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On the Cusp of Future Gene Therapies

Gene therapy is at an inflection point. Many gene and cell therapies have been approved in recent years following decades of effort. However, while these therapies target specific disorders, many have great potential to be extrapolated to other conditions and patient populations and this has been dramatically expanded by next-generation technologies. This paper, published by Nature, offers a brief review of the current and future gene therapies.

Current Successes in Gene Therapy

The field of gene therapy has been revived in recent years, with new therapies finally approved following decades of work. These novel therapies have been used to treat a range of clinical disorders, including neuromuscular disorder, inherited blindness and cancer. While these treatments have been ground-breaking for affected patients, they also provide a strong foundation for the development of future treatments for many other conditions.

For example, the successful in vivo AAV gene transfer to the human retina and central nervous system has been used to treat congenital amaurosis and spinal muscular atrophy, respectively. This research has also inspired AAV-based therapies for gene delivery to other organs, such as the liver to treat haemophilia. However, despite this success, ~50% of patients are currently excluded from AAV-based gene therapies due to pre-existing immunity to the viral capsids used. 

Recent technological advances and next-generation technologies have allowed us to side-step this immune obstacle. For example, AAV capsids can be modified to evade pre-existing neutralising antibodies, and other methods exist to temporarily clear antibodies from circulation. Furthermore, the engineering and profiling of non-viral nanoparticles for gene delivery has undergone considerable increases in throughput.

Gene Editing Technologies

Beyond the delivery of transgenes, gene editing technologies are providing a new modality for treatments. Recent successes in this technology include CRISPR-based gene editing for sickle cell disease and beta-thalassemia.

However, expanding existing treatments to new target tissues does not come without its challenges. The National Institute of Health (NIH) has announced a commitment of $190 million over 6 years to support a Somatic Cell Genome Editing Consortium. This group will address issues in delivery, safety, and modelling, and are likely to accelerate the progression of gene editing therapies over the following decades.

Gene Therapy of the Future

Current gene editing technologies use nuclease-based systems to cut DNA and stimulate DNA repair pathways to introduce desired sequence changes. While these therapies are only just beginning clinical testing, a plethora of next-generation editing technologies are hot on their heels. Many of these new therapies boast increased specificity, accuracy, efficiency, and applicability to different classes of disease. 

For example, base editing and prime editing interventions allow precise genomic alterations without requiring DNA breaks or the activity of the endogenous DNA repair pathways. Alternatively, RNA-targeted editing allows the temporary and reversible alteration of gene expression. This excludes the need for permanent changes to the genome and may increase the efficiency and safety of these approaches. 

Our ability to target DNA is also continuously growing. New CRISPR-Cas systems are constantly being derived from new engineered variants and various bacterial species. The rapid technological innovation in these editing fields is likely to dramatically broaden the scope of disease to which these approaches can be applied.

Functional Genomics

Innovation in functional genomics and our understanding of genome regulation will dramatically impact gene therapy in the near future. Currently, the function of ~6000 of the ~20,000 human genes is known. CRISPR also plays a vital role in facilitating the functional dissection of target gene sequences to aid this understanding. 

Furthermore, while traditional therapeutic interventions have focused almost exclusively on genes, ~98% of our genome consists of non-coding DNA and epigenetic regulators. These are estimated to be responsible for over 90% of susceptibility for common disease. In fact, the first example of an effective CRISPR gene editing approach involved the editing of a distal gene regulatory element to alter gene expression, rather than targeting the underlying genetic mutation.

Efforts such as the NIH ENCODE Consortium have mapped over 2 million gene regulatory elements. These exist across a range of human cell types and tissues, however, the function of most sites are unknown. Annotation of this dark matter of the genome may lead to a whole new scope of research and therapeutic targets.

Concluding Remarks

Gene therapy is arguably the most exciting area of biotechnology at the moment. Researchers are attaining unprecedented levels of control over nucleic acid delivery, immune system modulation and precise genome manipulation. These technologies were unimaginable ten years ago and will certainly unlock new scopes of medicine in the coming years. This small glimpse of a new world of technical capabilities has inspired whole new areas of research. Synthetic biology, cell reprogramming and high-throughput functional genomics may revolutionise the face of future biomedical research.