Cord blood is tested to treat adult stroke patients in allogeneic use

Dr. Kouzi

Research on Allogeneic Cord Blood for Stroke

 September 2019 by Frances Verter, PhD  

The possibility of using cord blood stem cells to treat adult stroke patients is an area of research that holds enormous potential. Stroke affects one in every six people worldwide, and is the world’s second most common cause of death1-3. The definition of a stroke is the sudden death of brain cells due to lack of oxygen, which happens when blood flow is disrupted in a region of the brain. In about 87% of strokes, the blood flow is disrupted by a blockage, and this is called an ischemic stroke, but stroke can also be caused by bleeding in the brain, and this is called hemorrhagic stroke. Stem cell therapies emerged as a paradigm for stroke about a decade ago. Contrary to long-held beliefs, we now know that the brain can recover to some extent after injury, and stem cell therapy offers a potential for multimodal repair mechanisms. “Immediately after stroke, several events, including edema, deafferentation, and inflammation, occur around the infarct, and some early functional recovery can be attributed to the resolution of edema and inflammation. However, this is usually limited, and other processes, including immunomodulation, angiogenesis, endogenous neurogenesis, and altered gene expression, may be involved in the longer-term recovery of function”. According to the resource CellTrials.org, over the period from January 2018 through July 2019, 77 clinical trials have been registered worldwide to treat stroke with cell therapy, with 68% of the trials listed on ClinicalTrials.gov and 32% listed in 9 other trial registries. The most common source for cells used in stroke cell therapy is bone marrow, at 43% of these 77 trials.  Some stroke therapies developed from bone marrow have a strong pipeline of development and are close to approval in their respective countries. The most common cell type used in stroke cell therapy is mesenchymal stem/stromal cells (MSC). The other common group is mononuclear cells (MNC) from a blood-based source comprise 35% of these trials. Stroke therapy with cord blood MNC make up 17% of the total trials. Cord blood is emerging as a serious competitor in cell therapy for stroke. The main reason is because MNC from cord blood trigger less graft-versus–host reaction than adult sources of MNC. Since 2011, every single stroke trial that sourced MNC from bone marrow or peripheral blood relied on autologous cells, where the patient had to undergo a harvest of his or her own cells. A recent trend is for stroke therapy with cord blood cells to push against the envelope of HLA matching. In March 2015, Duke University embarked on a novel phase 1 trial NCT02397018 to test the safety of treating stroke patients with an infusion of cord blood that was completely unmatched except for standard ABO blood typing. Ten patients between ages 45 and 79 that had suffered an ischemic stroke received intravenous infusions within 3 to 10 days after the stroke, and no adverse events related to the therapy were noted. The results from this trial were published in May 20 189. Currently, Duke and collaborators are running a larger phase 2 double-blind trial NCT03004976 at 6 medical centers with the target enrollment of treating 100 patients by March 2020. There are other notable examples of cord blood trials for stroke. The hybrid cord blood bank StemCyte has supported trials NCT01673932 in Hong Kong and NCT02433509 in Taiwan that treated patients with allogeneic cord blood having a minimum 4 out of 6 HLA match. In South Korea, the research center at Bundang CHA Hospital ran trial NCT01884155 in 2013, and in July 2019 they registered a phase 2 trial NCT04013646 that will treat stroke patients with allogeneic cord blood having a minimum 3 out of 6 HLA match. Also in July 2019, the for-profit clinic Blue Horizon International posted ISRCTN10678357 on the WHO trial registry, stating that they had a registry of 97 stroke patients treated in China with cord blood that only had ABO blood type match. If clinical trials of allogeneic cord blood therapy for stroke continue to meet their endpoints, this could be an exciting new application for donated cord blood.  In the United States, about 795,000 people suffer a stroke each year, and 140,000 are fatal1-3. If only 1% of these patients received cell therapy, that would be comparable to the total number of allogeneic stem cell transplants per year in the United States. Ultimately, a successful cord blood therapy will find itself in competition against cell therapy products for stroke that are already near approval.  The possibility to utilize cord blood cells as an “off-the-shelf” product (actually out of the cryogenic freezer) with no HLA matching would make cord blood more competitive against other cell therapies that are based on MSC and operate as universal donor products. Regardless of how the research on allogeneic cord blood for stroke evolves, it promises to be an exciting topic to follow. https://parentsguidecordblood.org/en/news/research-allogeneic-cord-blood-stroke

Heart regeneration by stem cells

Dr. Kouzi

HEALTH NEWS

AUG. 6, 2019 / 12:05 PM

Stem cell treatment may reverse heart attack damage

Byheart

Tauren Dyson

 (0) 

Researchers have developed a stem cell method to grow new tissue that can repair the harm caused by a heart attack. File Photo by Photographee.eu/Shutterstock

Aug. 6 (UPI) -- Surviving a heart attack is good, but the resulting damage can lead to potentially deadly organ damage. While the heart does not regenerate tissue on its own, researchers may have a way of repairing damage with new tissue.

