Hematopoietic Cells from Pluripotent Stem Cells: Hope and Promise for the Treatment of Inherited Blood Disorders

Abstract

Inherited blood disorders comprise a large spectrum of diseases due to germline mutations in genes with key function in the hematopoietic system; they include immunodeficiencies, anemia or metabolic diseases. For most of them the only curative treatment is bone marrow transplantation, a procedure associated to severe complications; other therapies include red blood cell and platelet transfusions, which are dependent on donor availability. An alternative option is gene therapy, in which the wild-type form of the mutated gene is delivered into autologous hematopoietic stem cells using viral vectors. A more recent therapeutic perspective is gene correction through CRISPR/Cas9-mediated gene editing, that overcomes safety concerns due to insertional mutagenesis and allows correction of base substitutions in large size genes difficult to incorporate into vectors. However, applying this technique to genomic disorders caused by large gene deletions is challenging. Chromosomal transplantation has been proposed as a solution, using a universal source of wild-type chromosomes as donor, and induced pluripotent stem cells (iPSCs) as acceptor. One of the obstacles to be addressed for translating PSC research into clinical practice is the still unsatisfactory differentiation into transplantable hematopoietic stem or mature cells. We provide an overview of the recent progresses in this field and discuss challenges and potential of iPSC-based therapies for the treatment of inherited blood disorders.

A scalable, GMP-compatible, autologous organotypic cell therapy for Dystrophic Epidermolysis Bullosa

“…Generation of organotypic epidermis was performed by following the protocol described previously 8 with minor modifications. Derived induced keratinocytes and unsorted passaged differentiated cells were expanded in Defined Keratinocyte SFM (Gibco TM ) until confluent then passaged onto devitalized human dermis seeded at a density of 1×10 6 cells. The medium was then gradually changed to 7F stratification media for 7 days, after which the dermal sheet was raised to the air-liquid interface.…”

“…The iPS cell-based approach provides a solution for the two main limitations of current somatic cell and gene therapy strategies: (i) iPS cells can be grown to virtually unlimited numbers providing a solid foundation for tissue organoid production-scalability and (ii) defined gene editing recreates a wild type allele while avoiding retroviral insertional mutagenesis. Thus, the combination of cell reprogramming, genomic correction of pathogenic mutations and composite cell transplantation has the potential to eradicate the impacts of disease-causing mutations in afflicted tissues [5][6][7] .…”

Preoperative diagnosis and management of inherited bleeding disorders in female adolescents and adults

“…Traditional antithrombotic therapies (anticoagulation, antiplatelet) may be required in females with IBDs needing other surgical and medical treatments. 2 , 55 – 57 , 59 – 63 The available anticoagulation drugs are used to reduce the risk of thrombosis but result in a concomitantly increased risk of bleeding ( Table 4 ). 61 , 62 Although perioperative management of patients who are receiving antiplatelet therapy is a common clinical occurrence, there are minimal high-quality studies to direct, continue or interrupt antiplatelet therapy, as well as concerning the role of bridging therapy.…”

“…Therapies to increase platelet count, mitigate platelet dysfunction and definitively correct inherited thrombocytopenia continue to be used. 30 , 31 , 55 …”

An Overview of Autophagy in Hematopoietic Stem Cell Transplantation

“…In addition, various research has revealed that the differentiation of induced pluripotent stem cells (iPSCs) or lineage reprogramming somatic cells into specific lineage can create a massive supply of stem cells. Also, many studies have shown that reprogramming protocols combined with gene-editing technology (CRISPR/Cas9) may prevent transplant-associated complications ( Rao et al, 2022 ). In a model of Huntington’s disease, administration of a small-molecule enhancer of rapamycin 28 (SMER28) can modestly increase autophagy and subsequent clearance of autophagy substrates ( Whitmarsh-Everiss and Laraia, 2021 ).…”