effects of aging eliminated in reprogramming protocols.
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Assessment Of The Efficacy Of Cell Transplants With Immunostaining Characterization
In the case of mDA progenitor neuron specifications, positive gene expression of common transcription factors FOXA2, LMX1A, and OTX2 and negative markers such as Afp, Gata4, and Brachyury have been quantitatively analyzed . More importantly, the upregulation and downregulation of these markers at a given stage in vitro governs the efficiency of cell fate determination. Unfortunately, these markers have been shown to coexpress in the diencephalic progenitor cells of the subthalamic nucleus . Furthermore, the expression of the positive genetic marker for DA neurons, tyrosine hydroxylase , a rate-limiting enzyme in dopamine synthesis , and the levels of GIRK2 have also been observed in many cell types in vitro . Moreover, common positive markers used to isolate high-quality DA progenitor cells include EN1 and SPRY1 Nurr1 FOXA2, LMX1B, and MSX1 , and the bicoid-related homeodomain factor Ptx3/Pitx3 . It is noteworthy that some discrepancies have been found with the requirement for the presence of floor plate-specific cell surface marker CORIN expression . A more recent study has identified a cell surface marker integrin-associated protein as a positive marker for FOXA2-positive DA progenitor cells .
Why Are Clinical Studies Important
All types of research are critical for improving care. Basic science research tests done in a laboratory can help us learn more about the human body and the causes of PD. Basic research can also point scientists in promising directions as they develop and refine treatments.
Clinical studies are essential because through them, discoveries made in the laboratory can help people with PD today and in the future. The Parkinsons Foundation is at the forefront of PD research and clinical studies are central to our vision. The Foundations Parkinsons Outcomes Project was the first study of its kind and continues to be the largest clinical study. Every year, insights from the study help optimize PD care, leading to better quality of life for people with PD today and better health for people with PD tomorrow.
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What Are The Stages Of Parkinsons Disease
- Parkinson Stage 1: Only mild symptoms occur in facial expressions or slight tremor. However, the daily life is only minimally affected and only one sided.
- Parkinson Stage 2: At this stage symptoms are getting worse and affect both sides. The tremor and waling problems are getting worse. Often this is the stage where L-Dopamine is employed.
- Parkinson Stage 3: Loss of balance and slowed movements characterize this stage. Living independently is still possible but symptoms significantly impair daily activities.
- Parkinson Stage 4: The Symptoms are severely limiting every activity, especially walking. Movements are still possible but may require aid. Usually living alone is not possible at this stage any more.
- Parkinson Stage 5: The final and most debilitating stage, where stiffness in legs makes movement impossible. The person requires full time nursing and is bound to the wheelchair. Usually many non-motoric symptoms set like delusions, hallucinations and depressions.
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Principal Investigators Of The Stem
- Malin Parmar, Project lead – Professor, Lund University
- Agnete Kirkeby, Pre-clinical development lead – Associate Professor, Lund University
- Roger Barker, Clinical Lead & Principal Investigator Professor, University of Cambridge and Honorary Consultant Neurologist, Cambridge University Hospitals NHS Foundation Trust
- Gesine Paul-Visse, Principal Investigator Adjunct Professor, Lund University and Senior Consultant Neurologist, Skåne University Hospital in Lund
- Håkan Widner, Sponsor representative/co-investigator Docent, Lund University and Senior Consultant Neurologist, Skåne University Hospital in Lund
- Hjálmar Bjartmarz, Co-Investigator Senior Consultant Neurosurgeon, Skåne University Hospital in Lund
- Paola Piccini, Brain imaging expert Professor and Honorary Consultant, Imperial College London
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Pure Substantia Nigra Mda Neuron
Recently, single cell gene profiling has been used to define subtype compositions during mouse and human midbrain development . Such technology extended the previous molecular definition of mDA neurons and enabled to further divide SN and VTA region into seven distinct molecular clusters . However, to what extent these molecular findings can be translated into hPSC-derived mDA neuron development remains unexplored. This is illustrated when profiling of hPSC-derived mDA neurons in La Manno et al., which seem to recapitulate key stages of in vivo ventral midbrain development. However, those cell preparations expressed many poorly defined radial glial and neuroblast markers and differed from the in vivo phenotypes in gene expression . Additionally, ALDH1A1 was not expressed in any of those PSC-derived mDA cells. This result may be due to the in vitro culture environment that does not fully support mDA neuron development or lack of proper induction of certain subtype-specific genes. In either case, those results indicate that there is considerable room for further improvements in mDA neuron derivation and maturation strategies.
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Bluerock Therapeutics Announces Completion Of Enrollment Of Phase 1 Trial In Patients With Parkinsons Disease
Initiation of global non-interventional study for patients with Parkinsons planned for the second half of 2022 as next step
CAMBRIDGE, Mass., May 31, 2022 BlueRock Therapeutics LP, a clinical stage biopharmaceutical company and wholly-owned subsidiary of BayerAG, announcedthe completion of enrollment of its Phase 1 , open-label trial of pluripotent stem cell-derived dopaminergic neurons in patients with Parkinsons disease . The purpose of thePh1 clinical trial is to evaluate the safety, tolerability, andpreliminaryefficacyof BRT-DA01 in patients with Parkinsons disease.
