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Century Therapeutics develops iPSC-derived cell therapies for cancer. Working to design drugs that can better evade identification by the host immune system and potentially allow patients to receive multiple doses of cell therapy. With the idea to get more durable responses.
An Allo-Evasion platform focused on iNK & iT (invariant) cells to target hematologic cancers and solid tumors. iPSCs are stem cells that can be made from almost any cell in the body. Allowing Century to create off-the-shelf therapies for patients. Their method uses the the CRISPR-MAD7 nuclease to modify the iPSC genome. Knocking out genes the reduce allogeneic immune-reactivity and prevent rejection by the patient’s immune system.
Building a pipeline to validate their platform. With its lead drugging CD19 for lymphoma. As well as developing programs with BMS for riskier targets such as Nectin-4 or multi-specific drug candidates.
Hypoimmune induced pluripotent stem cell–derived cell therapeutics treat cardiovascular and pulmonary diseases in immunocompetent allogeneic mice
The paper first generates hypoimmune (HIP) iPSCs by disrupting the B2M and Ciita genes, which are essential for major histocompatibility complex (MHC) class I and class II expression, and overexpressing CD47, which is a signal that inhibits phagocytosis. These HIP iPSCs were then differentiated into endothelial cells (iECs) and cardiomyocytes (iCMs).
The authors then evaluated the efficacy of transplanted HIP iECs in salvaging hindlimbs in allogeneic BALB/c mice with critical limb ischemia (CLI). They found that HIP iECs significantly improved perfusion and increased the likelihood of limb preservation compared to wild-type (WT) iECs.
The authors also evaluated the efficacy of transplanted HIP iCMs in treating myocardial infarction (MI) in allogeneic BALB/c mice. They found that HIP iCMs engrafted in the ischemic areas and improved invasive hemodynamic heart failure parameters.
Finally, the paper evaluated the efficacy of transplanted HIP iECs transduced to express a transgene for alpha1-antitrypsin (A1AT) in treating emphysema in allogeneic BALB/c mice with genetic A1AT deficiency. They found that A1AT-expressing HIP iECs successfully restored physiologic A1AT serum levels and prevented both structural and functional changes of emphysematous lung disease.
Demonstrating that HIP iPSC-derived cell therapeutics can be used to treat cardiovascular and pulmonary diseases (in mice) without the need for immunosuppression. This suggests that HIP iPSC-derived cell therapeutics have the potential to be developed into universal off-the-shelf products for the treatment of a wide range of diseases.
https://www.pnas.org/doi/abs/10.1073/pnas.2022091118
Enhanced differentiation of beta cells
The patent is linked to a type 1 diabetes cell therapy developed by Vertex Pharmaceuticals. The therapy uses induced pluripotent stem cells (iPSCs) to generate insulin-producing islet cells. Engineered to be hypoimmune, meaning that they are less likely to be rejected by the immune system. The islet cells are then transplanted into the patient, where they begin to produce insulin.
The patent describes several different ways to generate the hypoimmune iPSCs. One method is to knock out the B2M and CIITA genes, which are necessary for the expression of MHC class I and class II molecules, respectively. Another method is to overexpress the CD47 gene, which is a protein that inhibits phagocytosis by macrophages.
The patent also describes several different ways to differentiate the iPSCs into islet cells. One method is to use a multi-step differentiation protocol that involves the use of various growth factors and hormones. Another method is to use a single-step differentiation protocol that involves the use of a single transcription factor. For delivery, one method is to transplant the islet cells into the liver. Another method is to transplant the islet cells into a pouch that is implanted under the skin.
https://patentimages.storage.googleapis.com/55/30/e9/9482dc2796fe6d/WO2022147056A1.pdf
What are Yamanaka factors?
Yamanaka factors are a group of 4 transcription factors that can be used to reprogram adult cells into induced pluripotent stem cells (iPSCs). That have the potential to develop into any type of cell in the body:
1. Oct4
2. Sox2
3. Klf4
4. c-Myc
Yamanaka factors were discovered in 2006 by Shinya Yamanaka, who was awarded the Nobel Prize in Physiology or Medicine in 2012 for his work. Mouse iPS cells from mouse fibroblasts were first reported in 2006 by the Yamanaka lab at Kyoto University. Human iPS cells were then independently produced by Yamanaka’s and Thomson’s groups from human fibroblasts in late 2007.
This breakthrough allowed researchers to obtain pluripotent stem cells without the controversial use of embryos, providing a powerful method to "de-differentiate" cells whose developmental fates had been traditionally assumed to be determined. Furthermore, tissues derived from iPS cells will be a nearly identical match to the cell donor, which is an important factor in research of disease modeling and drug screening. With the long-term potential to reprogram cells to repair damaged tissues in the human body. To treat diseases such as Parkinson's disease, Alzheimer's disease, and diabetes.
Scientist Stories: Sonja Schrepfer, The Future of Stem Cells and Hypoimmune Cell Therapies
Schrepfer is Head of Hypoimmune Platform at Sana Biotechnology and an adjunct professor at UCSF