Stem cell therapy appears safe in advanced AMD, but questions remain
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Stem cell therapy still has many hurdles to clear before becoming a viable therapeutic option for age-related macular degeneration, but it may have the potential to transform treatment in the future.
“Overall, we have a huge problem with a major unmet need,” Rajesh C. Rao, MD, Leonard G. Miller Professor of Ophthalmology and Visual Sciences and associate professor in the departments of ophthalmology and visual sciences, pathology and human genetics at the University of Michigan and director of retina service at the VA Ann Arbor Healthcare System, told Healio. “We don’t have a treatment that really restores vision at the advanced stages of macular degeneration, so regenerative medicine is exciting for this area.”
Specifically, regenerative medicine, including stem cell therapy, has considerable appeal for a condition such as AMD in which cell types — in this case, photoreceptors and retinal pigment epithelium (RPE) — die and do not regenerate, according to Rao.
“The only time those cells grow is during the development phase and one way to grow more is when you capture this phase of development in the dish using stem cell technology,” Rao said.
At present, significantly more research is necessary before stem cell therapy would be ready for prime time, but early data from studies examining different ways of developing and implanting these cells in patients with ophthalmic conditions have demonstrated the safety of certain strategies.
“A lot needs to be worked out. The approaches [to stem cell therapy] are getting better, and I’m hopeful that one day, we’re going to have a cell-based therapy that is going to arrest the progression of AMD or hopefully improve vision in these patients because they desperately need something,” Rao said.
In this first part of a two-part series on stem cell therapy for AMD, Healio explores the evolution of the treatment for ocular diseases and the current state of research in the field.
Evolution of ocular stem cell therapy
Despite the promise of stem cells, some strategies have resulted in severe complications for patients. For instance, Rao said, one approach that involves isolating “stem cells” from fat has proven particularly harmful.
“In this process, individuals may undergo liposuction, and cells from the fat are then fractionated, treated and injected into the eyes,” Rao said. “This has led to pretty devastating outcomes, including bad retinal detachment and scarring with proliferative vitreoretinopathy.”
In a case series published in The New England Journal of Medicine in 2017, researchers reported on severe visual loss associated with ocular hypertension, hemorrhagic retinopathy, vitreous hemorrhage, combined traction and rhegmatogenous retinal detachment, or lens dislocation in three patients who underwent intravitreal injection with autologous adipose tissue-derived “stem cells.”
One problem with this approach, Rao said, is that it is not well understood which stem cells existing in fat are meaningful for the eye because the retina does not have frank fat tissue. Despite this concern, the regulations are looser for this type of procedure.
“This process is technically legal, but they do not have to go through the many steps for FDA approval because it is a so-called homologous use in which you are taking one tissue from one part of your body and putting it in another part of your body,” Rao said. “Some of the rationale for that over the years has been for other types of surgery, such as breast cancer reconstruction where you are taking fat from one part of the body and reconstructing the breast, but of course, in both those areas, fat tissues exist. It is a harder sell to say that for the retina.”
However, other strategies, such as those involving pluripotent stem cells, have shown promise in several studies. For this approach, researchers differentiate either embryo-derived pluripotent cells or adult cells that have been reprogrammed back into the embryonic stage, also known as induced pluripotent stem cells (iPSCs), into photoreceptors or RPE.
Additionally, researchers, including Rao and colleagues, are exploring an approach that involves collecting adult retinal cells from cadaver eyes, treating the cells so they return to a single-cell stage and allowing them to reproliferate before implanting them.
“A lot of these approaches are supported scientifically by peer-reviewed publications,” Rao said. “They have also gone through the FDA investigational new drug application process, unlike those approaches using adipose-derived stem cells.”
Encouraging safety data
As the field has evolved, stem cell therapy has taken several forms, according to Rao. One involves injecting the cells beneath the retina, whereas the other involves placing the cells on a biomimetic construct to achieve the geometry and architecture that exist on a flat surface.
With both approaches, however, two major concerns have emerged: regulation of a patient’s immune response to the treatment and the potential for introducing mutations into cell lines that may result in tumors or cancers. Nevertheless, early data have yet to bear out these safety signals, according to Rao.
