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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Fetal Mesenchymal Stem Cells in Cancer Therapy

There is compelling evidence that mesenchymal stem cells (MSCs) can be utilized as delivery vehicles for cancer therapeutics. During the last decade, bone marrow MSCs have been used as delivery vehicles for the local production of therapeutic proteins in multiple tumor types, taking advantage of their innate tropism to the tumor site and their low immunogenicity.

More recently, MSCs have been isolated from fetal tissues during gestation or after birth. Fetal MSCs derived from amniotic fluid, amniotic membrane, umbilical cord matrix (Wharton’s jelly) and umbilical cord blood are more advantageous than adult MSCs, as they can be isolated noninvasively in large numbers without the ethical reservations associated with embryo research.

Several studies have documented that fetal MSCs harbor a therapeutic potential in cancer treatment, as they can home to the tumor site and reduce tumor burden. This natural tumor tropism together with their low immunogenicity renders fetal MSCs as powerful therapeutic tools in gene therapy-based cancer therapeutic schemes. This review summarizes various approaches where the tumor-homing capacity of fetal MSCs has been employed for the localized delivery of anti-tumor therapeutic agents.

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Clinical Application of Adult Stem Cells for Therapy for Cardiac Disease

Cardiovascular disease is a major cause of death worldwide. Different medical and surgical therapeutic options are well established, but a significant number of patients are not amenable to standard therapeutic options. Cell-based therapies after clinical application have shown different results in recent years. Here, we are giving a comprehensive overview on major available clinical data regarding cell therapy.

Cell-based therapies and tissue engineering provide new promising platforms to develop upcoming therapeutic options. Initial clinical trials were able to generate promising results. A variety of different stem cell types have been used for the clinical application. Different adult cardiac stem cells and progenitor cells, including mesenchymal, CD34+ and CD133+ autologous human bone marrow–derived stem cells (BMCs), human myoblasts, and peripheral blood–derived stem and progenitor cells (PBSCs) have been used for the therapy for end-stage heart failure. Future experiments will show the importance of novel cell populations and clarify the mechanism causing cell therapy–mediated observed effects.

Several clinical trials have reported on sole therapy, as well as combined application of autologous adult stem cells with conventional revascularization. The reported promising findings encourage further research in the field of the translational research.

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The Personalized Stem Cells That Could One Day Treat Parkinson’s and Heart Failure

Could an injection of lab-cultured brain cells, created from a person’s own cells, reverse symptoms of Parkinson’s disease? That’s an idea that Aspen Neuroscience Inc., a startup based in San Diego, plans to test in human trials later this year.

In patients with Parkinson’s, neurons die and lose the ability to make the chemical dopamine, leading to erratic, uncontrollable movements. Aspen Neuroscience will test if the newly injected cells can mature into dopamine producers, stopping the debilitating symptoms of this incurable disease, says Damien McDevitt, the company’s chief executive officer. Tests in animals have shown promise, the company says.

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Umbilical blood stem cell transplant puts woman in HIV remission

A transplant of stem cells from the umbilical cord has resulted in a mixed-race woman going into remission for HIV for the first time.

The woman, known as the New York patient, has been clear of detectable HIV since 2017, after she received HIV-resistant stem cells that had been harvested from umbilical cord blood to treat her leukaemia. Stem cells are produced by bone marrow and can turn into different types of blood cells.

Several people have previously gone into remission from HIV after receiving stem cells from adult donors who carry two copies of a naturally occurring mutation of the CCR5 gene. This delta 32 mutation prevents the virus from entering and infecting healthy cells.

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Stem Cells and Cardiac Disease: Where are We Going?

