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Topics in Medicinal Chemistry 35

Christopher L. Cioffi Editor

Drug Delivery
Challenges and
Novel Therapeutic
Approaches
for Retinal Diseases
35
Topics in Medicinal Chemistry

Series Editors
P.R. Bernstein, Philadelphia, USA
A.L. Garner, Ann Arbor, USA
G.I. Georg, Minneapolis, USA
J.A. Lowe, Stonington, USA
N.A. Meanwell, Princeton, USA
A.K. Saxena, Lucknow, India
C.T. Supuran, Sesto Fiorentino, Italy
A. Zhang, Shanghai, China
Aims and Scope

Topics in Medicinal Chemistry (TMC) covers all relevant aspects of medicinal

chemistry research, e.g. pathobiochemistry of diseases, identification and validation
of (emerging) drug targets, structural biology, drugability of targets, drug design
approaches, chemogenomics, synthetic chemistry including combinatorial methods,
bioorganic chemistry, natural compounds, high-throughput screening, pharmacolog-
ical in vitro and in vivo investigations, drug-receptor interactions on the molecular
level, structure-activity relationships, drug absorption, distribution, metabolism,
elimination, toxicology and pharmacogenomics. Drug research requires interdisci-
plinary team-work at the interface between chemistry, biology and medicine. To
fulfil this need, TMC is intended for researchers and experts working in academia
and in the pharmaceutical industry, and also for graduates that look for a carefully
selected collection of high quality review articles on their respective field of
expertise.

Medicinal chemistry is both science and art. The science of medicinal chemistry
offers mankind one of its best hopes for improving the quality of life. The art of
medicinal chemistry continues to challenge its practitioners with the need for both
intuition and experience to discover new drugs. Hence sharing the experience of
drug research is uniquely beneficial to the field of medicinal chemistry.

All chapters from Topics in Medicinal Chemistry are published OnlineFirst with an
individual DOI. In references, Topics in Medicinal Chemistry is abbreviated as Top
Med Chem and cited as a journal.

More information about this series at http://www.springer.com/series/7355

Christopher L. Cioffi
Editor

Drug Delivery Challenges

and Novel Therapeutic
Approaches for Retinal
Diseases

With contributions by
C. M. Adams
B. Bakall
M. Choudhary
C. L. Cioffi

A. Jayagopal
K. Klein
G. Malek
K. Mears

J. P. N. Papillon
K. Petrukhin
M. W. Stewart

MD. I. Uddin
P.-L. Yao
Editor
Christopher L. Cioffi
Departments of Basic and Clinical
Sciences and Pharmaceutical Sciences
Albany College of Pharmacy and Health Sciences
Albany, NY, USA

ISSN 1862-2461 ISSN 1862-247X (electronic)

Topics in Medicinal Chemistry
ISBN 978-3-030-56618-0 ISBN 978-3-030-56619-7 (eBook)
https://doi.org/10.1007/978-3-030-56619-7

© Springer Nature Switzerland AG 2020

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Preface

According to the World Vision Report released by the World Health Organization
(WHO) on October 8, 2019, nearly 2.2 billion people suffer from vision impairment
worldwide, of which approximately 60 million people are blind. Retinal diseases
such as age-related macular degeneration (10.4 million), glaucoma (6.9 million), and
diabetic retinopathy (3 million) were noted as leading causes of irreversible blind-
ness throughout the world. Projections based on the most recent census data and
from studies funded by the National Eye Institute at the National Institutes of Health
predict that more than 8 million individuals will suffer from visual impairment or
blindness in the USA by 2050. Indeed, the ever increasing global prevalence of
retinal disease constitutes a major public health crisis and the need for safe and
effective treatments will continue to be of high importance.
Multiple research efforts over the past decade have led to a better understanding
of the underlying pathophysiology of various retinal diseases, resulting in significant
expansion within the ophthalmic drug discovery landscape. Suppression of VEGF-
mediated angiogenic signaling continues to provide an effective means by which to
halt the progression of choroidal neovascularization and stabilize visual acuity in wet
age-related macular degeneration patients. Approaches such as visual cycle modu-
lation and complement system regulation have emerged as potential approaches for
atrophic (dry) age-related macular degeneration, a retinal disease for which treat-
ments are currently unavailable. Intraocular pressure reduction has served as a
stalwart approach for the treatment of glaucoma while neuroprotective agents
provide a new class of drugs to help treat the disease. Lastly, the field has contributed
to the discovery of Luxturna®, the first gene therapy for any human inherited disease
approved by the US Food and Drug Administration and European Medicines
Agency. This breakthrough gene therapeutic is improving visual function outcomes
in individuals affected by retinal dystrophy caused by bi-allelic variants in the
RPE65 gene (Leber congenital amaurosis). This agent serves a milestone in treat-
ment for inherited retinal diseases and has provided momentum for the field that
currently has several ongoing gene therapy clinical trials for diseases including
retinitis pigmentosa, Stargardt disease, choroideremia, and achromatopsia.

