What is iPSCs?
Induced pluripotent stem cells (iPSCs) are derived from donor skin or blood cells that have been reprogrammed back into an embryonic-like pluripotent state thus enabling the development of an unlimited source of any type of human cell needed for therapeutic purposes. For example, iPSC can be differentiated into beta islet cells to treat diabetes, blood cells to create new blood free of cancer cells for a leukemia patient, immune cells to treat cancers, or neurons to treat neurological disorders.
In 2006, Dr. Sinya Yamanaka first discovered that intact mature cells could be reprogrammed to become immature stem cells (pluripotent stem cells) by introducing only a few genes. The resulting pluripotent stem cells are able to develop into all types of cells in the body. In 2012, Dr. Yamanaka and Dr. John Gurdon were awarded The Nobel Prize in Physiology or Medicine for the discovery that mature cells can be reprogrammed to become pluripotent cells (iPSCs). With this groundbreaking discovery, iPSC research has quickly become the foundation for new regenerative medicines.
iPSC-derived mesenchymal stem cells (iPSC-MSCs) and therapeutic potential
Mesenchymal stem cells (MSCs) are multipotent stromal cells derived from connective tissues, MSCs used in treatments show advantages over other approaches because they constitute a stem cell niche, support the growth of tissue-specific stem cells, and promote tissue regeneration. In addition, exogenous MSCs have shown immunomodulatory and regenerative potential in animal models of autoimmune and inflammatory diseases, as well as in clinical trials to treat these diseases such as Inflammatory Bowel Disease (IBD), COVID-19 related acute respiratory distress syndrome, via local delivery or systemic methods. Of note, MSCs are hypoimmunogenic, and the use of allogeneic MSCs is usually safe. This is because MSCs lack human leukocyte antigen class II antigen expression, which allows allogeneic administration without donor–recipient matching. Despite their promising therapeutic effects, tissue derived MSCs have several weaknesses, such as their limited expansion ability and variation across donors, production standardization difficulty, loss of differentiation capacity, and decreased therapeutic efficacy during expansion.
iPSCs have the potential to overcome these challenges, due to their capacity for multilineage differentiation and indefinite proliferation. Human iPSCs can be induced to differentiate into MSCs following a clinically compliant protocol (see below diagram). These iPSC-derived MSCs, called iPSC-MSCs, show greater expandability and therefore offer potential for use in tissue repair therapies.
The therapeutic potential of iPSC-MSCs have been shown in many animal models, for example in the models of IBD on mucosal healing. Human clinical trials of iPSC-derived cells have not previously been completed. For example, CYP-001 (iPSC-derived MSCs) is produced using an optimized, good manufacturing practice (GMP)-compliant manufacturing process. a phase 1, open-label clinical trial (no. NCT02923375) was conducted in subjects with steroid refractory acute graft-versus-host disease (SR-aGvHD). CYP-001 was safe and well tolerated. No serious adverse events were assessed as related to CYP-001. Overall response (OR), complete response (CR) and overall survival (OS) rates by day 100 were 86.7, 53.3 and 86.7%, respectively. The therapeutic application of iPSC-derived MSCs may now be explored in diverse inflammatory and immune-mediated diseases.
Written by: Feng Lin, M.D., Ph.D.