Gene- and Cell-Based Treatment Strategies for the Eye

101 Pages·2015·5.079 MB·English

by  Elizabeth P. Rakoczy (eds.)

Essentials in Ophthalmology
Series Editor: Arun D. Singh
Elizabeth P. Rakoczy Editor
Gene- and Cell-
Based Treatment
Strategies for the
Eye
Essentials in Ophthalmology
Series Editor
Arun D. Singh
For further volumes:
http://www.springer.com/series/5332

Elizabeth P. Rakoczy
Editor
Arun D. Singh
Series Editor
Gene- and Cell-Based
Treatment Strategies
for the Eye
Editor
Elizabeth P. Rakoczy
Department of Molecular Ophthalmology
Centre for Ophthalmology and Visual Sciences
The University of Western Australia
Crawley
Western Australia
Australia
Series Editor
Arun D. Singh
Department of Ophthalmic Oncology
Cole Eye Institute
Cleveland Clinic
Cleveland , Ohio
USA
ISSN 1612-3212
ISBN 978-3-662-45187-8 ISBN 978-3-662-45188-5 (eBook)
DOI 10.1007/978-3-662-45188-5
Springer Heidelberg New York Dordrecht London
Library of Congress Control Number: 2014958086
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Pref ace
This book tells the great story of how the treatment of eye disease might
change in the near future. The reader is explained how gene and cell therapies
work and the diffi culties scientists face in developing new technologies
(experimental details, funding, approvals, ownership). The leaders of the fi eld
give a rare insight into the development of treatments for Leber’s congenital
amaurosis, choroideraemia, retintis pigmentosa, and macular degenerations
that are expected to become part of the ophthalmologist’s arsenal in the near
future.
Crawley, WA, Australia Elizabeth P. Rakoczy
v

