Despite progress involving the use of induced pluripotent stem cells (iPSCs) within disease modeling and drug discovery applications, it will be a long path to achieve the broad-scale use of iPSC-derived cell types in human patients.
Within a preclinical context, cell types differentiated from iPSCs are tested for their therapeutic response by using animal models. Then, clinical trials are conducted to assure that essential parameters, such as tumorigenicity, dose toxicity, and immunogenicity, are assessed before authorizing the product for use in human patients.
iPSC-derived cells have the potential to be used as therapies for treating cardiovascular, neurological and metabolic diseases and repairing damaged cartilage, spinal, motor neuron and eye tissues resulting from genetic defects or injuries. In general, the targets for iPSC-derived therapies include any diseases or disorders for which there are no other viable treatments and where there is a need to repair or replace dysfunctional tissue.
Pipeline for iPSC-Derived Cell Therapeutics
As of today, only a handful of companies are forging the path toward iPSC-derived cell therapeutics.
These companies include:
- Semma Therapeutics, which was acquired by Vertex Pharmaceuticals for $950 million in late 2019, has been developing a treatment for Type 1 diabetes consisting of cells derived from iPSCs that behave like pancreatic cells.
- BlueRock Therapeutics, which was recently acquired by Bayer, has been targeting Parkinson’s disease and heart failure.
- Century Therapeutics was created by Versant Ventures in partnership with Fujifilm in July 2019 to develop iPSC-derived adaptive and innate immune effector cell therapies.
- Cynata Therapeutics manufacturers iPSC-derived MSCs using its proprietary Cymerus™ technology. It is testing these cells in the treatment of graft-versus-host disease (GvHD), critical limb ischemia (CLI) and osteoarthritis (OA).
- Fate Therapeutics has been using iPSC-derived NK and T cells for the treatment of cancer and immune disorders. In 2019, the company began in 2019 its first ever U.S. clinical trial of an iPSC-derived cell therapy product.
- Stemson Therapeutics has been developing a therapy for hair loss involving generation of de novo hair follicles.
- TreeFrog Therapeutics – TreeFrog Therapeutics has a 13,000 sq ft facility in France for the development and scale-up of its cell therapy manufacturing process that leverages human iPSCs. It plans to develop its own iPSC-derived therapies and support co-development programs.
iPSC-Derived Cell Therapeutics in Clinical Trials
While the companies above are involved with the development of iPSC-based cell therapeutics, not all of them have reached clinical-stage. The companies developing clinical-stage iPSC-derived therapeutics are described below.
In 2016, Cynata Therapeutics received a landmark approval to launch the world’s first formal clinical trial of an allogeneic iPSC-derived cell product (CYP-001) for the treatment of GvHD. In collaboration with Fujifilm, Cynata Therapeutics completed this Phase I trial in December 2018, reporting positive results.
Now, Cynata is now advancing its product candidate, CYP 004, into the world’s first Phase 3 clinical trial to involve an iPSC-derived cell therapeutic. The trial will also be the largest one ever completed, with an anticipated enrollment of 440 patients.
Fate Therapeutics is exploring the clinical use of FT516 and FT500, which are its off-the-shelf, iPSC-derived natural killer (NK) cell product candidates. In December 2019, Fate released promising clinical data from its landmark Phase 1 studies.
The Japanese company Healios K.K. is preparing, in collaboration with Sumitomo Dainippon Pharma, for a clinical trial using allogeneic iPSC-derived retinal cells to treat age-related macular degeneration (AMD).
Within Japan, there are numerous physician-led studies underway investigating the use of iPSC-derived cellular products within human patients. These clinical trials are for diseases such as macular degeneration, ischemic cardiomyopathy, Parkinson’s disease, solid tumors, spinal cord injury (SCI) and platelet production.
Details on each of these trials are provided below:
Clinical Trials for AMD
Significant progress has been made for retinal degeneration diseases, particularly for age-related macular degeneration (AMD). In 2009, preclinical data showed for the first time the recovery of visual function in patients injected with retinal pigment epithelium (RPE) differentiated from iPSCs in a rat model’s retina. A major breakthrough was made when the group led by Masayo Takahashi at the Riken Centre for Developmental Biology in Japan produced iPSC-RPE cell sheets in 2014.