v
vi Preface

This volume of Topics in Medicinal Chemistry “Drug Delivery Challenges and

Novel Therapeutic Approaches for Retinal Diseases” presents the current state of
ocular drug therapy, details the unique challenges faced for ocular drug discovery
and delivery, and highlights future therapeutic opportunities principally focused on
the areas of age-related macular degeneration, diabetic retinopathy, and glaucoma.
The volume begins with “Introduction: Overview of Retinal Diseases and Current
Ocular Drug Discovery,” which provides basic background information of the
human eye and mammalian retina required for readers unfamiliar with the field of
ophthalmic drug discovery. The purpose of this chapter is to help facilitate a
thorough understanding of the subsequent chapters of the volume that focus on
key ocular diseases, recent developments in drug discovery efforts toward treating
these diseases, and the challenges faced in the delivery of drugs to their intended
targets. Thus, this chapter provides a general overview of the gross anatomical
features of the human eye, the histology of the mammalian retina, and a description
of the series of reactions that constitute the visual retinoid cycle and the various key
proteins that facilitate it. In the subsequent chapter “Drug Delivery Challenges and
Novel Therapeutic Approaches for Retinal Diseases,” Stewart provides a compre-
hensive review of ocular pharmacokinetics and the unique challenges incurred with
regard to drug delivery to the posterior segment of the eye. The chapter includes
current and investigational drug delivery platforms designed to overcome the various
anatomical barriers presented by the eye that would allow for therapeutic concen-
trations of drug to reach the posterior segment.
In the chapter “Models of Pathologies Associated with Age-Related Macular
Degeneration and Their Utilities in Drug Discovery” Malek, Yao, and Choudhary
present the strengths and weaknesses associated with current in vitro and in vivo
models designed to facilitate the testing and development of potential novel drugs
for the treatment of age-related macular degeneration. This chapter is followed by
“Recent Developments in Agents for the Treatment of Age-Related Macular Degen-
eration and Stargardt Disease,” a chapter authored by Petrukhin that provides a
comprehensive review on the state of the art for age-related macular degeneration
and Stargardt disease drug discovery and highlights his pioneering work within the
visual cycle modulator field.
In the chapter “Targets and Strategies Toward the Development of Therapeutics
for Diabetic and Diabetic Macular Edema,” Uddin and Jayagopal summarize emerg-
ing therapeutic modalities that are being engineered to improve clinical management
of diabetic retinopathy and diabetic macular edema. This is an area of high impor-
tance as diabetic retinopathy is the most common vascular complication associated
with diabetes, a disease with worldwide prevalence of over 450 million individuals.
The following chapter “Recent Developments for the Treatment of Glaucoma” by
Adams and Papillon provides a well-organized, detailed, and comprehensive review
of current therapeutics for the treatment of intraocular pressure and ongoing cutting-
edge glaucoma drug discovery research. Continued research in this area is of critical
importance as glaucoma is one of the leading causes of irreversible blindness
globally, with a prevalence expected to grow to over 110 million individuals in
Preface vii

2040. Lastly, the volume concludes with “Emerging Gene Therapy Treatments for
Retinal Degenerative Diseases” by Bakall, Klein, and Mears, which provides a
concise overview of the current gene therapy treatments under investigation in
numerous clinical trials for inherited retinal diseases. These agents may ultimately
provide powerful treatment options for individuals suffering from progressive retinal
dystrophies such as retinitis pigmentosa, Leber congenital amaurosis, Stargardt
disease, choroideremia, and achromatopsia.
We are grateful to all of the authors who contributed to this special volume of
Topics in Medicinal Chemistry “Drug Delivery Challenges and Novel Therapeutic
Approaches for Retinal Diseases.” I would like to express my sincere gratitude to all
of the authors for their time and outstanding contributions to our volume. Their work
has provided a valuable resource for those working in the field of ocular drug
discovery. I would also like to thank all of the reviewers for their feedback and
constructive comments. Their assistance has helped ensure that our volume provides
a high quality resource for our readership.
Lastly, I would like to thank the series editors Drs. Bernstein, Garner, Georg,
Lowe, Meanwell, Saxena, Supuran, and Zheng for the invitation and opportunity to
compile this volume and for their support and encouragement throughout the course
of the project.