Researchers have developed a method of growing tissue outside the body using stem cell that can repair the harm caused by a heart attack, according to research published Monday in the journal Circulation. Following a heart attack, the organ can't regenerate tissue killed off by the event. This dead tissue can ultimately lead to lethal heart enlargement."To our knowledge," the researchers said in a press release, "this is the first study to show that DNA damage-free induced pluripotent stem cells can be selected by p53 activation in induced pluripotent stem cell cultures and that DNA damage-free cardiomyocytes have enhanced cardiac engraftment potential."The researchers say they can grow damage-free pluripotent stem cells outside of the body, then add those cells near the point of cell death. In a clinical setting, they say this approach has improved the ability of the heart's left ventricle to pump blood. For the study, the researchers used MDM2 inhibitor Nutlin-3a to activate transcription factor p53 within the pluripotent stem cells. This treatment killed off cells with DNA damage while skipping over the healthy ones, which were cultured and then differentiated into cardiomyocytes. The researchers injected 900,000 cardiomyocytes into the sides of the left ventricles of mice who had heart attacks. After four weeks, the engraftment worked on about 14 percent of the hearts compared to only 7 percent in engraftments made with control derived cardiomyocytes. "As this is a small molecule-based approach to select DNA damage-free cells," said Ramaswamy Kannappan, a researcher at the University of Alabama at Birmingham and study senior author. "It can be applied to any type of stem cells, though selection conditions would need to be optimized and evaluated. Other stem cell approaches for diseases such as neurodegenerative diseases, brain and spinal cord injuries, and diabetes might benefit by adopting our method."

Mesenchymal stem cells proliferation in the lab changes the initial properties of the cells

Dr. Kouzi

Mesenchymal stem cells collected from the cord tissue loose their stemness after prolonged  culture, according to the below publication. So we must collect the mesenchymal stem cells from the whole length  of the cord and do not cryopreserve the cord in pieces,  without previous extraction of the cells.  Proliferation of the cells  to reach the appropriate number of cells, according to the weight of the patient, does not be safe and effective for therapies. 

Identification of senescent cells in multipotent mesenchymal stromal cell cultures: Current methods and future directions  

WEICHAO Zhai,DERRICK YONG,JEHAN JOMAA EL-JAWHARI, RICHARD CUTHBERT, DENNIS MCGONAGLE,MAY WIN NAING. ELENA JONESDOI:  https://doi.org/10.1016/j.jcyt.2019.05.001

Regardless of their tissue of origin, multipotent mesenchymal stromal cells (MSCs) are commonly expanded in vitro for several population doublings to achieve a sufficient number of cells for therapy. Prolonged MSC expansion has been shown to result in phenotypical, morphological and gene expression changes in MSCs, which ultimately lead to the state of senescence. The presence of senescent cells in therapeutic MSC batches is undesirable because it reduces their viability, differentiation potential and trophic capabilities. Additionally, senescent cells acquire senescence-activated secretory phenotype, which may not only induce apoptosis in the neighboring host cells following MSC transplantation, but also trigger local inflammatory reactions. This review outlines the current and promising new methodologies for the identification of senescent cells in MSC cultures, with a particular emphasis on non-destructive and label-free methodologies. Technologies allowing identification of individual senescent cells, based on new surface markers, offer potential advantage for targeted senescent cell removal using new-generation senolytic agents, and subsequent production of therapeutic MSC batches fully devoid of senescent cells. Methods or a combination of methods that are non-destructive and label-free, for example, involving cell size and spectroscopic measurements, could be the best way forward because they do not modify the cells of interest, thus maximizing the final output of therapeutic-grade MSC cultures. The further incorporation of machine learning methods has also recently shown promise in facilitating, automating and enhancing the analysis of these measured data.

