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Therapies for Retinal Degeneration: Targeting Common Processes

Editors: Enrique J de la Rosa, Thomas G Cotter

Sight loss and blindness is a very prevalent cause of disability. Retinal diseases leading to visual loss affect many people worldwide and the search for adequate drugs remains a challenge and an important area of interest in the drug discovery field.

This book addresses approaches to the treatment of retinal diseases, targeting common processes and components. Despite their causative origins, which comprise genetic dystrophies, age-related degenerations, as well as pathologies associated with other diseases, a neurodegenerative component appears, sooner or later, in the course of the disease. As is the case for most neurodegenerative diseases, the available treatments are far from satisfactory. The aim of this book is to highlight research and drug development efforts in targeting such common processes as a potential path to provide treatments to the millions of affected people.

CHAPTER 1 - The Cellular Course of Retinal Degenerative Conditions

Nicolás Cuenca, Victoria Maneu, Laura Campello and Pedro Lax

In retinal degenerative diseases, the progressive death of neuronal cells is accompanied by retinal remodeling, together with alterations of retinal vascularization and functional deterioration, with a decrease in the electric response and visual acuity. Oxidative stress, apoptosis and inflammation are crucial pathways underlying the gradual photoreceptor cell death in retinal degenerative diseases, such as age-related macular degeneration or retinitis pigmentosa. Consequently, the gradual loss of photoreceptors triggers a morphological remodeling of the remaining retinal circuitry and the degeneration of second- and third-order neurons in the inner retina. This remodeling of the retina is accompanied by the activation of glial cells. It is important to remark that the exact mechanisms that cause cell death, as well as the nature of retinal remodeling, are not completely understood and a thorough understanding of these is essential for the development of effective therapies for retinal degeneration.

CHAPTER 2 - Immune Response of the Retina

Mei CHEN and Heping Xu

The immune system protects the host against noxious insults, to maintain homeostasis and restore functionality. The retina is known as an immune privileged tissue due to its unique anatomic and physiologic properties. The retina has its own defence system including resident immune cells and the complement system. Retinal degenerative diseases are a major cause of blindness worldwide; the aetiology of each differs and inflammation plays a pivotal role in the development of these diseases. For example, inherited retinal degenerations are caused by specific gene mutations, an inflammatory response is secondary to photoreceptor death and may further participate in disease progression. Dysregulation or malfunction of the parainflammatory response contributes to age-related macular degeneration. Diabetic retinopathy is a major microvascular complication of long-term diabetes, which has a significant impact on the immune system. Glaucoma is a heterogeneous disorder related to retinal ganglion cell death from increased intraocular pressure. Neurodegenerative insults and glial activation initiate an immune response to restore tissue homeostasis and facilitate tissue repair and remodelling. This chapter discusses the basic principles of the immune response to common retinal insults in pathophysiological conditions and the contribution of such responses to retinal degeneration.

CHAPTER 3 - Modulation of Calcium Overload and Calpain Activity

François Paquet-Durand, Per Ekström and Valeria Marigo

Fluxes of calcium ions (Ca2+) in rod photoreceptors are major regulators of steady-state and light-evoked intracellular reactions to stimuli. The homeostasis of Ca2+ is regulated by channels and pumps localized at the plasma membrane and in intracellular organelles. Photoreceptor degeneration is frequently associated with Ca2+ homeostasis disruption and stimulation of Ca2+ activated proteases, such as calpains. These events trigger molecular pathways leading to cell death. In this chapter we discuss Ca2+ channels and pumps as well as calpains as potential targets of new therapies for retinal degeneration.

CHAPTER 4 - CNS Targets for the Treatment of Retinal Dystrophies: A Win–Win Strategy

Enrique J. de la Rosa and Catalina Hernández-Sánchez

As an extension of the central nervous system (CNS), the retina shares with the brain certain developmental, physiological, and pathological characteristics. However, the underlying mechanisms and pathological signs common to neurodegenerative conditions of both the retina and brain have been relatively overlooked. In animal models and in human patients, marked retinal alterations have been demonstrated in Alzheimer's disease, Parkinson's disease, and multiple sclerosis, among other pathologies. Furthermore, neurodegeneration of the retina and brain appears to be mediated by similar mechanisms, which include protein aggregation, neuroinflammation, and cell death. Analysis of the retina, which is easily accessible to objective techniques, may therefore constitute an effective tool for the screening and follow-up of CNS neurodegeneration. Moreover, patients with retinal neurodegeneration could potentially benefit from the broad array of pharmacological compounds that have been designed and tested for the treatment of the aforementioned CNS pathologies. Supporting this view, we have shown that glycogen synthase kinase (GSK)-3 inhibitors, which have already been tested in clinical trials to treat several neurodegenerative conditions of the brain, attenuate retinal damage and vision loss in a mouse model of retinitis pigmentosa. Furthermore, systemic proinsulin treatment preserves visual and cognitive function in mouse models of retinitis pigmentosa and precocious aging, respectively.

