The prognosis in West syndrome is poor overall, although a small number of individuals recover, with both resolution of seizures and achievement of normal mental development. While the natural history of this disorder is, in general, well documented, major questions remain unanswered regarding the factors that influence, or predict, outcome, and the long-term benefits of various therapeutic modalities. As discussed in the preceding chapter, a number of therapies have demonstrated efficacy for the control of spasms and improvement of the EEG characteristics. In this chapter, the evidence for an effect of such treatment on long-term outcome is considered, and we attempt to distinguish changes that are simply a part of the natural history of the disorder from those that are truly associated with therapeutic intervention.

Long-Term Outcome

Considerable progress has been made in testing stem cell-derived retinal pigment epithelium (RPE) as a potential therapy for age-related macular degeneration (AMD). However, the recent reports of oncogenic mutations in induced pluripotent stem cells (iPSCs) underlie the need for robust manufacturing and functional validation of clinical-grade iPSC-derived RPE before transplantation. Here, we developed oncogenic mutation-free clinical-grade iPSCs from three AMD patients and differentiated them into clinical-grade iPSC-RPE patches on biodegradable scaffolds. Functional validation of clinical-grade iPSC-RPE patches revealed specific features that distinguished transplantable from nontransplantable patches. Compared to RPE cells in suspension, our biodegradable scaffold approach improved integration and functionality of RPE patches in rats and in a porcine laser-induced RPE injury model that mimics AMD-like eye conditions. Our results suggest that the in vitro and in vivo preclinical functional validation of iPSC-RPE patches developed here might ultimately be useful for evaluation and optimization of autologous iPSC-based therapies.

Clinical-grade stem cell-derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs

Retinal prosthesis systems have undergone significant advances in the past quarter century, resulting in the development of several different novel surgical and engineering approaches. Encouraging results have demonstrated partial visual restoration, with improvement in both coarse objective function and performance of everyday tasks. To date, four systems have received marketing approval for use in Europe or the United States, with numerous others undergoing preclinical and clinical evaluation, reflecting the established safety profile of these devices for chronic implantation. This progress represents the first notion that the field of visual restorative medicine could offer blind patients a hope of real and measurable benefit. However, there are numerous complex engineering and biophysical obstacles still to be overcome, to reconcile the gap that remains between artificial and natural vision. Current developments in the form of enhanced image processing algorithms and data transfer approaches, combined with emerging nanofabrication and conductive polymerization techniques, herald an exciting and innovative future for retinal prosthetics. This review provides an update of retinal prosthetic systems currently undergoing development and clinical trials while also addressing future challenges in the field, such as the assessment of functional outcomes in ultra-low vision and strategies for tackling existing hardware and software constraints.

https://journals.sagepub.com/doi/pdf/10.1177/2515841418817501

Advances in retinal prosthesis systems.

Inherited retinal degenerations (IRDs) represent a diverse group of progressive, visually debilitating diseases that can lead to blindness in which mutations in genes that are critical to retinal function lead to progressive photoreceptor cell death and associated vision loss. IRDs are genetically heterogeneous, with over 260 disease genes identified to date.1 The development of treatments and cures to modify the rate of disease progression has been limited to date, with some success of neurotrophic factor therapy and gene therapies reported from clinical trials.2–11 The best example of treatment success is gene augmentation therapy for IRD caused by mutations in the RPE65 gene, which recently received US Food and Drug Administration (FDA) approval, which in fact represented the first FDA-approved gene therapy (GT) for any genetically inherited disease.4–9 Recent developments in the IRD field have advanced understanding of the mechanisms responsible for vision loss, creating new opportunities to intervene in the course of disease by developing new therapeutic approaches. In 2013, a Delphi-style gathering of IRD experts led to the identification, by consensus, of top priorities to advance therapeutic efforts for IRDs, including the need for systematic genotyping, improved standardization of visual function testing, development of more rigorous and widespread data collection protocols, and increased data sharing.12 This document summarizes more recent advances in the IRD field and outlines specific knowledge gaps. These knowledge gaps present opportunities for further investigation to enable development of therapies that may slow down or prevent vision loss, or restore vision, in affected patients.

Atrophic age-related macular degeneration (AMD) is included among the target inherited retinal diseases of interest because first, understanding AMD may contribute to understanding of inherited macular diseases, and second, understanding of the genetics and mechanism of inherited macular degenerations may contribute to understanding of AMD.

/pdf/inherited-retinal-degenerations-current-landscape-and-15h6q0y3ee.pdf

Inherited Retinal Degenerations: Current Landscape and Knowledge Gaps.

Despite many reports of putative stem-cell-based treatments in genetic and degenerative disorders or severe injuries, the number of proven stem cell therapies has remained small. In this Review, we survey advances in stem cell research and describe the cell types that are currently being used in the clinic or are close to clinical trials. Finally, we analyse the scientific rationale, experimental approaches, caveats and results underpinning the clinical use of such stem cells.

Advances in stem cell research and therapeutic development

Age-related macular degeneration (AMD) remains a major cause of blindness, with dysfunction and loss of retinal pigment epithelium (RPE) central to disease progression. We engineered an RPE patch comprising a fully differentiated, human embryonic stem cell (hESC)-derived RPE monolayer on a coated, synthetic basement membrane. We delivered the patch, using a purpose-designed microsurgical tool, into the subretinal space of one eye in each of two patients with severe exudative AMD. Primary endpoints were incidence and severity of adverse events and proportion of subjects with improved best-corrected visual acuity of 15 letters or more. We report successful delivery and survival of the RPE patch by biomicroscopy and optical coherence tomography, and a visual acuity gain of 29 and 21 letters in the two patients, respectively, over 12 months. Only local immunosuppression was used long-term. We also present the preclinical surgical, cell safety and tumorigenicity studies leading to trial approval. This work supports the feasibility and safety of hESC-RPE patch transplantation as a regenerative strategy for AMD.

/pdf/phase-1-clinical-study-of-an-embryonic-stem-cell-derived-4vohryqfba.pdf

Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration.

Retinal degenerative diseases are the primary cause of irreversible visual impairment worldwide. At present, the available therapeutic options are very limited and can only delay the disease progress. Treatments to restore visual function are limited primarily to retinal prostheses, which require residual inner retinal and optic nerve function and provide vision typically at the ambulatory level or worse. Current research is focusing on the development of regenerative strategies delivering therapeutic cells aimed at replacing the damaged retina and supporting visual function. Stem cells are becoming a significant source for cell transplantation, but non-stem cell, predominantly autologous, sources have been used as well.

Odysseas Georgiadis

Papers

Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration.

Cell Delivery: Surgical Approaches