Albany, NY, USA Christopher L. Cioffi

Contents

Introduction: Overview of the Human Eye, Mammalian Retina,

and the Retinoid Visual Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Christopher L. Cioffi
Ocular Pharmacokinetics and Drug Delivery Challenges . . . . . . . . . . . . 43
Michael W. Stewart
Models of Pathologies Associated with Age-Related Macular
Degeneration and Their Utilities in Drug Discovery . . . . . . . . . . . . . . . . 83
Goldis Malek, Pei-Li Yao, and Mayur Choudhary
Recent Developments in Agents for the Treatment of Age-Related
Macular Degeneration and Stargardt Disease . . . . . . . . . . . . . . . . . . . . . 125
Konstantin Petrukhin
Emerging Therapeutic Modalities for Diabetic Retinopathy . . . . . . . . . . 161
MD Imam Uddin and Ashwath Jayagopal
Recent Developments for the Treatment of Glaucoma . . . . . . . . . . . . . . 189
Christopher M. Adams and Julien P. N. Papillon
Emerging Gene Therapy Approaches Under Clinical Investigation
for Retinal Degenerative Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
Benjamin Bakall, Kendra Klein, and Katrina Mears

ix
Top Med Chem (2020) 35: 1–42
DOI: 10.1007/7355_2020_94
© Springer Nature Switzerland AG 2020
Published online: 26 March 2020

Introduction: Overview of the Human Eye,

Mammalian Retina, and the Retinoid Visual
Cycle

Christopher L. Cioffi

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.1 The Anterior Segment of the Human Eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2 The Posterior Segment of the Human Eye . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2 The Components of the Mammalian Retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.1 The Photoreceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.2 Histology of the Mammalian Retina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.3 The Retinal Pigment Epithelium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3 The Retinoid Visual Cycle and Phototransduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3.1 The Canonical Retinoid Visual Cycle and Phototransduction . . . . . . . . . . . . . . . . . . . . . . . . . . 23
3.2 The Cone-Specific Visual Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
3.3 Proteins of the Visual Cycle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Abstract The human eye is a part of the sensory nervous system and is the organ
responsible for conscious light perception and vision. Its intricate and complex
anatomy has evolved to effectively focus incoming light from the surrounding
environment and to harness its energy by efficiently utilizing the physicochemical
properties of retinoids. This remarkable organ is capable of phototransduction,
which involves the conversion of photon energy into an integrated neural signal
that propagates through the optic nerve as an action potential to the visual cortex of
the brain. There, the neural signal is processed to give rise to color differentiation,
brightness perception, contrast, and depth perception. Loss of visual acuity or
blindness presents a significant negative impact on quality of life. Irreversible
blindness affects nearly 60 million individuals worldwide, with the leading causes
including age-related macular degeneration, glaucoma, and retinal vascular disease.

C. L. Cioffi (*)
Department of Basic and Clinical Sciences, Albany College of Pharmacy and Health Sciences,
Albany, NY, USA
Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences,
Albany, NY, USA
e-mail: christopher.cioffi@acphs.edu
2 C. L. Cioffi

In this chapter, we will provide basic background information of the human eye and
retina required for readers unfamiliar with the field of ophthalmic drug discovery.
The purpose of this chapter is to help facilitate a thorough understanding of the
subsequent chapters of this volume that focus on key ophthalmic diseases, recent
developments in drug discovery efforts toward treating these diseases, and the
challenges faced in the delivery of drugs to their ocular targets. Thus, this chapter
will provide a general overview that begins with the gross anatomical features of the
human eye followed by a description of the histology of the mammalian retina. We
will next provide morphological and functional details concerning the various cell
types that comprise the many layers of the retina, and we will conclude by describing
the series of reactions that constitute the visual retinoid cycle and the various key
proteins that facilitate it.

