Gene Therapy in Spinal Muscular Atrophy (SMA) Models Using Intracerebroventricular Injection into Neonatal Mice - Gene Delivery and Therapy for Neurological Disorders - page 297

Chapter 12

Gene Therapy in Spinal Muscular Atrophy (SMA) Models
Using Intracerebroventricular Injection into Neonatal Mice

Monir Shababi , Erkan Y. Osman , and Christian L. Lorson

Abstract

Successful gene therapy for neurodegenerative disorders in clinical trials depends upon the success of the
gene therapy applications in preclinical models of the disease. Preclinical animal studies often proceed to
larger animal models and are subsequently incorporated into the fi nal design of the clinical trials. Recent
gene therapy advancements with preclinical animal models of spinal muscular atrophy (SMA) have made
the move from the bench research to an actual treatment a more achievable reality. In this chapter, we
gathered the most recent gene therapy advancements in SMA animal models and discuss the possibility of
gene therapy clinical trials. We will also discuss the outcome of our gene therapy approaches in the trans-
duced tissues of SMA mice using single-stranded and self-complementary AAV vectors. One method of the
transgene delivery into the central nervous system (CNS) is intracerebroventricular (ICV) injection. In this
chapter, we provide a detailed protocol of the ICV injection into the murine brain at early postnatal time
points with photographs demonstrating each step of the process.

Key words Gene therapy, AAV vectors, SMN, SMA, ICV injection

1 Introduction

An important impediment of using gene therapy approach for neu-
rological diseases is the lack of knowledge regarding the molecular
and genetic basis of the disease. Discoveries of genetic, molecular,
and cellular origin of several neurodegenerative diseases along with
advances in gene transport systems have led to exciting therapeutic
interventions in the CNS disorders, although the genetic cause of
many neurological disorders is still unknown. Gene therapy with
CNS provides a wide variety of options to treat different neuro-
logical diseases. These options include, but are not limited to, (1)
transplantation of genetically modifi ed cells to replace the dead
cells, (2) direct delivery of a transgene which complements a miss-
ing gene, and (3) delivery of a therapeutic molecule (antisense oli-
gonucleotide, siRNA, microRNA) to repair the mutated gene or
silence the expression of an aberrant gene. The potential of basic