Key Words:

label-free, multipotent mesenchymal stromal cells, non-destructive, replicative aging, senescence

 

Identification of senescent cells in multipotent mesenchymal stromal cell cultures: Current methods and future directions

WEICHAO Zhai,DERRICK YONG,JEHAN JOMAA EL-JAWHARI, RICHARD CUTHBERT, 

DENNIS MCGONAGLE,MAY WIN NAING. ELENA JONESDOI: https://doi.org/10.1016/j.jcyt.2019.05.001

Abstract

Regardless of their tissue of origin, multipotent mesenchymal stromal cells (MSCs) are commonly expanded in vitro for several population doublings to achieve a sufficient number of cells for therapy. Prolonged MSC expansion has been shown to result in phenotypical, morphological and gene expression changes in MSCs, which ultimately lead to the state of senescence. The presence of senescent cells in therapeutic MSC batches is undesirable because it reduces their viability, differentiation potential and trophic capabilities. Additionally, senescent cells acquire senescence-activated secretory phenotype, which may not only induce apoptosis in the neighboring host cells following MSC transplantation, but also trigger local inflammatory reactions. This review outlines the current and promising new methodologies for the identification of senescent cells in MSC cultures, with a particular emphasis on non-destructive and label-free methodologies. Technologies allowing identification of individual senescent cells, based on new surface markers, offer potential advantage for targeted senescent cell removal using new-generation senolytic agents, and subsequent production of therapeutic MSC batches fully devoid of senescent cells. Methods or a combination of methods that are non-destructive and label-free, for example, involving cell size and spectroscopic measurements, could be the best way forward because they do not modify the cells of interest, thus maximizing the final output of therapeutic-grade MSC cultures. The further incorporation of machine learning methods has also recently shown promise in facilitating, automating and enhancing the analysis of these measured data.

Key Words:

label-free, multipotent mesenchymal stromal cells, non-destructive, replicative aging, senescence

 

NIPT for sickle cell anemia detection

Dr. Kouzi

Non-Invasive Prenatal Screening Test for Sickle Cell Appears Possible, Study Reports

 JULY 11, 2019

BY PATRICIA INACIO, PHD

 A non-invasive prenatal test to diagnose a risk of sickle cell disease in a baby is possible and may be available in clinics in a near future, if further testing confirms its efficacy, researchers in the U.K. report.

Julia van Campen presented the first results of the non-invasive test in the presentation “Non-invasive prenatal diagnosis of sickle cell disease by next generation sequencing of cell-free DNA” at the recent 2019 European Human Genetics Conference in Gothenburg, Sweden.

Sickle cell disease (SCD) is an autosomal recessive disease, meaning that a child has to inherit two mutated copies of the hemoglobin gene to develop it — one from each parent. If both parents have sickle cell trait, there is a 25 percent chance the child will have SCD.

Without early diagnosis and treatment, the life expectancy of children with SCD is only a few years.

Currently, sickle cell can only be diagnosed during pregnancy using an invasive test like amniocentesis that carries a risk, although small, of miscarriage, leading some parents to decline it. An earlier survey showed that if patients had the option of a non-invasive test, more would choose screening for the possibility of SCD.

“However, many couples are unaware that they are at risk until pregnancy occurs, even though carrier testing and follow-up genetic counseling is available through the UK National Health Service for those who are concerned that they may carry SCD,” Julia van Campen, a researcher at Guy’s and St Thomas, said in a press release. “It is important to raise awareness of SCD, which currently is limited.”

Researchers at Guy’s and St Thomas’ NHS Foundation Trust and Viapath Analytics, London, developed a non-invasive prenatal screening test that analyses the fetal DNA that circulates freely in the mother’s blood to determine the risk of her baby having SCD.

The test was developed in collaboration with the healthcare company Nonacus Ltd. in Birmingham.

“Although cell-free fetal DNA testing is already available for some disorders, technical difficulties have hampered the development of such a test for SCD, despite it being one of the most commonly requested prenatal tests in the UK, ” van Campen said.

Researchers analyzed blood samples from 24 pregnant carrying a mutated copy of the hemoglobin gene, and as such were sickle cell carriers. The scientists optimized their method to enrich the samples for the fetal DNA, and used a molecular barcode to identify the mutant and normal gene.

They successfully diagnosed SCD in 21 out of the 24 pregnancies using blood samples retrieved as early as eight weeks’ gestation. In the other three samples, results were inconclusive.

The test is undergoing further research to confirm its diagnostics potential before it might be brought into clinical practice. For regular use, the test needs to be not only reliable, but also fast and affordable.

“I am excited that this work has given better results than I had expected, and am hopeful that people will be able to build on this work to make this test available in the near future,” said van Campen.

“The development of non-invasive genetic tests that can be safely used during pregnancy is important to identify fetuses with severe disorders,” said professor Joris Veltman, director of the Institute of Genetic Medicine at Newcastle University and chair of the ESHG conference.

“These scientists have developed a novel state-of-the art genomics approach to do this for sickle cell disease in couples at risk. Their first results … indicate that their test is very promising,” Veltman added.

This approach might also aid in diagnosing similar disorders in a fetus. “We demonstrate that NIPD [non-invasive prenatal test] for sickle cell disease is approaching clinical utility. Other autosomal recessive disorders may benefit from a similar approach,” the study concluded.