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Long-term survival and behavioral efficacy human ESC-derived photoreceptors in Crx -/- mice

(T.A. Reh and Deepak Lamba)


Background and Significance:

Crx mutations in humans cause an untreatable form of blindness; the loss of this transcription factor leads to defects in the development of photoreceptors, and the cells ultimately undergo apoptosis.  At this time, there are few options for restoring vision to these individuals.  There has been recent progress in electrical and gene therapy-based prosthetic devices (to produce light responses in the unaffected retina cells); however, the loss of photoreceptors leads to secondary degeneration in the inner retina, and neither a mechanical nor genetic prosthesis is likely to prevent this secondary retinal degeneration. 


Cell replacement therapy remains a possibility for individuals with severe retinal degeneration; however, a reliable, well-characterized source of retinal cells is needed.  Embryonic stem cells (ESCs) provide such a source and derivatives of these cells are currently being used in three recently approved clinical trials for spinal cord injury and retinal diseases.  ESCs, derived from the inner cell mass of the blastocyst, can self-renew indefinitely under appropriate culture conditions and have the ability to produce any cells in the body. We have developed efficient methods for deriving retinal neurons from human embryonic stem cells (Lamba et al., 2006).  We have spent the last five years characterizing the cells and optimizing the protocols; the stem cell derived retinal cells express the same genes expressed by fetal retinal cells (Lamba and Reh, 2011), and can differentiate into all the different types of retinal neurons, including ganglion cells, amacrine cells, bipolar cells and both rod and cone photoreceptors. The cells have minimal contamination of other cell types, and show no tumor forming potential in transplants in animals.  We have collaborated with Geron over the past year to develop a better understanding of the issues we need to address prior to applying for FDA approval for a Phase I trial, and we now have in place a standardized process for manufacture of retinal cells that can be carried out under GMP conditions.


Will these human ESC-derived retinal cells actually work for cell replacement in patients?  We tested the ability of the ESC-derived retinal cells to integrate into normal mouse and rat retinas, and find they have the ability to move from the subretinal space and integrate with the normal retinal cells in both mouse and rat.  We also transplanted the human ESC-derived retinal cells into several mouse models of retinal degeneration, and again, they behaved much like transplants of mouse retinal cells, and integrated into the degenerating retinas.  What was interesting from these experiments was that we actually saw the best examples of integration in the Crx-/- mice.  The transplanted cells integrated into all layers of the retina, and the photoreceptors that developed in the outer nuclear layer appeared to make synaptic contacts with the host bipolar cells.  These encouraging morphological results led us to test by ERG recordings whether the human ESC-derived retinal cells were able to restore any light response to the animals, and we found that indeed we could detect an ERG-like signal (with appropriate latency and polarity of a b-wave) in the transplanted eye (Lamba et al., 2009).


At this point, the Crx -/- mice responded the best to the transplants of the human ESC-derived retinal cells out of all the models we have tested.  Therefore, moving forward we would like to consider people with Crx mutations as possibly the target population for a clinical trial.  From what we learned from Geron, we developed a plan for a potential clinical trial that will require additional safety studies.  First, we must ensure the transplanted cells do not form tumors in either the eye or elsewhere in the body.  Second, we must ensure that the transplanted cells will survive in the retina for extended periods of time.  Third, we must be able to show that the transplanted cells confer some potential for functional repair/efficacy over an extended period of time. 

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