For example, it is possible to target damaged cones without outer segments but with remaining cone tips by initiating photoreceptor hyperpolarization using halorhodopsin. 60,61,64 This will result in phototransduction by using the remaining cellular architecture. Alternatively, when photoreceptors are damaged, it is possible to apply optogenetics to retinal bipolar cells using ChR 59,65 and human rhodopsin. 62 When more significant retinal damage has occurred, one may target retinal ganglion cells (RGCs) with ChR 66–70 and/or melanopsin. 71 Yet another alternative is to use synthetic molecules that change confirmation under bright light, collectively known as chemical photoswitches. 72 Generally, these synthetic molecules contain light-activated azobenzene moieties. When introduced to a cell, they bind to plasma membrane channels and confer the ability for light activation. The aforementioned approaches are only a subset of the vast work being performed in vivo and in vitro in this area.
Although significant progress is being made with in this field, there are currently five companies with optogenetic product candidates under investigation for human visual restoration: 1) Retrosense therapeutics (Ann Arbor, MI), which was recently purchased by Allergan, 2) GenSight Biologics (Paris, France) in collaboration with Pixium Vision (Paris, France), 3) Applied Genetic Technologies Corporation (AGTC) (Alachua, FL) in collaboration with Bionic Sight, 4) Acucela Inc (Seattle, WA), and 5) LambdaVision (Hartford, CT).
Retrosense Therapeutics has created an AAV-2–based vector encoding the Type 1 opsin channelrhodopsin-2 (ChR2) for RGC transduction (RST-001) through intravitreal injection. Retrosense acquired the patent rights for this technology, developed at both Wayne State and Salus Universities. 74 In 2014, RST-001 received an Orphan Drug Designation by the FDA for the treatment of retinitis pigmentosa (RP) and is currently undergoing a Phase I/IIa, open-label, Dose-Escalation Study of Safety and Tolerability of Uniocular Intravitreal RST-001 in patients with RP (https://clinicaltrials.gov/ct2/show/NCT02556736). In 2016, Retrosense Therapeutics was acquired by Allergan and plans to expand the therapeutic scope of RST-001 to include dry AMD as a follow-on indication.
GenSight biologics has created a therapeutic agent (GS030) comprising a modified AAV-2 viral vector with a peptide on its heparin-binding site 59 (AAV2 7m8). The vector transduces RGCs with a modified ChR called ChrimsonR-tdTomato (ChrR-tdT), derived from the algal light-gated cation channel ChrimsonR (Ed Boyden, MIT). 59 Although there are many ChR variants, ChrR-tdT is a new red-light drivable channelrhodopsin with an absorption spectrum 45 nm more red-shifted than any previous ChR. Red-shifting the opsin absorption spectrum allows for theoretical greater safety (long as opposed to short wavelength light) and decreased remnant photoreceptor cross-talk. Gensight has been able to transduce RGCs efficiently and safely with GS030 in vivo macaque retinas after intravitreal administration. 57 Along with a light stimulation device provided by Pixium Vision, light responses through opsin-transduced RGCs were induced in normal monkey retinas under pharmacological block of endogenous phototransduction, suggesting that the combination of light-stimulating goggles and optogenetics is a viable method for treating retinal dystrophic diseases.
Applied Genetic Technologies Corporation (AGTC) (Alachua, FL) is currently developing an additional combinational optogenetic approach in collaboration with Bionic Sight. By using an AAV delivery system in concert with a neuroprosthetic “retinal code decipherer” developed by Bionic Sight, 75 this group aims to optogenetically endow the retina with opsins and stimulate the transduced cells with patterns of light that are visually meaningful. AGTC is currently seeking investigational new drug approval for this combinational approach, and further details are pending at this time.
Acucela Inc, a Kubota Pharmaceutical company, has also developed an optogenetic approach for the treatment of RP. Similar to the approaches of Retrosense and Gensight, Acucela will use an AAV-2 viral vector. Unlike the above approaches that use modified ChRs, Acucela's vector will transduce retinal ON bipolar cells with human rhodopsin (hRho). 57 Acucela believes that targeting cells upstream to RGCs will provide superior signal quality and amplification, perhaps with lower light levels, and possibly without the need for external light-emitting devices. Given that rhodopsin is an endogenous protein native to the human retina, there is a theoretically lower risk of immunologic reaction. Acucela is currently in preclinical testing, with estimated proof of concept in 2019.
