Viral vectors and delivery strategies for CNS gene therapy

Abstract

This review aims to provide a broad overview of the targets, challenges and potential for gene therapy in the CNS, citing specific examples. There are a broad range of therapeutic targets, with very different requirements for a suitable viral vector. By utilizing different vector tropisms, novel routes of administration and engineered promoter control, transgenes can be targeted to specific therapeutic applications. Viral vectors have proven efficacious in preclinical models for several disease applications, spurring several clinical trials. While the field has pushed the limits of existing adeno-associated virus-based vectors, a next generation of vectors based on rational engineering of viral capsids should expand the application of gene therapy to be more effective in specific therapeutic applications.

Figure 1. Gene therapy trials sinze 2000

(A) Total gene therapy clinical trials from 2000–2009 by vector, excluding nonviral delivery. (B) Gene therapy trials involving the central or peripheral nervous system (excluding cancer), from 2000–2009 by vector. This figure was compiled by searching the database at [201].

Figure 2. General categories of CNS gene delivery

In a broad sense, the difficulty of a gene therapy for any given disease depends on three factors: the range of vector delivery that must be achieved, the range of therapeutic effect that the transgene will impart, and how much knowledge about the disease is available to guide the choice of transgene and the extent that regulation is necessary. In this regard, a localized therapy with a secreted factor represents the easiest therapeutic approach, while a cell-autonomous transgene requiring widespread efficient vector delivery represents the most difficult. The third dimension (not shown) to predict the success of a gene therapy approach for any given disease is the available data about the disease to guide the design of an appropriate therapeutic gene cassette.

Figure 3. The blood–brain barrier represents a significant obstacle to CNS gene delivery

(A) Blood vessel through the brain parenchyma. (B) Cross-section of the blood vessel and the barriers a molecule would encounter crossing from the bloodstream into the brain parenchyma. A molecule would have to pass through the endothelial cell tight junctions or undergo transport across the endothelial cells themselves. Next the molecule would encounter the basal lamina and astrocytic endfeet.