Retinal degenerative diseases are a leading cause of irreversible blindness. Δ Cell replacement therapies show promise in restoring lost vision, but some hurdles remain in restoring visual circuitry in the retina and central connections in the brain. Δ
Forty million people are blind worldwide, a staggering statistic. Retinal cell death is the main cause of vision loss in genetic disorders such as retinitis pigmentosa, Stargardt disease, and Leber congenital amaurosis, as well as in complex age-related diseases such as age-related macular degeneration. Δ
For these blinding conditions, gene and cell therapy approaches offer therapeutic intervention at various disease stages. Broken down, 56% are affected by cataracts and uncorrected refractive errors, which can be handled easily with the available medical care. Δ
Other diseases, however, involve degenerative processes such as age-related macular degeneration (AMD) and pediatric blindness that are challenging because of the genetic causes. Δ
Great strides have been made in identifying the offending genes, with 300 genes having been identified in association with the death of photoreceptors, retinal ganglion cells, or neurons in the retina, according to Paul A. Sieving, MD, PhD, professor of ophthalmology and founding director, Center for Ocular Regenerative Therapy, University of California Davis School of Medicine, Davis, CA, and previous director, National Eye Institute (NEI).
“Many of these conditions could be addressed with regenerative therapies,” Dr. Sieving said. He predicted that the next two decades will see the emergence of potential treatments that can improve or restore vision, in contrast to the current treatments, i.e., intravitreal injections, laser photocoagulation, cryotherapy, and vitrectomy, that slow or ameliorate the disease process.
Medicine is adopting a new focus. Δ Physicians now are beginning to think initially about possible genetic factors involved in diseases. The next step, according to Dr. Sieving, is to further develop the understanding of disease mechanisms at the cellular/tissue level. Δ
This will bring physicians to the level of patientspecific clinical input to characterize the stage of disease progression for individual patients, he explained. Intervention is subdivided into before cell loss with pharmacotherapy and gene therapies and during/ after cell loss with restorative or replacement cell therapy and retinal prosthetics. Δ
Therapeutics at both ends of the spectrum include the new rho kinase inhibitors for glaucoma, latanoprostene bunod ophthalmic solution 0.024% (Vyzulta, Bausch + Lomb) and netarsudil ophthalmic solution 0.02% (Rhopressa, Aerie Pharmaceuticals), comparison of anti-vascular endothelial growth factor drugs for AMD, and a retinal prosthesis (Argus II, Second Sight). Δ
TheΔ NEI adopted the ambitious project, the Audacious Goals Initiative (AGI) for Regenerative Medicine, in 2013, with the specific goal of regenerating neurons and neural connections in the eye and visual system—“all ideas that were beyond the current reach of our science and technology,” Dr. Sieving said. Δ
This goal was immediately applicable to the loss of photoreceptor and retinal ganglion cells. “The AGI is a 10- to 15-year effort to catalyze innovation and advance vision research to develop cells suitable for transfer to the retina, especially cells from the neuroprogenitor cell lines,” he said. Δ
“This will be done through the difficult processes of cell transplantation and cell integration into the host retina. Δ” There is a three-fold strategy to accomplish this that includes development of functional imaging technologies to explore cell function, identify novel neural regeneration factors that support the environment when cells are transplanted, and generate translation-enabling animal models that are appropriate for human disease and have ocular structures similar to humans.
Regarding the last, most recently nine awards have been funded, seven of which are for work with non-human primate models. Adaptive optics is a technology that facilitates imaging of single retinal neurons.
