>>What genes are related to Stargardt macular degeneration? In most cases, Stargardt macular degeneration is caused by mutations in the ABCA4 gene. Less often, mutations in the ELOVL4 gene cause this condition. The ABCA4 and ELOVL4 genes provide instructions for making proteins that are found in light-sensing (photoreceptor) cells in the retina.<<
IMO, for meaningful results, ACT’s donor hRPE from their hESC source will certainly contain both the ABCA4 & ELOVL4 genes so that the donor’s hRPE can carry out the necessary phagocytosis action in which the SMD patient’s diseased RPEs were not able to. The donor’s hRPE, if allowed to by the donor’s immune system, should then be removing dead cells from the patient’s (1)photoreceptors, (2) RPEs and (3) Bruch membrane plus whatever other surrounding tissue would normally be kept “clean” by the RPEs. The Phase I safety aspect of the trial will be evaluating safe co-existence of the donor’s RPEs vs. patient’s RPEs and other patient’s surrounding eye tissues. The hope is that the RPEs, donor’s and patient’s, are the good guys and will not attack each other but co-exist peacefully. As long as the patient’s eye tissues remain in an immune-privilege state with no seeping bleeding, then there is a good chance for success. While peaceful co-existence was the case for the rat/mice/animal trials, the human genetic/immune system with the much longer life span exponential magnitude, will no doubt pose a much greater challenge. Hence the Phase I safety evaluation before being allowed to move forward with the Phase II Efficacy evaluation with greater than 50K cells.
These same concerns will also apply to the DAMD patients but perhaps without the ABCA4 & ELOVL4 genes replacement.
In time the donor’s RPE will need to be regenerated as dictated by its telomere actions. This regeneration will then be a major crossroad as to what ACT will evaluate as to the best course of action.
It is expected that the additional hESC injections will likely be needed after several months unless the patient begins to regenerate new hRPEs. The ACT team can then make an assessment at this time as to whether any of their autologous therapies would be more beneficial in complete restorative eye cells.
. . . ABCA4 gene mutations may also be associated with an increased risk for developing age-related macular degeneration, although not all studies are in agreement on this. If so, then success with Stargardt's might predict success with AMD.
I'm not sure that ACTC will be evaluating altered protein expression in the space behind the retina since that would require a biopsy. I'm thinking that successful growth of cells without teratoma formation combined with improved vision would be a proxy for normalized protein expression.
This invention generally relates to methods of reprogramming an animal somatic cell from a particular differentiated state to another state, and the use of such cells and tissues in the treatment of human diseases and age-related conditions. More particularly, the invention relates to an improved method utilizing a three-step process whereby the nuclear envelope of the somatic cell nucleus is first remodeled to that of an undifferentiated cell or a germ-line cell prior to the second step of transferring the remodeled nucleus into the cytoplasm of an oocyte or an undifferentiated cell. This nuclear remodeling step markedly enhances the efficiency of cellular reconstitution when the remodeled nucleus is transferred into embryonic or germ-line cytoplasm for the purpose of stem cell derivation. In addition, the removal of components of the nuclear envelope specific for differentiated cells, such as lamin A, and the reprogramming of chromatin results in a reactivation of telomerase activity, a lengthening of telomere length, and mechanisms of homologous recombination that repair tandemly-repeated DNA sequences. When pluripotent stem cells are derived by the present invention, they may be utilized in novel therapeutic strategies in the treatment of cardiac, neurological, endocrinological, vascular, retinal, dermatological, muscular-skeletal disorders, and other diseases.