Contents
1 Gene Therapy and Stem Cell Therapy: Overview . . . . . . . . . . . . 1
Aaron L. Magno, Samuel McLenachan,
and Elizabeth P. Rakoczy
2 Gene Therapy for Leber’s Congenital Amaurosis
Due to RPE65 Mutations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Jean Bennett
3 Gene Therapy for Choroideremia. . . . . . . . . . . . . . . . . . . . . . . . . . 27
Alun R. Barnard, Markus Groppe, and Robert E. MacLaren
4 Gene Therapy for Dominantly Inherited Retinal
Degeneration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Gwyneth Jane Farrar, Sophia Millington-Ward,
Arpad Palfi , Naomi Chadderton, and Paul F. Kenna
5 Age-Related Macular Degeneration: The Challenges. . . . . . . . . . 61
Elizabeth P. Rakoczy, Cecinio C. Ronquillo Jr.,
Samuel F. Passi, Balamurali K. Ambati, Aaron Nagiel,
Robert Lanza, and Steven D. Schwartz
6 Neovascular Age-Related Macular Degeneration:
Secretion Gene Therapy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Elizabeth P. Rakoczy, Chooi-May Lai,
and Ian J. Constable
7 Transplantation of Human Embryonic Stem Cell-Derived
Retinal Pigment Epithelium for the Treatment of Macular
Degeneration. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
Aaron Nagiel, Robert Lanza, and Steven D. Schwartz
8 Restoring Physiologic Barriers Against
Neovascular Invasion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Cecinio C. Ronquillo Jr., Samuel F. Passi,
and Balamurali K. Ambati
vii
1
Gene Therapy and Stem Cell
Therapy: Overview
Aaron L. Magno , Samuel McLenachan ,
and Elizabeth P. Rakoczy
1.1 Gene Therapy negatively infl uence protein production in many
ways. There are a wide range of mutations caused
In popular culture mutation has several mean- by change in a single or multiple nucleotides –
ings, but in this chapter mutation is used to refer missense, nonsense, insertion, frameshift, repeat
to a nonlethal genetic change that is associated expansion, and deletion mutations – that result in
with a disease. Gene mutations can occur in a the insertion of an incorrect amino acid, shorten-
person in two ways: they can be inherited from a ing of the protein, change in reading the genetic
parent or acquired during a person’s lifetime. code, or multiplication/deletion of certain amino
Mutations that are passed from parent to child are acid sequences. Many disorders are caused by a
called hereditary mutations. These types of muta- mutation in a single gene. Approximately 4,000
tions are present throughout a person’s life in vir- disease-causing mutations in a variety of genes
tually every cell in the body including the germ have already been identifi ed, and for these the
cells, the sperm, and the egg; thus, they are passed case-cause relationship between the mutation and
on from one generation to the next. In contrast, a disease has been confi rmed (McCarthy 2 000 ).
mutations that occur in the building blocks of the Depending on the location of the single base
body such as muscle, nerve, bone, blood, and mutation in the genetic code and the change
gland cells – called somatic cells – are not infl icted by it, the disease can be inherited in dif-
inherited. ferent ways. The inheritance pattern can be d omi-
Why do mutations cause disease? The muta- nant , each affected individual has one affected
tions in DNA can produce harmful proteins or parent and each child has a 50 % chance of inher-
iting the disease; r ecessive , an affected individual
has unaffected parents who carry one copy of the
A. L. Magno , PhD
mutated gene and each child has a 25 % chance
Department of Molecular Ophthalmology ,
of inheriting the disease; X -linked dominant , a
Lions Eye Institute , Perth , WA , Australia
e-mail: [email protected] mutation is carried on the X-chromosome by
either parent, no male to male transmission;
S. McLenachan , BSc(Hons), PhD
Department of Ocular Tissue Engineering , X-linked recessive , a mutation is carried on the
Lions Eye Institute , Nedlands , WA , Australia X-chromosome by either parent and the majority
e-mail: [email protected]
of the offspring affected are male; codominant ,
E. P. Rakoczy , PhD (*) two alleles are inherited together from different
Department of Molecular Ophthalmology , Centre for
parents producing slightly different protein prod-
Ophthalmology and Visual Sciences, The University
ucts and each child has a 25 % chance of inherit-
of Western Australia , Crawley , WA , Australia
e-mail: [email protected] ing the condition; and m itochondrial, a mutation
E.P. Rakoczy (ed.), Gene- and Cell-Based Treatment Strategies for the Eye, Essentials in Ophthalmology, 1
DOI 10.1007/978-3-662-45188-5_1, © Springer-Verlag Berlin Heidelberg 2015
2 A.L. Magno et al.
in the mitochondrial DNA, it can only be inher- (cid:129) Inactivate, or “knock out,” a mutated gene that
ited from the mother, 100 % inheritance. is functioning improperly (Farrar et al. 2 012 )
Diseases caused by many contributing factors (cid:129) Introduce a new gene into the body to help
are called complex or multifactorial disorders. fi ght a disease (Lai et al. 2 002 )
Many common medical problems such as macu- One of the biggest barriers to the effi cacy of
lar degeneration, heart disease, diabetes, and obe- gene therapy is the cell wall. Each cell, normal or
sity do not have a single genetic cause but might diseased, is a small universe that fearlessly guards
be associated with changes in multiple genes with its barriers to maintain its own unique character-
lifestyle and with environmental factors. Although istics. Thus, for a successful gene therapy, a spe-
complex disorders often cluster in families, they cial carrier molecule, called a vector, must be
do not have a clear pattern of inheritance. used to penetrate the cell wall and force the cel-
lular machinery to produce the therapeutic gene
product.
1.1.1 The Problem Viruses have evolved a way of penetrating the
cell wall, encapsulating and delivering their genes
T he treatment of genetic disorders has proven to be to human cells, albeit in a pathogenic manner.
diffi cult, and the majority of these conditions to date With the development of recombinant technolo-
remain untreatable. Recently, the introduction of a gies, the viral genome can now be manipulated.
new class of pharmaceuticals, called biopharma- The manipulation of the viral genome removes the
ceuticals, has offered some hope. Traditional phar- disease-causing and replication genes but retains
maceuticals interfere with a biological function by the genes useful for a vector (Vannucci et al. 2013 ).
modifying the biological pathways. They are usu- The space created by the removal of the disease-
ally small synthetic molecules although there are causing and replication genes is then used for the
examples that are produced by living organisms, insertion of the therapeutic gene or transgene.
like antibiotics. Biopharmaceuticals are active gene Thus, recombinant viruses become carriers of the
products or proteins that are produced by recombi- piece of human DNA that codes for the therapeutic
nant organisms. Functionally they have the poten- gene. At present recombinant viruses are the most
tial of treating the underlying cause of a disease or effective performing the double tasks of penetrat-
correcting a genetic mutation. When a treatment ing the cell wall and converting a mammalian cell
uses a biopharmaceutical that can modify the to become a source of the therapeutic gene prod-
genetic makeup of human cells with the introduc- uct. It is important to note that due to their genetic
tion of a DNA code, it is called gene therapy. modifi cations, none of the recombinant viruses
used as vectors can multiply.
The fi rst step of recombinant virus-mediated
1.1.2 The Solution gene delivery is the transduction of the target cells
with the recombinant viral vector. The vector then
Gene therapy initially targeted diseases caused unloads the genetic material into the cells that after
by the lack of a gene product due to a genetic a short delay start producing the therapeutic protein
mutation (Wolff and Lederberg 1994 ). However , thus restoring normal function of the target cell.
with the development of technology, the defi ni- Different types of viruses can be used as gene
tion of gene therapy has widened, and nowadays therapy vectors: retroviruses, lentiviruses, adeno-
it refers to recombinant virus-delivered genes, viruses, herpes viruses, and adeno-associated
nonviral-delivered genes, and gene-modifying viruses. In terms of ophthalmic applications,
technologies like antisense and RNAi technolo- adeno-associated viruses have been extremely
gies and targeted mutations. successful, and the rest of this chapter will con-
Gene therapy aims to: centrate on their description.
(cid:129) R eplace a mutated gene that causes disease Adeno-associated viruses (AAV) are a class of
with a healthy copy of the gene (Acland et al. small defective parvoviruses (Atchison et al.
2001 ) 1965; Hoggan et al. 1 966) . They are ubiquitous