The Challenge of Gene Therapy for Neurological Diseases: Strategies and Tools to Achieve Efficient Delivery to the Central Nervous System

Abstract

For more than 10 years, gene therapy for neurological diseases has experienced intensive research growth and more recently therapeutic interventions for multiple indications. Beneficial results in several phase 1/2 clinical studies, together with improved vector technology have advanced gene therapy for the central nervous system (CNS) in a new era of development. Although most initial strategies have focused on orphan genetic diseases, such as lysosomal storage diseases, more complex and widespread conditions like Alzheimer's disease, Parkinson's disease, epilepsy, or chronic pain are increasingly targeted for gene therapy. Increasing numbers of applications and patients to be treated will require improvement and simplification of gene therapy protocols to make them accessible to the largest number of affected people. Although vectors and manufacturing are a major field of academic research and industrial development, there is a growing need to improve, standardize, and simplify delivery methods. Delivery is the major issue for CNS therapies in general, and particularly for gene therapy. The blood-brain barrier restricts the passage of vectors; strategies to bypass this obstacle are a central focus of research. In this study, we present the different ways that can be used to deliver gene therapy products to the CNS. We focus on results obtained in large animals that have allowed the transfer of protocols to human patients and have resulted in the generation of clinical data. We discuss the different routes of administration, their advantages, and their limitations. We describe techniques, equipment, and protocols and how they should be selected for safe delivery and improved efficiency for the next generation of gene therapy trials for CNS diseases.

Cholesterol Hydroxylating Cytochrome P450 46A1: From Mechanisms of Action to Clinical Applications

“…These extensive studies provided strong support for CYP46A1 as a therapeutic target and suggested that a one-time CYP46A1 delivery approach could be translatable to human patients. Feasibility and safety proof-of-concept experiments in non-human primates are ongoing in preparation for the submission of a first clinical application in human patients ( Piguet et al, 2020 ).…”

Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies

“…In vivo gene therapy for leukodystrophies requires therapeutic gene transfer to the CNS which is compromised by the skull, the blood – brain barrier (BBB) and cerebrospinal fluid (CSF) – brain barrier (CBB). Delivery methods for rAAV to the brain include direct intraparenchymal (IP) injection, intracerebroventricular (ICV), lumbar intrathecal (IT) intra cisterna magna targeted intrathecal (ICM) and IV injections as well as nasal delivery which have been addressed in excellent recent reviews ( Hocquemiller et al, 2016 ; Piguet et al, 2017 , 2020 ; Hudry and Vandenberghe, 2019 ). In the following section, we review the advances in understanding of AAV vector targeting to provide context for the likely dominance of such gene therapy vector strategies for treating leukoencephalopathies in the future.…”

Novel treatments in Epilepsy guided by Genetic Diagnosis

“…Delivery is the major issue for central nervous system therapies in general, and particularly for gene therapy, the blood brain barrier restricts the passage of vectors thus strategies to bypass this obstacle are a central focus of research. Gene therapy products can be tailored to solve the pathophysiological mechanisms, including the use of gene replacement, gene silencing, transplicing, modulation of cellular pathways to improve phenotype or expression of suicide gene (Piguet et al 2021). There are only few gene therapies approved for the management of neurological disorders including two for SMA (Zolgensma-Novartis and Spinraza-Biogen) (Servais et al 2021).…”