“Both of those approaches have been evaluated in clinical trials, and so far, it appears that they are generally safe,” Rao said.
For instance, results from two open-label phase 1/2 studies in which patients were treated with suspensions of stem cells, published in The Lancet in 2015, were promising.
“Our results show that [human embryonic stem cell]-derived cells were well tolerated for up to 37 months after transplantation in individuals with atrophic AMD and Stargardt’s macular dystrophy. So far, in the two clinical trials, there were no serious adverse safety signals attributed to the transplanted cells. Potential safety concerns about the use of [human embryonic stem cells] in people, including the possibility of teratoma formation, immune reactions and the risk of cells differentiating into unwanted ectopic cell types, were not noted. According to literature reports, teratoma formation was expected to arise within the first few months after transplantation, but this was not the case in our patients who have been followed up for a median of 22 months,” the researchers wrote.
“To the best of our knowledge, this is the first report of the results of medium-term to long-term safety and tolerability after transplantation of cells derived from pluripotent stem cells in individuals with any disease.”
Similarly, a brief report published in NEJM in 2017 showed that the vision of one patient with neovascular AMD stabilized 1 year after undergoing stem cell therapy. In this case, the patient underwent implantation with a sheet of RPE differentiated from iPSCs generated from the patient’s skin.
“At 1 year after surgery, the transplanted sheet remained intact, best corrected visual acuity had not improved or worsened, and cystoid macular edema was present,” the researchers wrote, although they cautioned against broader extrapolation of their results.
Rao acknowledged that the procedure itself carries risks, especially when it involves implantation of a large bioengineered interface underneath the macula, as this requires large incisions and introduces the potential for bleeding and scarring. However, these issues are part of the learning curve accompanying any new procedure.
“As surgeons become more experienced with these techniques, those kinds of outcomes are less and less,” Rao said.
A question of efficacy
Despite the positive safety data, questions about the benefits of stem cell therapy in AMD exist, according to Rao.
Specifically, studies have yet to show that stem cell therapy actually improves vision in AMD. However, Rao said that the phase 1 trials investigating these treatments are unlikely to demonstrate that type of outcome due to their design and intent.
“The field hasn’t yet seen a huge breakthrough in these transplants being meaningful for vision change. That being said, the trials are not powered for large numbers of patients, as a phase 3 trial would be, to see if these approaches might improve vision,” Rao said.
Moreover, the patient population included in these trials may have complicated the ability to demonstrate the treatment’s benefits, according to Rao.
“When you do a phase 1 trial, you’re testing for safety: Is the surgical procedure safe? Are the cells safe?” Rao said. “That means a lot of the patients who initially received those treatments had advanced disease, and some may make the argument that it might be unlikely to ever see improvement when these patients were so far down the road of damage. And that’s where a lot of these trials start.”
Furthermore, researchers are playing catch-up in terms of how best to assess the overall integration of stem cells after implantation in patients with ocular diseases, according to Rao.
“When you inject pigmented cells like RPE underneath the retina, you may see pigment. The question is, does that pigment mean the cells are engrafting properly?” Rao said. “You can use OCT, which can pick up pigment, but it’s hard to know whether the cells as they’re injected are integrating and reconnecting the host photoreceptors with the transplanted RPE.”
In this case, Rao said, general ways of assessing improvement, such as visual acuity, may not be sensitive enough to determine whether the cells achieved proper engraftment or perhaps did but not to the extent that they can restore function.
“Everyone is hoping that you put the cells in and achieve a big improvement in vision and then perhaps don’t have to worry about the fine anatomic details about whether the cells plugged back into the network. But that’s probably a really high bar to pass right now. ... Imaging and testing of function are open questions, and there have to be ways to improve on those things,” Rao said.
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Healio Interviews
References:
- Kuriyan AE, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1609583.
- Mandai M, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1608368.
- Schwartz SD, et al. Lancet. 2015;doi:10.1016/S0140-6736(14)61376-3.
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