Year: 2019
Type: editorial
Abstract: Three years ago, Human Molecular Genetics commissioned a compendium on gene therapy approaches and advances (1). At that time, we had already witnessed substantial growth and development in the field and were in the midst of human trials, a solid advance from the stage that existed in 2011 (2). In 2016 we were closing in on possible approvals for genetic reagents that, when delivered, would dramatically and positively affect people’s lives. Today, there are drugs approved by both the Federal Drug Administration and European Medicines Agency. Regulatory agencies have approved treatments for inherited disorders including a rare inherited retinal dystrophy (caused by autosomal recessive mutations in the gene RPE65), a motor neuron disease (spinal muscular atrophy type 1, SMA-1) and a lipoprotein lipase deficiency, although the latter is no longer available for use. In addition, lentiviral-mediated ex vivo correction of primary immunodeficiencies and inherited hemoglobinopathies have been approved. For acquired disorders, T cells modified to express chimeric antigen receptors (CAR-T cells) received regulatory approval for B cell malignancies, setting the stage for similar CAR-T type therapy development. While individually each drug required enormous effort for approval, the path has now been paved for others to follow. In this issue, we have compiled reviews from experts in various fields where gene therapy approaches are being developed and refined. These reviews outline where we are to date, explain the barriers that remain for specific indications and discuss the roadmap for future advances. The hard work of careful and thoughtful scientific studies by many in the gene therapy field over the past several decades is finally bearing fruit—measured in the profound improvements experienced by patients, young and aged, with inherited genetic diseases or acquired disorders such as cancer. There has been recent important progress in viral and non-viral vectors, as well as the technologies for continued advancements that could open the door for new translational applications. For lentivirus vectors transgene expression cassettes are taking advantage of host-cell regulatory factors for enhanced control of gene expression. And, the scope and efficiency of cell targeting are being improved by expanding the variety of envelopes used to pseudotype the virion during vector production. For encapsidated vectors like recombinant adenoassociated viruses, in vivo evolution, capsid shuffling and the continued discovery of new serotypes deepen the toolbox of virions that can provide for transduction at lower doses or greater specificity for a given tissue or cell type. Improving the activity of the gene product being expressed is another important step forward, as it lowers the vector doses required for efficacy. Indeed, factor IX (FIX) Padua for hemophilia B (FIX deficiency) has 8-fold increased activity compared to the wild-type protein. Similarly, an anti-sickling hemoglobin variant is being used for the treatment of patients with sickle cell disease and thalassemia. Thus gene therapy advances are being extended not only by improvements in gene delivery technology but also through the use of advances in gene editing technologies and protein engineering. For example, through development of higher specific activity molecules that allow lower doses of vector, or of truncated proteins that preserve function and fit the packaging limitations of gene delivery vehicles (e.g. B domain-deleted FVIII; microdystrophins and alternative CRISPR systems). These discoveries should encourage researchers to identify variants with characteristics that can be harnessed for improved gene therapy dosing for additional disorders. The field will continue to apply new vectors and expression cassettes to a myriad of diseases, some of which have a poorly defined natural history. The gene therapy community should question whether we have the depth of experience in understanding the variance, or the root cause of that variance, to know if clinical outcomes have been improved with treatment. Can artificial intelligence algorithms or machine learning be used to help unravel new features of a clinical course that we miss when considering patients and their responses to treatment in isolation? Should we have different criteria or motivations when the goal is not to cure, but to improve to some defined degree, the quality of life rather than, or in addition to, the clinical course of disease? In the next compendium, some years ahead, we hope to have addressed these important questions and to be able to share with you additional advances in gene therapy that will have emerged from the collective creativity of a re-energized field.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddz182
Authors: Beverly L Davidson, Valder R Arruda
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2971752154