Fast Facts: Gene Therapy

A New Therapeutic Direction?

R. Herzog, L. Popplewell, Roland W. Herzog, Linda Popplewell

• Publisher: S. Karger
• Year: 2020
• Print ISBN: 9783318066661
• eBook ISBN: 9783318066678
• Topic: Medicine
• Subtopic: Family Medicine & General Practice

Gene therapy has emerged as a discipline in medicine that can provide treatments for diseases that have no other therapies available, save lives of patients for whom there is no other hope and replace suboptimal treatments with lasting cures. 'Fast Facts: Gene Therapy' provides an overview of the field, looking at the main vector systems used to transfer the therapeutic gene constructs, the molecular mechanisms and the history of gene therapy, as well as the safety and ethical considerations of this important advance. Multiple examples of diseases that are already successfully treated with gene therapy are given, with discussion of treatments that hold promise for the future. This book will be informative and of value to health professionals, researchers, students and anyone with an interest in this exciting and fast-moving area.

4	Gene therapies with proven clinical efficacy

Several gene therapy drugs are now approved by the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) to be marketed as medicines (Table 4.1). Others have shown strong efficacy in early clinical studies and are therefore being evaluated in Phase III trials.^1–4 Examples of gene therapies with track records of clinical efficacy are described in the following sections and summarized in Table 4.2.

Hereditary blindness

Prior to gene therapy, no treatment was available for certain forms of hereditary blindness. However, the ability of adeno-associated virus (AAV) vectors to transduce retinal cells on subretinal administration has enabled the development of therapies for such diseases. This effort ultimately led to the first gene therapy drug approved by the FDA for the treatment of a genetic disease in late 2017.^5–8

Leber congenital amaurosis. In Leber congenital amaurosis type 2 (LCA2), mutations in the RPE65 gene prevent the expression of retinal pigment epithelium 65 kDa protein (RPE65), thereby impairing the process of visual photo-transduction and severely limiting vision. Inheritance is autosomal recessive. Affected infants typically already have decreased visual responsiveness at birth.

Initially, three independent clinical studies demonstrated that a single subretinal injection of AAV2 vector expressing the therapeutic RPE65 gene improved vision in treated regions of the retina.⁵ This improvement was stable for at least 3 years. One protocol was successfully expanded to pediatric patients.⁹ Importantly, early intervention substantially improved the potential for restoring vision. Patients showed an increase in pupillary light responses of 2 log units or more, with one child gaining light sensitivity near to that of age-matched normal-sighted individuals.

TABLE 4.1

Approved gene therapy medications*

Yescarta (axicabtagene ciloleucel; FDA, EMA): CAR-T cell therapy directed against CD19 in adult patients with relapsed or refractory DLBCL after two or more lines of systemic therapy Kymriah (tisagenlecleucel; FDA, EMA): CAR-T cell therapy directed against CD19 in patients up to 25 years of age with B-cell acute lymphoblastic leukemia that is refractory or in second or later relapse; and in adult patients with relapsed or refractory DLBCL after two or more lines of systemic therapy Luxturna (voretigene neparvovec; FDA, EMA): AAV vector for the treatment of Leber congenital amaurosis (by subretinal injection) Zolgensma (onasemnogene abeparvovec-xioi; FDA): AAV vector for the treatment of patients younger than 2 years of age with spinal muscular atrophy (by systemic delivery) Imlygic (talimogene laherparepvec; FDA, EMA): oncolytic viral therapy based on herpes simplex virus expressing GM-CSF for the treatment of unresectable lesions in patients with melanoma recurrent after initial surgery Strimvelis (EMA): retroviral vector for the treatment of ADA–SCID by HSC gene therapy

*At the time of writing. AAV, adeno-associated virus; ADA–SCID, adenosine deaminase deficiency–severe combined immunodeficiency; CAR, chimeric antigen receptor; DLBCL, diffuse large B-cell lymphoma; EMA, European Medicines Agency; FDA, (US) Food and Drug Administration; GM-CSF, granulocyte-macrophage colony-stimulating factor; HSC, hematopoietic stem cell.

As a safety precaution, patients participating in these early studies had received gene transfer to only one eye. Likely facilitated by the immune-privileged nature of the eye, subsequent vector administration to the contralateral eye was successful, with study participants demonstrating gradually improved sensitivity to dim light, activation of the visual cortex and improved navigational skills.⁶ Equally important, there were no adverse effects to their previously treated eye. As perhaps expected, functional gains from gene transfer to the second eye were more pronounced in younger patients. Children receiving the gene therapy experienced vast improvements in their quality of life, such as being able to attend school or participate in sports.

TABLE 4.2 Examples of successful treatments of human patients with gene therapy
Disease	Vector	Site of gene transfer	Route of administration	Target cells/tissue	Transgene product
LCA	AAV2	In vivo	Subretinal	Retinal epithelial cells	RPE65
SMA	AAV9	In vivo	Intravenous	Motor neurons	SMN1
MLD	Lentivirus	Ex vivo to autologous HSC	HSC transplant	CNS	ARSA
ADA–SCID	Retrovirus	Ex vivo to autologous HSC	HSC transplant	Immune system	ADA
Hemophilia A	AAV (different capsids)	In vivo	Intravenous	Hepatocytes	Factor VIII
Hemophilia B	AAV (different capsids)	In vivo	Intravenous	Hepatocytes	Factor IX
B-ALL	Lentivirus	Ex vivo to primary T cells	T-cell transplant	CD19-expressing cells	CD19-specific CAR
DLBCL	Lentivirus	Ex vivo to primary T cells	T-cell transplant	CD19-expressing cells	CD19-specific CAR
AAV, adeno-associated virus; ADA, adenosine deaminase; ADA–SCID, ADA deficiency–severe combined immunodeficiency; ARSA, arylsulfatase A; B-ALL, B-cell acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; HSC, hematopoietic stem cell; LCA, Leber congenital amaurosis; MLD, metachromatic leukodystrophy; RPE65, retinal pigment epithelium 65 kDa protein; SMA, spinal muscular atrophy; SMN1, survival of motor neuron 1, telomeric.

Success with LCA2 gene therapy has generated interest in developing gene therapy for other retinal diseases. For instance, successful outcomes of a gene therapy trial for choroideremia have been reported.¹⁰ In these patients, mutations in the X-linked CHM gene (which encodes Rab escort protein 1 [REP-1]) cause slow and progressive degeneration of photoreceptors, choroid and retinal pigmented epithelium, typically leading to complete blindness by middle age. REP-1 has important functions related to intracellular protein traff...

Table of contents

• Cover
• Title Page
• Copyright
• Contents
• List of abbreviations
• Glossary
• Introduction
• Principles of gene therapy
• Gene therapy techniques
• Ethical and safety considerations
• Gene therapies with proven clinical efficacy
• Genome editing
• Research directions – the next wave of treatments
• Useful resources
• Index