Keywords Anterior chamber, Anterior segment, Choroid, Macula, Photoreceptors,

Phototransduction, Posterior chamber, Posterior segment, Retina, Retinal pigment
epithelium (RPE), Retinoids, Visual cycle

Abbreviations

AMPA α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

bb Basal bodies
BBB Blood-brain barrier
BRB Blood-retinal barrier
cc Connecting cilium
CFH Complement factor H
cGMP Cyclic guanosine monophosphate
CIS Cone inner segment
CNG Cyclic nucleotide-gated
CNS Central nervous system
CNTF Ciliary neurotrophic factor
COS Cone outer segment
CRABP Cellular retinaldehyde-binding protein
CRBP Cellular retinol-binding protein
ER Endoplasmic reticulum
ERG Electroretinogram
GABA γ-Aminobutyric acid
GDP Guanosine diphosphate
GPCR G protein-coupled receptor
GTP Guanosine triphosphate
ILGF-I Insulin-like growth factor-I
ILM Inner limiting membrane
IMH Isomerohydrolase
IPM Interphotoreceptor matrix
IRBP Intracellular retinol-binding protein
Introduction: Overview of the Human Eye, Mammalian Retina, and the Retinoid. . . 3

IS Inner segment
LEDGF Lens epithelium-derived growth factor
LGN Lateral geniculate nucleus
LRAT Lecithin-retinol acyltransferase
mGlu6 Metabotropic glutamate 6
NPE Nonpigmented epithelial cells
OLM Outer limiting membrane
ONL Outer nuclear layer
OS Outer segment
PDE Phosphodiesterase
PDGF Platelet-derived growth factor
PE Phosphatidylethanolamine
PE Pigmented epithelial cells
POS Photoreceptor outer segment
RBP4 Retinol-binding protein 4
RDH11 Retinol dehydrogenase 11
RDH5 Retinol dehydrogenase 5
RDH8 Retinol dehydrogenase 8
RGC Retinal ganglion cell
RIS Rod inner segment
ROS Rod outer segment
RPE Retinal pigment epithelium
STRA6 Stimulated by retinoic acid 6 protein
TGF-β Transforming growth factor-β
TMD Transmembrane domain
TTR Transthyretin

1 Introduction

1.1 The Anterior Segment of the Human Eye

The anatomy of the human eye is clinically divided into two segments known as the
anterior and posterior segments, which combine to form a globular asymmetric
spheroidal shape with a diameter of approximately 24 mm (Fig. 1) [1–4]. The
anterior segment constitutes the front third of the eye and is further subdivided
into the anterior and posterior chambers. The anterior chamber is the region of space
located between the innermost layer of the cornea and the iris and is filled with
aqueous humor. The posterior chamber is the narrow region extending from the iris
to the suspensory ligaments of the lens (zonule fibers) [1–4].
4 C. L. Cioffi

Fig. 1 The gross anatomical features of the human eye. Adapted with permission from Tefi/
Shutterstock.com

1.1.1 The Anterior Chamber: Cornea

The cornea is the transparent collagenous structure located at the front of the eye that
encapsulates the anterior chamber. It serves both to provide a physical barrier to the
anterior segment and to refract incoming light onto the lens [1–4]. It is a part of the
external fibrous tunic and is continuous with the conjunctiva at the junctional region
known as the limbus. The cornea is innervated by ciliary branches of the ophthalmic
nerve. It is approximately 0.5 mm thick, is avascular, and consists of three cellular
and two interface layers, which are listed below from the outermost (external) to
innermost (internal) layer [5]:
1. Corneal epithelium: a thin layer of cells that transitions into the conjunctival
epithelium (nonkeratinized stratified squamous epithelium). This layer regener-
ates quickly and provides a smooth surface to absorb oxygen and nutrients from
tears, which are then distributed to the other layers of the cornea. The epithelium
is also innervated with sensory nerve endings.
2. Bowman’s layer (anterior limiting membrane): a layer composed primarily of
type I collagen fibrils, as well as laminin, nidogen, perlecan, and other
proteoglycans.
3. Corneal stroma (substantia propria): a thick central layer composed primarily of
water and collagen fibers. This layer also contains keratocytes. The unique
arrangement and spacing of the collagen proteins are what allow the cornea to
be transparent [6, 7].
Introduction: Overview of the Human Eye, Mammalian Retina, and the Retinoid. . . 5

4. Descemet’s membrane (posterior limiting membrane): a layer of collagen type IV

and VIII fibrils that is a basement membrane that lies between the corneal stroma
and the corneal endothelial layer. This layer is produced by the corneal endothe-
lium and serves as a protective barrier against infection and injuries [8].
5. Corneal endothelium: a single layer of specialized mitochondria-rich squamous
cells on the innermost posterior surface of the cornea that faces the anterior
chamber. This layer regulates solute and fluid transport between the aqueous
humor and corneal stroma.