Patients with Parkinsons disease are faced with life changing challenges and uncertainties that are not addressed by current treatments, said Ahmed Enayetallah, M.D., Ph.D., Senior Vice President, Clinical Development, BlueRock Therapeutics. We are excited that our Phase 1 clinical trial has completed enrollment and believe it is a critical next step toward the development of a novel cell therapy that has the potential to transform the treatment landscape for this devastating disease.
About the BRT-DA01 Phase 1 Trial
More information about the Phase 1 trial is available at clinicaltrials.gov
As a next step, BlueRock Therapeutics plans to initiate a global non-interventional study in the second half of 2022.
More information about the non-interventional study is available at clinicaltrials.gov
About Parkinsons Disease
About BlueRock Therapeutics
About Bayer
Forward-Looking Statements
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Well Be Watching Progress Closely
Claire Bale, Head of Research Communications at Parkinsons UK, said:
Were encouraged to hear that approval has been given to do the first ever trial for stem cell treatment in people with Parkinsons.
Stem cells carry real hope as a future treatment for the 127,000 people living with the condition in the UK. Parkinsons UK has invested more than £3 million in cutting edge stem cell research to help develop new and better treatments for Parkinsons, faster.
With all clinical trials, ensuring that the treatment is safe and effective is paramount and along with the international research community we will be watching the progress of the trial very closely.
If successful this could be the beginning to further, much larger studies with stem cells taking us closer to a new potential treatment for Parkinsons.
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Parkinsons Patient Enrolls In Stem Cell Therapy Trial At Uthealth Houston In An Effort To Slow Disease Progression
In the thick of the 2008 financial crisis, Marty Young Jr. then a partner and CFO of a private equity firm and board chair for insurance and oil and gas companies simply thought he was stressed when his fingers twitched while using a computer mouse.
But over the years, Youngs anxiety over the hand twitching led him to stop flying his private airplane, a longtime hobby of his.
People had been telling me they thought I had Parkinsons disease, but when I did the research, I learned there was no cure, and I didnt think there was any reason to see a specialist until my symptoms worsened, said Young, now 69 years old and retired.
However, in 2019, he saw a movement disorder specialist, who diagnosed Young with Parkinsons disease and later referred him to Mya C. Schiess, MD, professor in the Department of Neurology and director and founder of the Movement Disorders and Neurodegenerative Diseases subspecialty clinic and fellowship program with McGovern Medical School at UTHealth Houston.
Schiess had recently launched a randomized, double-blinded, placebo-controlled Phase II clinical trial investigating whether mesenchymal adult stem cells could reduce or even halt the progression of Parkinsons disease. Wanting to help researchers find a cure for the neurodegenerative disorder, which is diagnosed in approximately 60,000 people in the U.S. annually, Young decided to enroll in the trial the first of its kind in the nation.
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Extranigral Pathology In Pd
Over time, most individuals with PD develop pathology at various CNS and non-CNS sites, leading to levodopa-unresponsive motor symptoms as well as non-motor symptoms. Frequent falls and freezing of gait are motor symptoms that often do not respond to levodopa, and thus are not likely to be ameliorated by DA neuron replacement. Non-motor symptoms such as dementia, psychosis and some sleep disturbances are also not likely to be substantially ameliorated by replacing DA neurons, as these phenomena are thought to relate, at least in part, to damage to neuronal networks besides those traditionally studied in PD, such as the cholinergic and noradrenergic systems,.
Recent advances in our understanding of the networks affected in PD have highlighted their complexity, but compared with the DAergic pathways, the networks involved in non-levodopa-responsive systems are poorly described. It is therefore likely that an optimal effect requires greater characterization of the precise networks affected in each patient and a tailored combination of cells delivered to the relevant locations.
First Transplant Trial Of Lab Made Dopamine
Following successes in monkeys, researchers in Japan have announced a clinical trial to transplant dopamine-producing brain cells made in the lab from iPS cells will start in 2018.
We will eagerly be awaiting more information and the outcome of this and the other trials mentioned in this post and hope that it will contribute to more research in this area, and future opportunities for those in the UK to take part.
Potential of this type of therapy: Dopamine-producing brain cells are the type of cell lost in Parkinsons and transplanting them into the brain may be the best hope for repairing the damage and reversing the condition, making this study one of the most exciting ones to follow going forwards. Potential challenges to this approach are all about safety these techniques are still very new, so we dont know much about the long-term safety of lab-made cells.
