There has been a great deal of discussion of embryonic stem cell-derived retinal pigment cells and the transplantation of these cells into the retinas of two human patients who subsequently showed improvements in their vision. One of these patients had a degenerative eye disease called “Stargardt’s macular dystrophy,” and the other had dry, age-related macular degeneration.
Stargardt Macular Dystrophy (SMD) is one of the main causes of eyesight loss in younger patients (affects 1/10,000 children), and retinal damage begins somewhere between the ages of 6 – 20. Visual impairment is usually not obvious to the patient until ages 30 – 40. Children with SMD usually notice that they have difficulty reading. They may also complain that they see gray, black or hazy spots in the center of their vision. Additionally, SDM patients take a longer time to adjust between light and dark environments.
Mutations in the ABCA4 gene seem to be responsible for most cases of SDM. Defects in ABCA4 prevent the photoreceptors from disposing of toxic waste products that accumulate within build up in the disc space of the photoreceptors. These toxic waste products are a consequence of housing light-absorbing pigments, and intense light exposure. The pigment, all-trans retinal, binds to membrane lipids, and this forms a compound called NRPE (short for N retinylidene-phosphatidylethanoliamne, which is a mouth-full). The protein encoded by ABCA4 moves NRPE into the cytoplasm of the photoreceptor cells, but if ABCA4 is not functional, NRPE accumulates in the disc space and binds more all-trans retinal to form a toxic sludge called “lipofuscin.” Lipofuscin is taken up from the photoreceptors by the RPE cells and it kills them (see Koenekoop RK. The gene for Stargardt disease, ABCA4, is a major retinal gene: a mini-review. Ophthal Genet. 2003;24(2):75–80). Mutations in other genes (ELOVl4, PROM1, and CNGB3) also cause SDM.
Dry, age-related macular degeneration is associated with the formation of small yellow deposits in the retina known as “drusen.” Drusen formation leads to a thinning and drying of the macula that eventually causes the macula to lose its function. There is loss of central vision and the amount of vision loss is directly related to the amount of drusen that forms. Early stages of age-related macular degeneration is associated with minimal visual impairment, but is characterized by large drusen and abnormalities in the macula. Drusen accumulates near the basement membrane of the retinal pigment epithelium. Almost everyone over the age of 50 has at least one small druse deposit in one or both eyes. Only those eyes with large drusen deposits are at risk for late age-related macular degeneration.
All of this is to say that these diseases are progressive. They have no cure and little can be done for treatment. Secondly, people rarely get better. However, both patients in this study showed quantifiable improvements. The patient with age-related macular degeneration went from being able to see 21 letters in the visual acuity chart (20/500 vision for the patient, with 20/20 being perfect vision) to 28 letters (20/320). This improvement remained stable after 6 weeks. The patient with SMD was able to detect hand motions only, but after the stem cell injection, she could count fingers and see one letter in the eye chart by week 2, and was able to see five letters (20/800) after 4 weeks. She also was able to see colors and contrast better and had better dark adaptation in the treated eye.
Now there are some caveats for this report. First of all, the patient with SMD showed distinct structural improvements in the retina of the injected eye. This patient also had distinct improvements in visual acuity. However, the patient with dry, age-related macular dystrophy had no detectable structural improvements in the injected eye. The paper states, “Despite the lack of anatomical evidence, the patient with macular degeneration had functional improvements.” Additionally, the non-injected eye also showed some visual improvements. Note the words of the paper: “Confounding these apparent functional gains in the study eye, we also detected mild visual function increases in the fellow eye of the patient with age-related macular degeneration during the postoperative period.” Therefore, this experiment is highly preliminary and has equivocal results. The SMD patient does show recognizable improvements, but this is only one patient.
While we are considering the efficacy of embryonic stem cells in the treatment of retinal degenerative diseases, a paper that was published in 2009 shows that bone marrow stem cells that have a cell surface marker celled “CD133” can become retinal pigment (RPE) cells. This paper was published in the journal “Stem Cells,” and the principal author was Jeffrey Harris who did his work in the laboratory of Edward W. Scott at the University of Florida. These cells were extracted from the bone marrow of mice and implanted into the retinas of albino mice. Since the donor mice had pigmented skin and fur coats, the bone marrow cells were capable of making pigmented cells. Once the CD133 cells were implanted, they survived and became pigmented. When examined in postmortem sections, it was exceedingly clear that the transplanted CD133 cells expressed RPE-specific genes and assumed a RPE-like morphology. Additionally, the implanted bone marrow cells also contributed functional recovery of retina. A second set of experiments showed that human CD133 cells from umbilical cord could also integrate into mouse retinas and differentiate into RPEs.
This paper shows that embryonic stem cells are probably not necessary for retinal repair of RPE-based retinal degeneration. Umbilical cord CD133 stem cells or bone marrow stem cells can differentiate into RPEs when transplanted into the retina. While this paper does not address whether or not such differentiation occurs in human patients, such results definitely warrant Phase I studies. Thus once again, embryonic stem cells seem not be necessary.