Masterarbeit
Developmental and Regulatory Challenges Regarding AAV-Based Gene Therapy for CNS Disorders ***
Christof Kugler (2020)
Summary
Language: English
Disorders of the central nervous system (CNS) have traditionally been difficult to treat. The medical literature has described a plethora of diseases that affect various cell types in different parts of the brain, spinal cord, or eye. Consequently, a large pool of treatment modalities has been developed, ranging from rehabilitative procedures, application of stimuli, or prescription of medicinal products such as small molecules or biologicals. Recently, gene therapy medicinal products (GTMPs), a sub-class of advanced therapy medicinal products (ATMPs), garnered renewed interest and hold promise to change course of some of these diseases.
What is particularly interesting about gene therapy approaches for CNS disorders is the notion that administration induces a long-lasting, if not permanent, treatment effect. This approach is rendered even more attractive when one considers the inaccessibility of the brain (or other parts of the CNS), which is stringently sealed off from surrounding circulation by the blood-brain barrier. Consequently, gene therapy offers the potential to introduce corrective components through a single administration.
Adeno-associated viral vectors (AAVs) are the workhorses of many gene therapy trials worldwide. In comparison to other (viral) delivery vehicles they possess favorable characteristics such as stable host cell transduction, adequate packaging capacity to deliver almost any therapeutic gene, and absence of host genome integration. However, inherent characteristics such as induction of the host immune system pose significant translational impediments. Furthermore, developmental challenges regarding host tissue tropism, route of delivery and production-related issues must be overcome to garner regulatory approval.
To this end, I performed a systematic literature review of AAV-based gene therapy approaches for CNS disorders. This work will introduce and discuss key aspects that drive AAV development, review pre-clinical trials of the past three decades, and highlight current clinical trials that pursue gene therapeutic approaches through AAV delivery. In light of recently approved in vivo GTMPs regulatory challenges will also be discussed. Indeed, in its 2025 strategic reflection paper on regulatory science EMA identified the translation of ATMPs into patient treatments an overarching goal that should draw increased attention.
Pages: 52