Autologous iPSC-RPE for AMD
The above-mentioned successes led to the initiation of the first iPSCs clinical trial in 2014 itself. Scientists at the RIKEN Centre in Japan transplanted an autologous iPSC-RPE cell sheet just below the affected retina, without immunosuppression, in a 77-year-old woman with AMD. One year after the transplantation, the progression of the degeneration simply halted, an area with photoreceptors recovery was observed, and the patient’s vision remained stable. There were no symptoms of immune rejection or tumor development.
Allogeneic iPSC-RPE for AMD
In addition, in March 2017, Japanese scientists announced that a 60-year-old man was the first patient to receive iPSC-RPE cells derived from another person (allogeneic source). Moreover, a clinical-grade iPSC bank for collecting and storing healthy HLA homozygous donors is now being established at the Centre for iPS Cell Research and Application (CiRA) in Kyoto (Japan). Ultimately, in July 2019, scientists at Osaka University started a clinical trial for limbal stem cell deficiency, a condition in which corneal stem cells are lost. The scientists grafted a sheet of iPS-derived corneal cells into the cornea of a patient, and within one month, her vision seemed to have improved.
iPSC-Derived Dopaminergic Neurons for Parkinson’s disease
Another condition that has attracted attention is Parkinson’s disease, a neurological disorder. In 2008, it was confirmed that symptoms and dopaminergic function of rat models improved when administered with iPSC-derived dopaminergic neurons. Recently, in Japan, dopaminergic progenitor cells differentiated from iPSCs were grafted into an animal model of Parkinson’s disease and the affected animal showed an improvement of symptoms.
These dopamine precursor cells were created from allogeneic iPSCs produced by Jun Takahashi’s research group at Kyoto University. In October 2018, the clinical trial using iPSCs started when these precursors were grafted into the brain of a human patient in his 50s, with a total of seven patients recruited for the study.
iPSC-Derived NK Cells for Solid Cancers
In 2016, the injection of iPSC-derived natural killer (NK) cells into an animal model provided proof of their potential for effective immunotherapy treatment for ovarian cancer. In February 2019, allogeneic iPSC-derived NK cells produced by scientists from the University of Minnesota, in collaboration with Fate Therapeutics, were granted approval by FDA for a clinical trial. The study will aim to treat nearly 64 patients with different cancer types.
iPSC-derived Cells for GvHD
Clinical trials have been initiated using iPSC-derived cells for graft-versus-host disease (GVHD). The Australian company Cynata Therapeutics has been granted the approval to proceed with a clinical trial of its allogeneic iPSC-derived mesenchymal stem cell (MSC) product, known as CYP-001. The company has established the safety of its Cymerus™ iPSC- derived MSCs and demonstrated preclinical efficacy in a humanized animal model. In 2018, a Phase I trial was successfully completed in 16 steroid-resistant GVHD patients with positive results, positioning the company to advance into phase II trials this year.
iPSC-derived Cells for Osteoarthritis (World’s First iPSC Trial to Enter Phase 3)
Cynata Therapeutics is preparing to test its product candidate CYP-004 in a Phase 3 clinical trial enrolling up to 440 patients. CYP-004 is an allogeneic, iPSC-derived mesenchymal stem cell (MSC) product derived using Cynata’s proprietary Cymerus™ technology. Led by the University of Sydney and funded by the Australian Government National Health and Medical Research Council (NHMRC), the trial will assess whether the cells can improve patient outcomes in osteoarthritis (OA). It will be the world’s first clinical trial involving an iPSC-derived cell therapeutic to enter Phase 3 and the largest one ever completed.
iPSC-derived Cells for Spinal Cord Injury
Several preclinical studies in spinal cord injuries using iPSC-derived neural progenitor cells in animal models have provided evidence for remyelination and locomotor function recovery. In February 2018, the Japanese government gave an approval to Professor Hideyuki Okano for a clinical trial that will involve the treatment of patients with spinal cord injuries at Keio University.
iPSC-derived Cardiomyocytes for Ischemic Cardiomyopathy
In 2017, iPSC-derived cardiomyocytes were grafted on to a porcine model of ischemic cardiomyopathy by Kawamura, et al., using a cell-sheet technique. Cardiac function was significantly improved, and neovasculogenesis was observed. Recently, scientists from Osaka University were granted approval for a clinical trial to transplant allogeneic sheets of tissue derived from iPSCs onto the diseased hearts of three human patients.
Similarly, a group of scientists from Kyoto University were granted approval to begin a transfusion trial using platelets derived from iPSCs into an individual with aplastic anemia.
To learn more about the market for iPSCs, view the “Global Induced Pluripotent Stem Cell (iPS Cell) Industry Report 2020.”
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