Problems with Gene Therapy

Final lecture before the test! This lecture was super light on content- most of the slides (and there were only 14) included a bunch of ethical questions to think about as well as links to other associations for students who want more information. I'm just going to deal with the content part, so this will be a short blog post.

Factors that have slowed gene therapy development

Despite decades of research into gene therapies, several factors have hindered development of actual treatments. For starters, most corrections are only short-lived, particularly when whole-cell transplantation is used as the cells may be attacked by the immune system. Therefore, multiple doses are normally needed, which might be difficult due to said immune response. Delivery to cells can also be problematic as you need a vector that can accommodate the desired gene and deliver it to its target. Furthermore, most target cells are somatic, non-dividing cells, so the correction won't be propagated. Finally, many diseases involve multiple genes, and possibly a combination of genes and environmental factors, making it difficult to design a gene therapy.

Since I just mentioned vectors, I'll go into vectors in a bit more detail. As mentioned here, the main vectors used are adenoviruses, AAVs, HSV and retroviruses. All of these (except for AAVs) can provoke immune responses. Retroviruses can be particularly problematic as they randomly integrate into the genome (unlike AAVs which always integrate into chromosome 19), which may interrupt a normally functioning gene.

New developments that are helping gene therapy

Of course, it's not all gloom and doom. Several strategies are being used to help the development of gene therapy. For example, as mentioned here, siRNAs, exon skipping, and CRISPR-Cas9 have all been explored for their potential to alter gene expression. Another factor helping gene therapy development is improved liposomal targeting of the brain, which may help treat Parkinson's and Alzheimer's. Yet another new development is Chimeric Antigen Receptor (CAR) T-cell therapy, in which T-cells are isolated from the patient, engineered to express chimeric antigen receptors (CARs) that recognise cancer cells, and reinfused into the patient.

Not many gene therapy drugs have made it through to market, but here's a few that have:

1. Glybera was the first drug to make it to market (in 2012). It is a treatment for lipoprotein lipase (LPL) deficiency, and consists of a human LPL gene delivered by an AAV1 viral vector.
2. Kymriah is a CAR drug used to treat acute lymphoblastic leukaemia (ALL).
3. Yescarta is another CAR drug used to treat large B-cell leukaemia.