Cell-Based Therapies

1. Cell-Based Therapies

Cell-based therapies utilize stem cells to replace or restore dysfunctional retinal cells, often with trophic factors to support cell survival and growth^[1]. Pluripotent stem cells, such as induced pluripotent stem cells (iPSCs), hold promise for retinal diseases as they can differentiate into retinal pigment epithelium (RPE) cells that support photoreceptor function. iPSC-derived RPE cell replacement shows potential in delaying disease progression and restoring vision loss in cases where the RPE layer is damaged^[2].

Bone marrow stem cells (BMSCs), including mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), are extracted from the bone marrow. While BMSCs have more limited differentiation capacity compared to pluripotent stem cells, they can generate tissue-specific cells. Notably, BMSCs possess the ability to transdifferentiate and migrate towards lesion sites [97]. While full differentiation into photoreceptors has not been confirmed, recent preclinical studies demonstrate their release of beneficial factors, including anti-angiogenic and neurotrophic factors, insulin-like growth factor-1 (IGF-1), Th2-related cytokines, and the class II major histocompatibility complex (MHC II)^[3].

Damage to the RPE layer can lead to vision loss, making stem-cell-derived RPE an intriguing treatment option for retinal diseases. RPE offers trophic support to remaining photoreceptors and its well-known morphology and physiology make it a suitable candidate for stem cell therapies. The eye's immune privilege and favorable microenvironment further enhance the feasibility of stem cell therapies^[4][5]. Co-transplantation of fetal RPE and mesenchymal stem cells (MSCs) in mice demonstrated improved electroretinograms (ERGs), increased rhodopsin levels, decreased caspase-3 expression, and enhanced survival of transplanted cells. Coculture transplantation outperformed single-cell transplantation, presenting opportunities for advancing retinal disease treatments^[6].

Stem-cell-based therapies hold potential for treating retinal diseases associated with RPE dysfunction and loss, such as age-related macular degeneration (AMD) and Stargardt's macular dystrophy (SMD). While safety of stem-cell-derived RPE transplantation has been confirmed, further investigation is needed to assess visual outcomes. Optimal timing of RPE transplantation, occurring after RPE dysfunction but before photoreceptor injury, is crucial for preserving photoreceptor function. However, systemic immunosuppression required for stem-cell-based therapies may limit their use in patients with comorbidities, reducing the pool of eligible candidates^[5].

Retinal progenitor cells (RPCs) derived from developing human fetal neural retina show promise as another type of stem cell. RPCs express photoreceptor markers and have the ability to secrete trophic factors, supporting retinal survival and potentially enabling photoreceptor replacement^[7][8][9]. Preclinical studies demonstrate the regenerative potential of stem cells, as they can differentiate RPCs into photoreceptors and establish functional synapses with the host, potentially stabilizing or reversing vision loss.

An example of successful vision restoration through stem-cell-based implants is the "California Project to Cure Blindness Retinal Pigment Epithelium" (CPCB-PRE1), where a monolayer of human embryonic stem cell-derived RPE cultured on a Bruch's membrane-mimicking media improved vision and slowed progressive vision loss in a phase I/IIa clinical study^[10][11][12].

Gene-Based Therapies

2. Gene-Based Therapies

Gene therapy has emerged as a promising approach for addressing retinal diseases caused by genetic mutations, such as retinitis pigmentosa (RP). With its ability to target the root cause of the disease, gene therapy holds the potential to restore vision in affected individuals. The specific approach employed depends on whether the inherited retinal disease stems from a recessive or dominant genetic mutation.

For recessive mutations, a gene complementation approach is typically utilized, while dominant mutations are preferably addressed through gene suppression, with or without gene complementation. To enable gene therapy, scientists have developed various techniques, including the use of viral and non-viral vectors, as well as CRISPR-Cas9 gene editing. These techniques allow for targeted delivery and the expression of corrective genes within the retina^[13].

Viral vectors utilized in gene therapy can be categorized into three subtypes: adenovirus (Ad), adeno-associated virus (AAV), and lentivirus (LV). Among these, AAV has garnered significant attention for treating inherited retinal diseases due to its small size (25 nm), enabling efficient targeting of the retinal layers. Additionally, AAV exhibits low immunogenicity, making it a favorable candidate for long-acting treatments^[14]. However, due to its limited capacity to accommodate large genomes (packaging capacity of 4.7 kb), AAV is primarily used to treat recessive diseases such as Stargardt's disease^[14].

