Blog March 18, 2019

Nobel Award Winning Science Reaches the Clinic — Finally

maculardegenerationIn 2006, Japanese scientist Shinya Yamanaka turned back the biological clock of mature mouse cells, reprogramming them into stem cells capable of becoming any cell types. This accomplishment led to his sharing a Nobel Prize in Physiology or Medicine in 2012 with Sir John Gurdon, another pioneer in the field of regenerative medicine. The scientific community hailed such cells, termed induced pluripotent stem cells (iPSCs), as offering a potential alternative to more controversial embryonic stem cells for research and potential therapeutic applications. Additionally, IPSCs have the advantage of being patient-specific, avoiding the potential risks of immune rejection faced with embryonic stem cell-based therapeutics.


Animal studies have shown the potential of iPSCs for treating eye diseases for at least 10 years. Moreover, retinal cells created from embryonic stem cells were first safely transplanted into patients in a clinical trial eight years ago, and a California research team is shortly set to begin a Phase 2 trial using embryonic stem cells. Despite these achievements, no clinical studies have been conducted with iPSCs before now, due to earlier questions about their safety, including potential tumor formation and the risk of differentiation into unwanted cell types.


But today, a team of U.S. researchers is moving forward with the first U.S. iPSC clinical trial for the potential treatment of age-related macular degeneration (AMD), and Fate Therapeutics recently announced that an iPSC-based cancer study has been cleared by FDA to begin.


Eye diseases have been of great interest as potential applications for stem cell therapies because of the ease of delivering treatments and the fact that the eye is an immuno-privileged organ, alleviating concerns of potential immune rejection. AMD, in particular, has been an important focus because of the high clinical need: it is the leading cause of blindness in adults over age 50, estimated to affect 196 million people globally by 2020. AMD is caused by the death of retinal pigment epithelial (RPE) cells, a nutrient- and oxygen-rich layer in the eye that keep rods and cones alive. When RPE cells die, as a result of age, high blood pressure, or smoking, the photoreceptors also die, resulting in blindness.


Researchers from the U.S. National Eye Institute turned CD34+ hematopoietic progenitor cells into iPSCs and induced them to differentiate into RPE cells, which they grew in a single layer on a resorbable biological scaffold. In animal trials, scaffold-grown RPE cells integrated within the retina better than cells inserted into the eye via droplets.


The researchers are now poised to begin a Phase 1 clinical trial and have considerable hopes for success. In the animal trials, immunostaining confirmed that the implanted RPE cells expressed the protein Rpe65, a marker of functional RPE cells important for the regeneration of the visual pigment within the photoreceptors. Further tests showed that the implanted cells properly exhibited phagocytosis activity, a crucial function that involves trimming the photoreceptors’ outer segments to maintain a healthy size. Additionally, the researchers detected normal electrical pulses from the photoreceptors in the animals that received RPE transplants, while the photoreceptors in control animals continued to die over time.


If this study is successful, what other indications might be particularly promising for the use of iPSCs? Will iPSCs supplant the use of embryonic stem cells and if so, why? Watch this space.