CHAPTER 5 - Modulation of p75NTR/Pro-NGF as a Therapeutic Approach for Degenerative Retinopathies

H. Uri Saragovi, Alba Galán and Pablo F. Barcelona

This chapter describes the experimental validation of neurotrophins/neurotrophin receptors as therapeutic targets for the treatment of retinal neurodegenerative disorders. Neuropathies often have inflammatory or vascular pathologies as part of the disease mechanism (e.g. glaucoma, diabetic retinopathy, and retinitis pigmentosa) leading to neuronal death. Maintenance of neuronal phenotype and neuronal survival are promoted by the neurotrophins/neurotrophin receptors. Historically, these have been valued as potentially useful pharmacological targets to foster neuroprotection or neuroregeneration. This is the concept of “neurotrophin protection”. Paradoxically, during embryonic development neurotrophins/neurotrophin receptors can promote synaptic pruning and neurodegeneration, and in adult disease states this process is recapitulated to drive neuronal death. This is the concept of “neurotrophin toxicity” and blocking this process may be beneficial. This chapter compares the traditional therapeutic strategy of “neurotrophin protection” with the emerging “anti-neurotrophin toxicity” therapeutic strategy. Each approach may have a unique value for specific diseases or for specific stages of disease progression; may be combined given that they address different mechanisms of action; or may complement neuroregenerative strategies.

CHAPTER 6 - Modulation of cGMP-signalling to Prevent Retinal Degeneration

Valeria Marigo, Per Ekström, Frank Schwede, Andreas Rentsch and François Paquet-Durand

In the photoreceptors of the retina, the second-messenger molecule cyclic guanosine monophosphate (cGMP) occupies centre stage in the phototransduction cascade. Remarkably, cGMP is also involved in hereditary photoreceptor degeneration caused by a variety of different genetic insults. This provides an entry point for the development of inhibitory cGMP analogues for a mutation-independent treatment. Here, we outline how cGMP signalling can be targeted for the treatment of retinal degeneration, how inhibitory cGMP analogues may be designed and formulated, and how test systems of rising complexity can be used to identify new compounds with photoreceptor neuroprotective properties. In this context, we cite the European Union-funded DRUGSFORD project and provide an example for the efficacy of a specific cGMP analogue to prevent photoreceptor loss and preserve retinal function.

CHAPTER 7 - PEDF Peptides in Retinal Degenerations

Alberto M. Hernández-Pinto and S. Patricia Becerra

Pigment epithelium-derived factor (PEDF) is a multifunctional member of the serine proteinase inhibitor (serpin) superfamily. This widely studied protein is considered an ocular guardian because it protects the retina from degeneration induced by cell death, pathological neovascularization, tumorigenesis and inflammation. Studies of the independent activities of PEDF are challenged by the presence of other properties of the same molecule. This chapter summarizes approaches for such investigations using peptide synthesis, protein chemistry and recombinant DNA technologies based on the three-dimensional structure of PEDF to separate and alter them individually. The major focus is to discuss relevant applications of PEDF mimetics for protection against retinal degenerations.

CHAPTER 8 - Beyond Anti-inflammation: Steroid-induced Neuroprotection in the Retina

Alice C. Wyse-Jackson, Gillian Groeger and Thomas G. Cotter

Steroids are routinely used to treat inflammation throughout the human body. Indeed, for decades, glucocorticoids have been used to reduce inflammatory processes in retinal eye disease. Most recently, their direct protective effects on photoreceptors has been investigated, although the evidence surrounding this neuroprotection is conflicting. Alternatively, the sex steroids oestrogen and progesterone have been shown conclusively to promote photoreceptor cell survival; yet retinal administration in a clinical setting has still to commence. This review chapter collates the most up to date and relevant information to determine whether these steroid groups protect photoreceptors via similar signalling pathways. Routes of administration and mechanisms of action are detailed, to determine if lessons learnt from one group may be applied to the other. Through this comparison, we demonstrate that there is great potential in developing these steroids as neuroprotective therapies for retinal degenerative disease

CHAPTER 9 - Alternative Experimental Models of Ciliary Trafficking and Dysfunction in the Retina

Stephen P. Carter, Janina Leyk, Oliver E. Blacque and Breandán Kennedy

The cilia of cells constituent to the retina are fundamental to vision. Of the ∼250 genes causative of inherited retinal degeneration, 20% mediate functions related to photoreceptor primary cilium formation, structure or function. Primary cilia are sensory and signalling organelles emanating from the plasma membrane of most cells. They regulate a variety of biological processes, including left/right body axis asymmetry, limb patterning, central nervous system development and sensation. Cilia function by forming a specialised region of plasma membrane which concentrates specific signalling components, such as for sonic hedgehog signalling and phototransduction. Here, we review the roles of ciliary signalling and trafficking pathways in retinal biology and disease with a focus on the potential of non-rodent, metazoan experimental models for shedding light on these processes.