1.1.2 The Anterior Chamber: Iris

The iris is a thin, disclike, pigmented diaphragm positioned posterior to the cornea
and anterior to the lens that controls the amount of light entering the eye by changing
the size and diameter of the pupil [1–4]. The regions of the iris include the pupillary
zone, which is the inner area whose edge forms the boundary of the pupil, and the
ciliary zone, which is the region that extends to the ciliary body. The iris is divided
into two layers: the fibrovascular stromal layer and the epithelial layer. The stroma
resides at the front of the iris and is connected to the sphincter and dilator muscles
that contract and enlarge the pupil, respectively. The epithelial layer lies beneath the
stroma and is heavily pigmented and serves to prevent light from passing through the
iris to the retina. The sphincter and dilator pupillae are smooth muscles innervated by
parasympathetic and sympathetic fibers, respectively, which work in concert with
other ocular tissues to control the size of the pupil diameter under varying light and
physiological conditions [1–4].

1.1.3 The Posterior Chamber: The Lens

The lens is a transparent biconvex body encapsulated posteriorly to the iris and
anteriorly to the vitreous body [1–4, 9]. Along with the cornea, the lens serves to
refract incoming light and focus it onto the retina. Broadly, the lens presents two
surfaces, known as the anterior and posterior surfaces. The convexity of the posterior
surface is steeper than that of the anterior surface. Both surfaces have a central point
known as the anterior and posterior poles, respectively, which are connected via the
lens axis. The anatomy of the lens can be divided into three layers [9]:
1. Lens capsule: an elastic and smooth basement membrane comprised of collagen
(collagens I, III, and IV), glycosaminoglycans, and glycoproteins that covers the
entirety of the lens surface. The elastic quality of the capsule allows for changes in
the shape of the lens depending on tensile forces imparted by attached suspensory
ligaments. The capsule is derived from the lens epithelium layer.
2. Lens epithelium: a layer of cells sandwiched between the lens capsule and lens
fibers in the anterior portion of the lens. The epithelium helps to maintain optimal
osmotic concentration and volume of the lens, which is bathed in aqueous humor.
The epithelial cells of this layer also differentiate into lens fibers by mitosis where
they are then displaced toward the equator.
6 C. L. Cioffi

3. Lens fibers: make up the bulk of the lens and are inwardly displaced elongated
hexagonal epithelial cells that are arranged in concentric rings, flattened, and
tightly packed together with little intercellular space. They are attached via
mechanical junctions that include desmosomes and gap junctions. The fibers
are elongated from the equatorial region and terminate at the posterior and
anterior poles (lens sutures) in concentric layers. Fibers at the equator and near
the lens surface are nucleated, whereas cells located deeper within the lens fibers
have lost most of their organelles.

1.1.4 The Posterior Chamber: The Ciliary Body

The ciliary body serves three functions; (1) production and resorption of aqueous
humor, (2) maintenance of the suspensory ligaments composed of zonule fibers that
are attached to the lens to hold it in place, and (3) facilitation of the accommodation
reflex [1–4, 10, 11]. Structurally, the ciliary body is a circular ring of tissue attached
to the scleral spur and positioned behind the posterior-facing side of the iris. It
separates the posterior chamber from the vitreous body and presents a shape
resembling a right triangle that includes two components: the ciliary muscle and
the ciliary processes. It is innervated by parasympathetic inputs that originate in the
Edinger-Westphal nucleus and propagate via the oculomotor nerve to the ciliary
ganglion. Sympathetic innervation originates from the cervical superior ganglion
and the carotid plexus, and sensory fibers originate from the trigeminal ganglion by
way of the ophthalmic nerve. The ciliary body connects the choroid with the iris [1–
4, 10, 11].

1.1.5 The Ciliary Muscle

The ciliary muscle resides at the base of the ciliary body and facilitates accommo-
dation via modulation of the shape of the lens [1–4, 10, 11]. Suspensory ligaments,
made up of zonular fibers, protrude from the ciliary muscle and are connected to the
lens to hold it firmly in place. The contraction of the muscle relaxes tension on the
anterior zonule suspensory ligaments and increases tension on the posterior zonule
attachments, which allows the natural elasticity of the lens to cause it to adopt its
original accommodative rounded shape, thereby increasing its thickness and the
curvature of the anterior and posterior capsule [12]. In contrast, relaxation of the
muscle leads to a tightening of anterior and relaxation of posterior zonule ligaments,
which forces the lens to flatten and reduce its thickness. Changes in lens convexity
alter its refractive capability, which, in coordination with adaptations in pupil
diameter, modulate optical power and allow for optimal focusing on images as
their distance varies [1–4, 10, 11].
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