There are also several groups approaching various forms of optogenetically endowed sheets, polymers, or prosthetics, 76,77 including LambdaVision, Inc, which has developed a protein-based subretinal implant coated with bacteriorhodopsin (a light-activated proton pump). This allows for the creation of an ion gradient that is used to stimulate the bipolar and ganglion cells. The flexible implant consists of multiple layers of oriented bacteriorhodopsin that are between two ion-permeable membranes. Preclinical trials are currently underway.
An additional approach to restoring sight is based on introduction of visual information by patterned electrical stimulation of the remaining inner retinal neurons. In the setting of retinal degeneration, inner retinal neurons and RGCs survive retinal degeneration to a large extent, providing a pathway for reintroducing information into the visual system. Cells can be polarized in an electric field, causing the opening of the voltage-sensitive ion channels on the depolarized side of the cell. This increases the cell potential as a whole and can result in generation of an action potential in spiking neurons.
Retinal implants are usually classified based on their anatomical placement as epiretinal, subretinal, and suprachoroidal (Figure 8). In an epiretinal approach, a stimulating array is placed on top of the retinal surface and typically stimulates RGCs. 78 Epiretinal arrays can be implanted with relative ease and can also be removed in case of postsurgical complications or device failure. The ultimate goal of direct RGC stimulation is to emulate the natural retinal code. 79 Rapid (1–3 ms) response of the RGCs to electrical stimulation with a single action potential enables precise control of the elicited spike sequence. However, because different types of RGCs respond to different aspects of the image (light intensity, direction of motion, etc.), they require different codes. Identification and selective activation of cell types in the diseased retina pose great challenges. In particular, epiretinal electrodes stimulate not only the nearby cells, but also the axons from distant cells passing through the adjacent nerve fiber layer (Figure 8). Consequently, patients may report distorted arcuate visual percepts instead of round localized spots of light. 80
In a subretinal implant, electrodes are located underneath the inner nuclear layer and replace the degenerated photoreceptors (Figure 8B). 81 Graded responses induced in the inner retinal neurons by electrical stimulation are transmitted through the retinal network to the RGCs, which convert them into trains of action potentials. In this fashion, the retinal signal process is partially preserved, and encoding of visual information by the subretinal implant is simplified. Preserved features include flicker fusion at high frequencies, 82 antagonistic center-surround organization 83 and nonlinear summation of subunits in receptive fields, 82 as well as ON and OFF responses. 84 Another theoretical advantage of the subretinal placement is that it provides close and stable proximity of electrodes to the target neurons. However, implantation in the subretinal space can be more difficult than the epiretinal approach, and removal of the implant is also more challenging.
With the suprachoroidal approach, the implant is placed between the choroid and the sclera (Figure 8B). Such implants are designed to help with low-resolution peripheral vision, 85 which cannot be easily attained with the other approaches. However, the larger distance between stimulating electrodes and retinal neurons restricts attainable spatial resolution.
A further distinction is the way information and power are delivered to the implant (1–3).
Clinically tested retinal implants represent an important proof of concept that sight can be restored even after decades of profound blindness because of retinal degeneration, albeit currently with rather low resolution. Significant research efforts are under way to increase the number of pixels in implants to thousands, to improve the localization of electric stimulation for high-resolution interfaces, and to better encode neural activity. Continuous progress in 3-dimensional electroneural interfaces, novel materials, and image processing will help advance the field of prosthetic vision toward functional restoration of sight in patients suffering from retinal degeneration.