During the last 10 years we have witnessed the development of a new field in research termed Stem Cell Therapy. Classically, it was considered that cells had a limited division and differentiation ability; however, this dogma was challenged when new exciting results about cell multi/pluripotency were presented to the scientific community. It was found that cells from one adult tissue source were able to originate cells of a very different type. The possibility of transplanting these cells into damaged organs with the aim of substituting sick or dead tissue, triggered many studies to understand the plasticity of the stem cells and their potential in pathological situations. Nowadays, much more is understood about stem cells, although of course, many questions, especially about their mechanism of action, still need to be answered. Their benefit after transplantation has been shown experimentally and even clinically in some cases; however, the degree of stem cell contribution through their own differentiation into the transplanted tissue, has turned out to be generally low, and increasing evidence indicates that a trophic effect must play an important role in such a benefit. A better understanding of the paracrine mechanisms involved could be of great relevance in order to develop new therapies focused on stimulating endogenous cells. On the other hand, more sophisticated methods for cell transplantation combined with bio-engineering techniques have been devised in cardiac disease models. In this review we will try to provide a critical overview of the stem cell studies performed until now and to discuss some of the questions raised about the mechanisms that are involved in their putative reparative effect in cardiovascular diseases, and their origin.

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Mesenchymal stem cells for the prevention and treatment of bronchopulmonary dysplasia in preterm infants

Bronchopulmonary dysplasia (BPD) is considered one of the major complications of preterm birth (Farstad 2011Jobe 2001). Bronchopulmonary dysplasia develops as a consequence of impaired lung development, exacerbated by the imbalance between pro‐inflammatory stimuli and anti‐inflammatory defense mechanisms typical of the preterm infant (Jobe 2001Speer 2006).

The definition of BPD has been evolving since its first description as 28 days of oxygen exposure with characteristic radiographic changes (NIH 1979). Subsequently, oxygen dependency at 36 weeks’ postmenstrual age was shown to better predict long‐term respiratory outcomes (Shennan 1988). The current definition of BPD stratifies infants below 32 weeks requiring supplemental oxygen for at least 28 days into three severity groups (mild, moderate, and severe), depending on the presence and the amount of supplemental oxygen and the mode of respiratory support at 36 weeks’ postmenstrual age (Ehrenkranz 2005Jobe 2001). The ‘physiologic’ definition of BPD was proposed in an attempt to address the significant intercenter variability in oxygen administration (Lapcharoensap 2015). At 36 weeks’ postmenstrual age, infants receiving less than 30% supplemental oxygen are challenged by reducing the fraction of administered oxygen during a standardized test. Infants who are unable to maintain saturations above 90% during the test are diagnosed with BPD (Walsh 2003). The incidence of BPD varies depending on the definition, complicating the course of up to 40% of the infants born between 22 and 28 weeks’ gestation (Stoll 2010). It must be noted that, although by definition BPD cannot be diagnosed before 28 days of life, a respiratory disease defined as oxygen and/or ventilator‐dependency from 7 to 28 days of life represents the initial phase of the chronic process leading to BPD, thus classified as “evolving BPD” (Walsh 2006). Infants suffering from BPD are at increased risk of death and long‐term pulmonary and neurodevelopmental morbidities (Anderson 2006Bhandari 2006). Several treatments have been used in an attempt to prevent or treat BPD. Unfortunately, even the most promising strategies have not been able to confirm the initial enthusiasm in robust randomised controlled trials (RCTs). A recent meta‐analysis combining all the available pharmacological options to prevent BPD found that only five out of the 21 drugs tested (vitamin A, caffeine citrate, dexamethasone, inositol, and clarithromycin) in RCTs may reduce the incidence of BPD. Among these, meta‐analysis could confirm the data only for vitamin A and dexamethasone, due to the lack of multiple trials for the other drugs (Beam 2014). Moreover, vitamin A showed only a very modest effect (Darlow 2011), while the use of dexamethasone is limited in preterm infants by its well‐known long‐ and short‐term side effects (Watterberg 2010). Despite the continuous advance of neonatal care, BPD remains a significant burden for the preterm population, lacking a safe and effective treatment.

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