Non-viral vectors have also been explored for gene delivery due to their reduced risk of immune responses and their ability to deliver larger genes compared to viral vectors. However, unlike viral vectors, non-viral vectors have not yet demonstrated efficient delivery of genetic material into cells, primarily due to the lack of efficient mechanisms for nucleus entry^[15].

The gene-editing system known as CRISPR-Cas9 has emerged as a valuable tool for gene expression and suppression. It has shown promise in silencing dominant mutations using the non-homologous end-joining pathway in inherited retinal diseases. However, the success of CRISPR-Cas9 is highly dependent on factors such as guide RNA design, the type of target cell, the choice between viral or non-viral vectors, and host-related considerations^[16].

Currently, the only approved gene therapy for treating a retinal disease is Luxturna, which targets the RPE65 gene and utilizes an AAV vector to treat Leber Congenital Amaurosis type 2 (LCA2). LCA2 is a suitable candidate for gene therapy as it involves an enzyme expressed in the RPE layer, which is more accessible for AAV targeting compared to the photoreceptor layer. However, most other inherited retinal diseases involve gene transfer to the photoreceptor layer, posing a challenge for gene therapy^[15].

Despite the potential of gene therapy for treating inherited retinal diseases, its practical application is complicated by the wide variety of gene mutations causing these conditions. A comprehensive understanding of pathogenesis is necessary, and further research is required to assess the long-term outcomes and safety of this therapy^[17].

Optogenetics

3. Optogenetics

Optogenetics has emerged as a new approach for treating inherited retinal diseases (IRDs). Unlike gene therapy, which aims to restore mutated genes, optogenetics involves introducing photosensitive proteins (opsins) to the degenerated retina. By doing so, it restores function and provides photosensitivity to remaining retinal cells, primarily non-light-sensitive cells like bipolar and retinal ganglion cells.

Two types of opsins are used: microbial opsins (type 1) and animal opsins (type 2), each with different light sensitivity and functions. Type 1 opsins directly affect ion channels or pumps, while type 2 opsins indirectly affect ion channels through intracellular G-protein-coupled receptor signaling cascades. The choice of opsin depends on the desired effect, mimicking either an "off" or "on" response^[18][19][20].

Phase I/II clinical trials are currently underway for optogenetic therapy, building upon the established proof of concept. However, further research is still required to understand the structure, molecular transport modes, dynamics, and optical properties of photosensitive proteins^[17].

Verdict

4. Verdict

When considering treatment options for inherited retinal diseases (IRDs), retinal prostheses may appear less attractive compared to cell-based and gene-based therapies. However, each approach has its strengths and challenges, and having multiple options allows for leveraging strengths to overcome weaknesses. For instance, a study by Nascimento-dos-Santos et al. demonstrated the synergistic effect of combining gene therapy (AAV2-PEDF) with cell therapy (human mesenchymal stem cell) in promoting neuroprotection and axonal outgrowth in the retinal ganglion cell (RGC) layer^[21].

Optogenetics presents another intriguing solution for enhancing retinal prostheses, as highlighted by Lagali et al. Optogenetic prostheses eliminate the need for invasive surgery and reduce biocompatibility concerns. They also offer potential solutions to address the limited visual restoration achieved by retinal implants, relying on high brightness displays and appropriate optics^[22]. Moreover, a study by Gongxin Li et al. demonstrated that optogenetic implants incorporating ChR2-expressing cells achieved better resolution than current implants, hinting at the possibility of a new generation of retinal prostheses^[23].

While retinal prostheses face challenges in terms of vision quality and surgical risks, their combination with cell, gene, or optogenetics therapy holds promise for greater neuroprotection and improved vision restoration. Consequently, interdisciplinary collaboration among ophthalmologists, geneticists, stem cell biologists, engineers, and others is crucial to advance and refine therapeutic approaches, ensuring optimal outcomes for patients. Continued research and development of these diverse treatment avenues remain essential for the effective management of inherited retinal diseases.