Although the aforementioned technologies have been frequently labeled as buzzwords in medicine and ophthalmology as a whole, the field of retina is making tangible advancements in using them in clinical practice. For example, gene-based therapies and retinal prosthetic devices have both found use in properly selected, albeit thus far limited, patient populations. However, when compared with the development of small molecules and macromolecules by large-scale biopharmaceutical companies, the technologies discussed herein present unique challenges to the health care ecosystem in regard to regulation, reimbursement, and realization of value. 91 Despite this, the future is promising. The reimbursement road is complex, and accommodating such seminal technologies may require new payment models. Hopefully, economies of scale will eventually reduce the cost burden.
In addition to the scientific and clinical challenges presented by stem cell therapy, effective solutions in the emergent field of stem cell therapy for the retina must address unique regulatory challenges. First of all, the structure, composition, potency, and purity of cell-based therapies are complex and difficult to measure. In addition, many cell-based therapies are developed by smaller pharmaceutical companies that often do not have the resources or scope to perform large, controlled, and appropriately powered clinical trials. 91 As opposed to drugs, stem cell–based therapies may also continue to reside in the patient in perpetuity. Finally, close regulatory oversight is necessary to prevent patient harm and ensure only proven therapies are offered.
To address these regulatory challenges, the FDA Commissioner Scott Gottlieb, MD, released a comprehensive new policy to facilitate the development of innovative regenerative medicine products on November 17, 2018. This policy by the FDA's Center for Biologics Evaluation and Research (CBER) (https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ucm537670.htm) attempts to strike a balance between enhancing the approval of promising technologies while simultaneously limiting the involvement of unscrupulous individuals or companies preying on desperate patients. Essentially, the regenerative medicine advanced therapy (RMAT) designation provides all the benefits of fast-track and breakthrough therapy designations, with the additional bonus of early interactions to guide the creation and satisfaction of intermediate and surrogate endpoints. So far, no offering has passed through the FDA with the RMAT designation, 92 but the CBER (which also manages gene-based therapies) has approved 16 therapies to date. 93 Although several offerings are in the pipeline as discussed above, there is currently no FDA-approved stem cell–based therapy for ophthalmology.
Regarding gene-based therapies, the voretigene neparvovec-rzyl (Luxturna) approval was expedited by several designations such as with priority review, orphan drug, and breakthrough therapy. 95 Now approved, Luxturna is currently the most expensive “drug” ever introduced in the United States, at a total cost of $850,000 to treat both eyes. Although its cost is high, it is interesting to note that the physician reimbursement for this time-consuming procedure is not modified or unique. Insurance companies (depending on the plan) may cover a significant amount of the expense for the patient, but there is very likely a large sum that reduces one's deductible or out-of-pocket maximum. The Centers for Medicare and Medicaid Services (CMS) will provide a large share of reimbursement and will set the example for how current and future gene-based therapies will be reimbursed. Spark Therapeutics is working on several solutions to this problem 96 for Luxturna including 1) rebate programs based on effectiveness at set time intervals, 2) working with CMS on eliminating the base Medicaid drug rebate, and 3) allowing for installment payment plan reimbursement. They are also working directly with commercial payers and specialty pharmacies to negotiate payment while leaving those parties to separately negotiate with treatment centers for reimbursement. Large pharmaceutical companies are surely monitoring the negotiations of new payment models by this relatively small company with a first-of-its-kind commercial product and will likely base their strategies on its success or failure. In addition, the regulatory and reimbursement issues for optogenetic therapies will most likely parallel those of gene-based therapies at large.
The only currently FDA-approved retinal prosthetic device is the Argus II Retinal Prostheses (which also carries a CE mark). Despite its relatively limited patient application when compared with drugs (implantation in more than 200 patients 86 to date, including 75 implantations in 2017 97 ), the Argus II is a technological tour de force. The device is reliable and stable, with no reported device failures within 3 years after implantation 86 (a total of 88.2 subject-years). The device and company paved the way forward not only scientifically and regarding the clinical application of retinal prosthetic devices, but also from a regulatory and reimbursement perspective. The insertion of the device is associated with its own current procedural terminology code, with further codes available for device tuning and maintenance. Second sight is currently enrolling patients in a clinical trial for the implantation of a cortical visual prosthetic device called Orion I (NCT03344848), which may serve as another groundbreaking advancement in our field.
Figures designed by E. H. Wood and S. Muscat.
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