The technology allows evaluation of structural relationships between, for example, the photoreceptor cells and retinal pigment epithelium (RPE) or the movement of red blood cell flow through the capillaries, Dr. Sieving explained. Δ Δ
“The new imaging under development by the AGI will look at the function of those cells to evaluate metabolic activity using highly selective wavelengths to stimulate specific molecules in the retinoid cycle of the visual pigments,” Dr. Sieving said. Δ “This will bring us closer to imaging actual cell dysfunction during disease progression and allow a closer look at therapeutic rescue.” Δ
The most recent newly funded trials include, for example, a single-center study to assess the safety and feasibility of cultivated autologous limbal epithelial cell transplantation for treating limbal stem cell deficiency conducted by Ula Jurkunas, MD, at Massachusetts Eye and Ear, Boston; a phase I/II randomized, prospective cross-over study of intravitreal autologous bone marrow CD34+ stem cell therapy for retinal vein occlusion conducted by Susanna Park, MD, PhD, at the University of California Davis; and induced pluripotent stem cell (iPSC)-derived RPE transplantation for dry AMD conducted by Kapil Bharti, PhD, at the NEI Intramural Research Program. Δ
These studies are harvesting cells with stem cell-like properties to be used as human therapies. In addition to the research supported by the NEI, Congress in 2016 established the 21stCentury Cures Act that funded the National Institutes of Health (NIH) Regenerative Medicine Innovation Project (RMIP) with the stated goal of accelerating the regenerative medicine field by supporting clinical research on adult stem cells, including autologous stem cells.
This act mandated coordination between the NIH and FDA to push forward the field of regenerative medicine. The NIH has granted an award to study ABCB5+ stem cells for limbal stem cell deficiency to Markus Frank, MD at Boston Children’s Hospital. Δ
The RMIP also funded preclinical research that include study of precision genome surgery in autologous stem cell transplant to Stephen Tsang, MD, PhD, at Columbia University; preclinical testing of iPSC-derived RPE to treat macular degeneration to Alan Marmorstein, PhD, at Mayo Clinic Rochester; and transplantation of adult, tissue-specific RPE stem cells as therapy for non-exudative AMD to Jeff Stern, MD, PhD, at the Regenerative Research Foundation. In addition to these, numerous studies are under way that are investigating RPE cell therapy for wet and dry AMD, Stargardt’s disease, retinitis pigmentosa, RPE tears, and Best disease, Dr. Sieving pointed out.
Dr. Sieving added that this area of research comes with high rewards as well as high risks. “There are major challenges ahead and risks for developing translational cell therapies,” he said.
“This includes the possibility of cell proliferation and tumor formation, identification of these cells as foreign by the patients’ immune system and subsequent elimination of the cells, or transfer of a deleterious genetic mutation by the transplants themselves.”
These potential problems necessitate careful screening of the cells for a normal gene complement.
In addition to the 40 million people who are blind worldwide, 285 million are visually impaired. The eye is especially well suited to gene therapy because it is a small compartment that facilitates targeted delivery of drugs, a small amount of vector is required, and there is a low risk of systemic toxicity.
In addition, numerous animal models already have been established. Voretigene neparvovec-rzyl (Luxterna, Novartis), is the first FDA-approved ocular gene therapy that is indicated for Leber congenital amaurosis and one of the first ever human diseases Dr. Sieving noted, to be treated by in vivo gene therapy. “As ophthalmologists, we can now literally provide sight for the blind,” he noted.
There currently are more than 45 ongoing ocular gene therapy trials for inherited retinal dystrophies and new trial for AMD, making for an energetic clinical trial landscape, he said and explained that positive outcomes will be the basis for further advances.
Dr. Sieving is currently working on retinoschisis gene therapy; this genetic X-linked recessive disease affects 8,000 to 12,000 males in the United States. In this study, an AAV serotype 8 vector carrying the human RS1 gene, Thus far, 12 patients have been treated and the investigators have observed “a preliminarily potentially positive signal” indicating that the vector has entered the retina and closing the schisis cavities in one participant.
The still unanswered questions about gene therapy are inflammation and immune rejection, efficacy, best modes of vector delivery, and the durability of the effect. According to Dr. Sieving, the future is bright for regenerative therapies for ocular disease.
Clinicians expect some therapies to enter the clinic in the next 10 to 20 years. “Our field is rich in innovation in ophthalmology and vision science, that is, visual cortical prostheses, nano-medicine, tissue engineering, drug and gene delivery systems, clinical endpoints, artificial intelligence, and disease modeling at the cellular level, and new clinical endpoints such as functional cellular imaging of retinal neurons,” he concluded.