Adeno-Associated Viral Gene Therapy for Retinal Disorders - Gene Delivery and Therapy for Neurological Disorders - page 203

Chapter 9

Adeno-Associated Viral Gene Therapy
for Retinal Disorders

Samantha R. de Silva , Michelle E. McClements ,
Mark W. Hankins , and Robert E. MacLaren

Abstract

Gene therapy is ideally suited to the treatment of inherited retinal degenerations in order to prevent
blindness. The target area of the outer retina is small and relatively immune privileged, which facilitates the
delivery of small volumes of vector without generating signifi cant immune reactions. Moreover, most of
the currently untreatable forms of blindness have a genetic component, either monogenic such as in reti-
nitis pigmentosa or as a result of several genes interacting along a common pathway, such as age-related
macular degeneration, the commonest cause of legal blindness in the developed world. The self-contained
nature of the eye also facilitates the application of gene therapy for sustained expression of intraocular
proteins, such as inhibitors of angiogenesis or growth factors that might confer neuroprotection to dying
cells. In this chapter, we review the indications and applications of gene therapy, concentrating specifi cally
on adeno-associated viral (AAV) vectors, describing the protocols for production and administration of
AAV vectors to the eye in the laboratory setting.

Key words Gene therapy, Adeno-associated viral vector, Retinal disorders

1 Introduction

The retina is highly specialized with a complex but well-characterized
cellular structure (Fig. 1 ) that initiates the phototransduction pro-
cess. Light induces isomerization of 11- cis retinal to all- trans reti-
nal in photoreceptors, activating a G protein-coupled transduction
cascade which results in hyperpolarization of the photoreceptor
cell [ 1 , 2 ]. This signal is propagated to second-order neurons such
as bipolar cells and then via ganglion cells to the optic nerve [ 3 ].
Retinal pathology may affect any of these cell types, but in this
chapter we will focus on inherited retinal conditions which pre-
dominantly affect functioning of the retinal pigment epithelium
(RPE) or photoreceptors.
The clinical diagnosis of retinitis pigmentosa (RP) is the most
common presentation of inherited retinal degeneration and affects