Clinical Application of Umbilical Cord Mesenchymal Stem Cells Preserves β-cells in Type 1 Diabetes

Type 1 diabetes (T1D) is a chronic autoimmune disease associated with complications that reduce the quality of life of affected individuals and their families. The therapeutic options for T1D are limited to insulin therapy and islet transplantation; these options are not focused on preserving β-cell function and endogenous insulin. Despite the promising outcomes observed in current clinical trials involving allogeneic Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) infusion for the management of T1D, the precise underlying mechanism of action remains to be elucidated. In this correspondence, we propose prospective mechanisms of action of WJ-MSCs that may be mediating their observed capability to preserve β-cell function and prevent T1D progression and provide recommendations for further investigations in clinical settings. We also highlight the efficacy of WJ-MSCs for therapeutic applications in comparison to other adult MSCs. Finally, we recommend the participation of muti-centers governed by international organizations to implement guidelines for the safe practice of cell therapy and patients’ welfare.

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Growing number of cord blood stem cell transplants worldwide

To the more than 50,000 transplants performed and reported worldwide through the use of umbilical cord blood must be added 34,133 performed in China alone (source: Parent’s Guide to Cord Blood Foundation), bringing the total number to 85,000. However, it must be specified that several bags are often used in China for the same transplant using both allogeneic and autologous umbilical cord stem cells and adult spinal cord.

Cord Blood Releases for Therapy

In total, the numbers in this table add up to 34,133 cord blood therapy releases. This is not equivalent to the number of cord blood “transplants”. In a traditional cord blood transplant, the patient receives myeloablative chemotherapy and then has their immune system regenerated with cord blood alone. In China, stem cell transplants for malignancies often combine different types of graft sources, such as cord blood together with bone marrow, or a combination of autologous and allogeneic cord blood. Many releases from Chinese banks are sibling transplants for non-malignant hemoglobinopathies. Plus, in China both autologous and allogeneic CBU are often released for clinical trials of regenerative medicine applications, such as osteoarthritis, stroke, and Alzheimer’s disease, among others.

During the year 2020, six cord blood banks in China cumulatively released 4907 CBU for therapy, based on statements found in the news category of their websites. By comparison, the 2020 annual report from WMDA claimed that 1670 cord blood transplants had been supplied by banks in the entire continent of Asia, which includes all Asian countries as well as the geographic region that many consider the Middle East. The Chinese medical community holds an annual national cord blood conference. At their 10th conference held 19-21 May 2023, it was announced: “It is understood that the application of umbilical cord blood has exceeded 85,000 cases worldwide, and the number of applications of umbilical cord blood in China has exceeded 30,000.” This statement was made by Professor Fang Jianpei, Chairman of the Cord Blood Application Committee of Guangdong Maternal and Child Health Care Association and Chief Physician of Pediatrics at Sun Yat-sen Memorial Hospital of Sun Yat-sen University.

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Eli Cured of Sickle Cell by Stem Cells from Brother

When Eli was born in 2010, his parents were delighted to finally have a child. They had been trying to conceive for years and had gone through multiple fertility treatments. But challenges soon confronted them when Eli was diagnosed with Sickle Cell Disease shortly after birth. Sickle Cell Disease causes red blood cells to be sickle-shaped and stiff, instead of round and flexible. The sickle cells do not carry oxygen well, causing the patient to feel chronic fatigue. Sometimes the sickle cells stick to each other and form clumps that block blood vessels; this is very painful and can be dangerous depending on where in the body it happens. There is a misconception that Sickle Cell Disease is only a problem in Africa, but it is also the most common inherited disease in the United States1. Sickle Cell Disease is caused by a genetic mutation; when both parents are carriers there is a 25% chance that their child will inherit two copies of the mutation and have the disease.

Currently the CDC estimates that 1 in 13 African Americans are carriers and 1 in 365 African American babies have the disease2. Sickle Cell impacts other ethnic groups as well, and altogether there are 100,000 Sickle Cell patients in the US2. Also, many people do not realize that Sickle Cell can impact the health-related quality of life for the patient’s entire family, especially the parents of a child with Sickle Cell3. It turned out that Eli had a more severe case of Sickle Cell Disease. He was frequently anemic from low red blood cell counts. He became sick easily and had pain crises when a blood vessel became blocked. Often his parents had to take him to the hospital emergency room and sometimes he was admitted to the hospital for long-term stays. His parents consulted with expert doctors at both Boston Children’s Hospital and Dana-Farber Cancer Institute to come up with a treatment plan that would give Eli a normal life. They knew that a stem cell transplant could cure Eli, and that a sibling would be the best donor. Finally, Eli’s parents welcomed his baby brother Gus and made sure to save his cord blood at birth. On top of having the cord blood, Gus matched Eli close enough genetically to be a bone marrow donor as well.

