Investigating Cell Therapy for Advanced Atrophic Macular Degeneration
There is currently no proven effective treatment for the advanced form of dry, or atrophic, age-related macular degeneration (AMD). Geographic atrophy (GA) in the central macula is expected to affect 3.8 million adults by the year 2050.1 While there are ongoing studies of pharmaceutical agents targeting neurotrophic factors, visual cycle modulation, or various points along the complement or inflammatory cascade that may slow the progression of early non-exudative AMD to GA,2 advanced GA is characterized by retinal neuron loss. Thus, surgical approaches with cell-based therapy are under investigation for the treatment of GA.3
There are two main approaches with regards to cell-based therapy for retinal disease that require implantation of cells in the subretinal space: regenerative and trophic. The regenerative approach is a strategy that utilizes embryonic-derived stem cells. These human cells are differentiated to human retinal pigment epithelial (RPE) cells and offer a replacement for RPE cells lost in diseases such as GA and Stargardt disease.4 In a trophic-based approach, undifferentiated human umbilical tissue-derived cells (hUTC) offer a means to support degenerating cells with paracrine effects from the transplanted cells through the release of various cytokines and potentially with cell-to-cell interactions. This report will outline these two main approaches that are currently in phase I/II trials in humans.
The regenerative strategy has a long history of preclinical animal work. Various studies have demonstrated the proof of concept, while other studies have brought attention to important considerations, such as immunologic graft rejection or graft survival depending upon which type of stem cell line was utilized. A particular advance came with the purification of a human embryonic stem cell (hESC) line by Ocata (formerly, Advanced Cell Technology; Marlborough, MA). The hESC line offers advantages over other stem cell lines in that the hESC line can be differentiated to provide theoretically unlimited amounts of RPE cells for implantation. The particular hESC line was derived from an excess embryo that was originally intended for in vitro fertilization reproductive use. The embryo was donated under informed consent for use in research.
The Ocata approach involves transvitreal implantation of hESC-derived RPE cells. The surgical procedure includes a standard 23- or 25-gauge pars plana vitrectomy with induction of a posterior vitreous detachment. A 41-gauge subretinal cannula is used to create a localized neurosensory retinal detachment adjacent to the site of GA with balanced salt solution. Following the creation of a subretinal “bleb,” a 38-gauge subretinal cannula is utilized to deliver the hESC-derived RPE cells. The current trial is a dose escalation safety trial where 50,000 to 200,000 hESC-derived RPE cells in a 150μl volume are delivered to the subretinal space. Following inspection of the peripheral retina, a fluid-air exchange is performed. The patient is then held in the supine position for 4 to 6 hours. Unique to this protocol is the use of systemic immune suppression as an adjunct to the protocol. The perioperative immune suppression consists of mycophenolate (Cellcept) and tacrolimus (Prograf) starting 1 week prior to surgery, with both agents continued until the sixth postoperative week. Mycophenolate is continued for 6 additional weeks with no immunosuppression thereafter. Future trials may refine this regimen.
There have been multiple trophic-based strategies that have shown efficacy in cell-based therapy;3 the approach with hUTC has been evaluated in the Royal College of Surgeons rat model of retinal dystrophy and has been found to rescue degenerating photoreceptors better than other cell lines (placenta-derived cells, mesenchymal stem cells, and dermal fibroblasts).6 The current surgical trial for GA utilizes non-stem cell human umbilical cord-derived mesenchymal cells developed by Janssen (Titusville, NJ), a division of Johnson & Johnson, and is a dose-escalating safety and feasibility study.
The current surgical technique entails a trans-scleral microcatheter-based delivery of hUTC to the subretinal space adjacent to the region of GA. Following a limited conjunctival dissection with surface cautery, a scleral cut-down is performed with a beaver blade approximately 9 mm posterior to the limbus. The sclera is then retracted with a specialized scleral speculum that is sutured in place to allow for the eventual advancement of a 250-micron subretinal microcatheter (iScience Interventional, Menlo Park, CA). Following choroidal perforation, a subretinal bleb is created with Healon under direct visualization endoscopically (Endo Optiks, Little Silver, NJ). The microcatheter is then advanced through this opening in the subretinal space posteriorly. The catheter has an illuminated tip to allow for precise localization (adjacent to the region of GA) under the view of the endoscope. A high precision pump is then used to inject the hUTC into the subretinal space. The catheter is carefully withdrawn and all sclerotomies are closed with standard techniques. This surgical approach is in evolution since some patients developed retinal tears and detachments.
Immunosuppression is not necessary for the survival of this particular cell line. Another key point is that a trans-scleral approach for stem cell implantation is necessary with the hUTC line. Preclinical investigations found a higher rate of preretinal membrane formation when a transvitreal approach was used; thus, a trans-scleral approach is preferred.
Current Status and Future Directions
At this time, there is no proof that cell therapy works for atrophic AMD. Preliminary and early human clinical trial results from Janssen and Ocata demonstrate that these distinct cell lines are tolerated in the subretinal space. While preliminary results from both clinical trials suggest that there may be improvement in visual acuity, these data must be interpreted with caution since there may be intervention and ascertainment biases, and there were no randomized control subjects. Other cell therapy lines and approaches are also being explored. One group, Regenerative Patch Technologies Inc. (Glendale, CA), employs human embryonic-derived RPE cells, but places these cells on a synthetic membrane as a transplant patch; preliminary animal studies show promise and human testing is forthcoming.
Reference(s):1. Rein DB, Wittenborn JS, Zhang X, et al. Forecasting age-related macular degeneration through the year 2050: the potential impact of new treatments. Arch Ophthalmol. 2009;127:533-540. 2. Meleth AD, Wong WT, Chew EY. Treatment for atrophic macular degeneration. Curr Opin Ophthalmol. 2011;22:190-193. 3. Tibbetts MD, Samuel MA, Chang TS, Ho AC. Stem cell therapy for retinal disease. Curr Opin Ophthalmol. 2012;23:226-234. 4. Schwartz SD, Hubschman JP, Heilwell G, et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet. 2012;379:713-720. 5. Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow up of two open-label phase 1/2 studies. Lancet. 2015;385:509-516. 6. Lund RD, Wang S, Lu B, et al. Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease. Stem Cells. 2007;25:602-611.
About our author(s):
Allen C. Ho, MD
Professor of Ophthalmology, Thomas Jefferson University
Director of Retina Research, Wills Eye Hospital