Stem cells definitely hold huge potential for developing therapies for Parkinsons, but we still have a number of questions to answer and challenges to address before they will be a therapeutic option for people with the condition. We still dont know enough about if these transplant therapies will improve both motor and non-motor symptoms of Parkinsons, such as problems with thinking, memory, pain, and anxiety. We also need to know:
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Assessment Of The Efficacy Of Cell Transplants With Imaging
Last, concurrent with the high demand for the optimization of cell graft visualization in PD, growing emphasis has been placed on enhancing the sensitivity and precision of the spatiotemporal resolution of functional neuroimaging. En route to successful cell transplantation as a therapeutic regenerative method for Parkinsons disease, neuroimaging techniques have to be employed for better patient care. Some key features required to elucidate the therapeutic efficacy of transplanted cells for clinical diagnostics are innervation, survival, differentiation, and functional biochemistry composition. Furthermore, it is crucial that these imaging techniques are time efficient, safe, non-invasive, and allow repeated measures in an individual to determine longitudinal post-operative progression in patients with cell transplantation . In this section, we summarize the pros and cons of current imaging modalities used in tracking cell grafts in PD and their respective biomarkers .
Table 2. Imaging modalities used in cell transplantation for PD.
Paving The Way To New Horizons
Two years after the study began, time seems to be on Kim and Lopezs side. The cells are still alive, and the study has shown favorable outcomes. However, the one-person model was not a traditional blind study. Lopez knew he was receiving the therapy. Did his mindset create a placebo effect? Why only one patient?
Since our approach is personalized therapy, even the big scale trial should start from an individual patient, Kim said. So, we thought that we better start with a single patient and gain all experiences and information to move on.
The one-person study introducing personalized therapy seems to have paved the way for additional research. However, Kim noted that a double-blind study is needed to conclude its safety and efficacy.
I am grateful to Lopez who funded the trial and accepted the risks. He and Kim, together with all patients and doctors that participate in Parkinsons research, have the people with Parkinsons as their catalyst to keep pressing forward. Sometimes its hard to see the forest through the trees, but the goal is the same: a therapy for us all. Ultimately, that is what is important even if it is one person at a time.
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Parkinsons Disease And Its Treatment
Parkinsons disease is the second most common neurodegenerative disease worldwide, yet remains without a cure. Typical motor symptoms of Parkinsons disease are slowness of movement, tremor and stiffness and later also gait difficulties. It is not well known how the disease arises or develops, but the core pathology common to all patients is the loss of dopamine neurons in the midbrain.
The treatment of Parkinsons disease has for over 50 years relied on symptomatic pharmacological therapies that are highly effective, especially in the early years of the diagnosis. However, such therapies are ultimately limited by the development of side effects that relate to the systemic delivery and non-physiological dopamine levels. Targeted regenerative cell therapies designed to restore specifically the lost dopaminergic input to the motor system of the brain would therefore represent a major advance in treating Parkinsons disease.
Further References For Msc Bmc Stemcell Secretome And Evs
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Phase 1 Trial Of Stem Cells In Treating Bradykinesia To Open In Us
The participants will be followed for a year by IMAC doctors and physical therapists. The trial enrolled a total 15 patients five in each dosing group ages 55 or older, who began experiencing bradykinesia for at least three months before enrollment. Participants were allowed to continue treatment with levodopa or other standard treatment.
The trial is underway at three of IMACs U.S. clinical centers: Chesterfield, Missouri Paducah, Kentucky and Brentwood, Tennessee.
Bradykinesia is one of the early signs of Parkinsons disease. It is characterized by slow movements, delayed reaction times, and decreased amplitude of movements that is, smaller movements.
Although the mechanisms underlying bradykinesia are not completely understood, it is generally accepted that inflammation is one of its key drivers.
Stem cells are characterized by their ability to divide indefinitely while giving rise to various cell types, prompting its interest as a regenerative medicine for disorders like Parkinsons.
MSCs are a subtype of stem cells that are found across different tissues, but at high rates in the umbilical cord. Other tissues include the bone marrow and fat. They have anti-inflammatory properties, supporting their potential to treat bradykinesia by easing inflammation.
Ricardo Knight, MD, the medical director of the Mike Ditka IMAC Regeneration Center in Arlington Heights, Illinois, is the trials lead investigator.
Mesenchymal Stem Cell Therapies For Neurodegenerative Diseases
While there have been significant advances in the symptomatic management of these diseases that improve quality of life and at times survival, the available medications likely only slow the progression of neuronal death by a few months. The idea of using cell therapy to treat neurodegenerative diseases has been around for decades, most notably in Parkinson’s Disease where a variety of cell transplant investigations have been performed with success.
According to a recent study conducted by Nathan P. Staff et al,
“The precise mechanism by which MSCs may exert beneficial effects in neurological disease is still being elucidated, but it appears that multiple different mechanisms may contribute. First, MSCs have been shown to secrete neurotrophic growth factors, including glial cell-derived neurotrophic factor , vascular endothelial growth factor, and brain-derived neurotrophic factor ,which can be further enhanced under specific culture conditions.Neurotrophic growth factors have been shown to improve neuronal survival in a number of preclinical models of neuron injury, including ALS, PD, and MSA transgenic animalsand nerve injury models. â Second, MSCs strongly modulate the immune system and can aid wound healing, and this mechanism has been exploited in disorders such as graft versus host disease and Crohnâs disease. From a neurodegenerative perspective, it has become increasingly recognized that neuroinflammation plays a significant pathomechanistic role.”
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