By now it was 2020, and Eli was nearly 10 years old. But due to the Coronavirus pandemic, there were multiple delays and Eli did not get his stem cell transplant until May of 2021. The family decided to take advantage of all their options and go ahead with a combined transplant of both cord blood and bone marrow from baby Gus. Within a year after the stem cell transplant, Eli had normal blood counts and there was no sign that he was ever diagnosed with Sickle Cell Disease. Eli has had zero pain crises and no hospital visits since his transplant.

“Since the procedure, he’s been flying with amazing colors. The doctors couldn’t be more happy that everything has gone so well. And we couldn’t be happier either!” – Eli’s Mom

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Xiaoan’s history: cured by his own cord blood 19 years later

In December 2021, Xiaoan, who had just turned 18, suddenly developed symptoms such as ulcers and blood spots. After a series of examinations, Xiaoan was diagnosed with aplastic anemia. Aplastic Anemia is an auto-immune condition where over-reactive T-cells in the blood have been triggered to attack the body’s own bone marrow. Xiaoan also had “PNH clones” in the blood (paroxysmal nocturnal hemoglobinuria), which is a hallmark of severe aplastic anemia. This severe attack can lead to complete bone marrow failure and death. While seeking treatment in many domestic hospitals, Xiaoan’s parents learned that: At present, umbilical cord blood hematopoietic stem cell transplantation is one of the effective methods for treating aplastic anemia, and the cure rate of cord blood transplants with the patient’s own autologous cord blood is high. This gave Xiaoan’s family, who had been shrouded in the haze of the disease, a new light of hope, because as early as 2003, when the child was born, Xiaoan’s parents had stored umbilical cord blood hematopoietic stem cells for the child in the Tianjin Cord Blood Bank.

After Xiaoan’s treatment plan for autologous umbilical cord blood transplantation was determined, the hospital and Xiaoan’s parents contacted Tianjin Cord Blood Bank as soon as possible. Upon receiving the news, the staff of the cord blood bank immediately devoted themselves to the preparations for the release of the cord blood. Re-examination by professional technicians showed that the umbilical cord blood hematopoietic stem cells that had been “sleeping” for 19 years were in good condition, and all indicators met the release standards. In December 2022, Xiaoan was transferred to Beijing Lu Daopei Hospital, a well-known specialized hospital for blood diseases in the country, and was officially prepared to receive a stem cell transplant. With the efforts of the staff, the precious cord blood was successfully delivered to the transplantation hospital. December 25, 2022 is of great significance to Xiaoan’s family. After the all-out treatment by Director Xiong Min of Beijing Lu Daopei Hospital, Xiaoan underwent reinfusion of umbilical cord blood hematopoietic stem cells on the same day, and this precious seed of life returned to the owner smoothly. About a month later, Xiaoan was released from intensive care, and all physical indicators recovered well. He was discharged from the hospital in February of 2023 and returned to normal life.

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Stem Cell Transplants May Safely Slow MS Progression, Suggests Study

A new study has suggested that stem cell transplants using a patient’s own stem cells to “reset” their immune system can safely slow the progression of relapsing–remitting multiple sclerosis (MS) and should be considered as the standard-of-care for severe disease. The research is published in The Journal of Neurology Neurosurgery & Psychiatry.

Identifying more treatments to benefit MS patients

MS is an inflammatory disease affecting almost 3 million people worldwide. It is thought to be an autoimmune disorder – in which the body’s immune system attacks its own tissues – and affects the central nervous system, attacking the protective myelin sheath that covers nerve fibers, leading them to deteriorate.

The disease has many symptoms, such as fatigue, difficulty walking and vision problems. But not everyone with MS is affected in the same way. The most common presentation is relapsing–remitting MS (RRMS), characterized by flare-ups of the disease followed by periods of recovery. However, RRMS over time can progress to secondary progressive MS (SPMS), which is more severe.

MS has no cure, but disease-modifying treatments (DMTs) can be used to help curb inflammation and delay relapses. However, a treatment called autologous hematopoietic stem cell transplantation (aHSCT) – commonly used to treat blood cancers – was first used to treat MS in the 1990s. aHSCT essentially “resets” a patient’s immune system, first wiping it out with chemotherapy and then rebuilding it using their own blood stem cells harvested before treatment. This is thought to eradicate the self-reactive immune system and rebuild one with better control over disease-causing cells.

“Another name for aHSCT is high-dose chemotherapy with stem cell support, which perhaps better describes the procedure,” said the study’s senior author Dr. Joachim Burman, an adjunct senior lecturer at Uppsala University, speaking to Technology Networks.

aHSCT was recognized in Sweden as a treatment for MS in 2016 but has yet to be implemented in clinical guidelines in many countries. In the current study, Burman and colleagues analyzed data from a Swedish MS registry, investigating the safety and efficacy of aHSCT when used in routine healthcare settings – which are more representative of the general population – rather than clinical trials.