CHAPTER 10 - Drug Delivery Systems for the Treatment of Diseases Affecting the Retina and Optic Nerve

I. Bravo-Osuna, V. Andrés-Guerrero, Irene T. Molina-Martínez and R. Herrero-Vanrell

Diseases affecting the retina and the optic nerve are the major causes of irreversible blindness in the elderly population. Succesful therapy of these pathologies requires frequent administration of the active molecule close to the retinal target site. Intraocular drug delivery systems (IDDS) are emerging therapeutic tools in the treatment of diseases affecting the posterior segment, as they are able to provide effective concentrations of the drug for a long period, thus avoiding successive injections. Depending on their size, IDDS are classified in implants, microsystems and nanosystems. This chapter covers a general description of the IDDS useful for the treatment of diseases affecting retinal structures.

CHAPTER 11 - Gene Therapies for Retinal Degenerations

L. Petit and V. Kalatzis

Advances in our understanding of the molecular pathogenesis of retinal degenerative disorders have led in the past 25 years to the development of a new treatment modality for several forms of retinal diseases, in which gene-based therapies may delay, prevent and even reverse blindness. To enable a full overview of this field, we start this chapter by describing the general principle of gene therapy and the properties of the retina that make it amenable to gene therapy. We then discuss current clinical trials – highlighting the growing application of retinal gene therapy – and the areas that require further effort before retinal gene therapy is applied to new and more complex therapeutic indications.

CHAPTER 12 - Stem Cell Therapies for Retinal Repair and Regeneration

Karen Eastlake, Weixin Wang, William D. B. Lamb and G. Astrid Limb

Neural cell damage is the main feature of retinal degenerative disorders and constitutes the major cause of blindness in patients affected by retinal disease. Present treatments aim to prevent disease progression but do not reverse lost vision, for which stem cell-based therapies are the only hope for restoration or maintenance of visual function in individuals affected by severe disease. This chapter summarizes recent progress in the stem cell field and describes advances made on the clinical application of these cells for treatment of retinal degeneration. In addition, it highlights research being actively pursued to promote endogenous regeneration of the neural retinaas an alternative to transplantation.

CHAPTER 13 - The Application of Lipid Nanoparticles for Retinal Degenerative Diseases

Raju V. S. Rajala, Ammaji Rajala and Yuhong Wang

Several nanotechnology podiums have gained remarkable attention in the area of medical sciences, including diagnostics and treatment. In the past decade, engineered multifunctional nanoparticles have served as drug and gene carriers. The most important aspect of translating nanoparticles from the bench to bedside is safety. These nanoparticles should not elicit any immune response and should not be toxic to humans or the environment. Lipid-based nanoparticles have been shown to be the least toxic for in vivo applications, and significant progress has been made in gene and drug delivery employing lipid-based nanoassemblies. There are several excellent reviews and reports on the general use and application of lipid-based nanoparticles; our review focuses on the application of lipid-based nanoparticles for the treatment of ocular diseases, and recent advances in and updates on their use.

CHAPTER 14 - Biologicals in Retinal Therapy

Emma Connolly and Sarah L. Doyle

Biologics have revolutionised the treatment of many serious and chronic illnesses and have pushed traditional small-molecule drugs out of favour. The revolution began for retinal disease in 2006 when the United States Food and Drug Administration approved Lucentis (ranibizumab) for the treatment of wet age-related macular degeneration. The retinal biologics market is now the biggest market segment in ophthalmology and it keeps growing as newer biological agents come on line and acquire regulatory approvals for treating new disease indications. This chapter covers the current biologics in use for the treatment of retinal disease and the new biologics currently being trialed. There are many classes of biological agent; however, this chapter focuses on monoclonal antibodies and recombinant peptides in the treatment of retinal diseases that have either a common neovascular component or those that have a common inflammatory pathology.

Publication details

http://dx.doi.org/10.1039/9781788013666-00230

  • Print publication date: 25 Sep 2018
  • Copyright year: 2019
  • Print ISBN: 978-1-78262-949-8
  • PDF eISBN: 978-1-78801-366-6
  • ePub eISBN: 978-1-78801-536-3

More information on https://pubs.rsc.org/en/content/ebook/978-1-78262-949-8