A “significant advantage” over DMTs

The researchers analyzed data from 174 RRMS patients treated using aHSCT prior to 2020 – the average age was 31 years and 64% were women.

In the first three years after the procedure, 20 patients (11%) received DMTs – however, nearly three-quarters of patients showed no evidence of disease activity after 5 years and almost two-thirds showed no activity after 10 years.

Looking at the level of disability among patients, of the 149 patients who displayed disability prior to treatment, 54% improved, 37% remained stable and 9% worsened.

“Another important finding is that the treatment effect is durable. Ten years after the procedure only 35% had evidence of disease activity and only 11% needed to restart some other treatment. It is likely that some of the patients will never need treatment for MS again,” Burman added.

The safety of the therapy is also a considerable concern, as it is perceived as a high-risk procedure – five patients required treatment in intensive care, but none died as a result of treatment. Infections were common – 61 contracted a bacterial infection within 100 days of the procedure and 23 experienced a viral infection, with 3 patients developing shingles. The most common side effect observed in 68% of patients was febrile neutropenia – a high fever and low white blood cell count.

“Patients treated in routine healthcare come in all flavors and are more complicated than patients in clinical trials, which are generally more homogenous,” Burman explained. “Prior to this study, one concern had been that the number of adverse events would be higher in routine care. Reassuringly, there were very few serious adverse events and no treatment-related mortality, so I think it is fair to say that this procedure can be performed quite safely.”

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Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing

Hereditary anemia has various manifestations, such as sickle cell disease (SCD), Fanconi anemia, glucose-6-phosphate dehydrogenase deficiency (G6PDD), and thalassemia. The available management strategies for these disorders are still unsatisfactory and do not eliminate the main causes. As genetic aberrations are the main causes of all forms of hereditary anemia, the optimal approach involves repairing the defective gene, possibly through the transplantation of normal hematopoietic stem cells (HSCs) from a normal matching donor or through gene therapy approaches (either in vivo or ex vivo) to correct the patient’s HSCs. To clearly illustrate the importance of cell and gene therapy in hereditary anemia, this paper provides a review of the genetic aberration, epidemiology, clinical features, current management, and cell and gene therapy endeavors related to SCD, thalassemia, Fanconi anemia, and G6PDD. Moreover, we expound the future research direction of HSC derivation from induced pluripotent stem cells (iPSCs), strategies to edit HSCs, gene therapy risk mitigation, and their clinical perspectives. In conclusion, gene-corrected hematopoietic stem cell transplantation has promising outcomes for SCD, Fanconi anemia, and thalassemia, and it may overcome the limitation of the source of allogenic bone marrow transplantation.

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Salvador’s story: using stem cells to treat autism

Salvador, a five-year-old Portuguese boy who was diagnosed with autism spectrum disorder, recently underwent treatment using stem cells from his own umbilical cord blood with the aim of improving his condition. The procedure was carried out in August 2022, at Duke University Hospital, in the United States of America (USA), within the scope of the Expanded Access Protocol (EAP) led by Prof. Joanne Kurtzberg, internationally renowned pioneer in the use of umbilical cord blood. It is estimated that, in Portugal, 1 in 1000 children of school age lives with autism spectrum disorder1. (Editor’s Note: At the end of 2022 the Expanded Access program stopped enrolling children with autism.)

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Stem cell therapy for neurological disorders

Neurological disease encompasses a diverse group of disorders of the central and peripheral nervous systems, which collectively are the leading cause of disease burden globally. The scope of treatment options for neurological disease is limited, and drug approval rates for improved treatments remain poor when compared with other therapeutic areas.

Stem cell therapy provides hope for many patients, but should be tempered with the realisation that the scientific and medical communities are still to fully unravel the complexities of stem cell biology, and to provide satisfactory data that support the rational, evidence-based application of these cells from a therapeutic perspective. We provide an overview of the application of stem cells in neurological disease, starting with basic principles, and extending these to describe the clinical trial landscape and progress made over the last decade. Many forms of stem cell therapy exist, including the use of neural, haematopoietic and mesenchymal stem cells.

Cell therapies derived from differentiated embryonic stem cells and induced pluripotent stem cells are also starting to feature prominently. Over 200 clinical studies applying various stem cell approaches to treat neurological disease have been registered to date (Clinicaltrials.gov), the majority of which are for multiple sclerosis, stroke and spinal cord injuries. In total, we identified 17 neurological indications in clinical stage development. Few studies have progressed into large, pivotal investigations with randomised clinical trial designs. Results from such studies will be essential for approval and application as mainstream treatments in the future.

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