Intended for healthcare professionals


Nucleic acid based therapies: developing frontier for precision medicine

BMJ 2018; 360 doi: (Published 23 January 2018) Cite this as: BMJ 2018;360:k223
  1. Munir Pirmohamed, professor
  1. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
  1. munirp{at}

Affordability will be the key challenge

The genomic revolution, heralded by completion of the human genome project, is providing unprecedented knowledge of the underlying genetic basis of disease. In the UK, the 100 000 genomes project is beginning to uncover the genetic basis of rare diseases, ending the diagnostic odyssey that many families have had to face up to now. Precision diagnosis, however, is only the first step in the development of new precision therapies. The molecular basis of disease needs to be understood to enable the development of treatments targeted at individuals with specific mutations, to repair or overcome the underlying molecular defect.

Understanding of the molecular basis of cystic fibrosis has already led to the development of small molecules, such as ivacaftor, that improve the functioning of the cystic fibrosis transmembrane conductance regulator (CFTR) in people with the G551D gene mutation—around 4% of those with cystic fibrosis.1 Identifying novel mutations can also allow the repurposing of existing medicines. An example is the use of high dose riboflavin in childhood motor neurone disease, a condition caused by mutations in the riboflavin transporters SLC52A and SLC52A.2

Gene therapy for haemophilia

Over the past year, some big advances have been made using nucleic acid based therapies. People with haemophilia A, an X linked disorder, currently require frequent infusions of factor VIII to prevent bleeding episodes. A recent small and preliminary dose ranging study using an adenovirus gene therapy vector showed that factor VIII concentrations returned to normal 52 weeks after a single infusion in six out of seven participants, with a reduction in bleeding episodes and rescue factor VIII infusions.3 If the results were replicated in much larger studies this could be a remarkable advance for patients with a disablingdisease. Key to this will be the confirmation of long term effectiveness and safety, including whether the body mounts immune responses to the viral vector.

Gene therapy has had a chequered history, but improved methods of packaging gene inserts and their delivery may finally be on the verge of producing transformational developments, not only for patients with haemophilia A3 but also for those with sickle cell disease,4 junctional epidermolysis bullosa,5 and RPE65 mediated inherited retinal dystrophy.6

Antisense therapy

Antisense oligonucleotides provide another form of nucleic acid therapy. These single stranded oligonucleotides bind to their complementary mRNA, affecting splicing and restoring protein synthesis.7 This is exemplified by the antisense oligonucleotide nusinersen, recently licensed for the treatment of spinal muscular atrophy, which works on the SMN2 gene, producing a full length protein. A randomised controlled trial in 121 patients showed that treatment early in life significantly reduced mortality and improved motor function.8 The cost is, however, enormous ($750 000 (£530 000; €610 000) for the first year and $375 000 per year thereafter), which prompts questions about whether it is affordable.

Antisense therapy can also be used to prevent the formation of a mutated protein.7 A lot of media excitement was generated by the announcement of a phase I trial finding that the drug Ionis-HTTRx, reduced the levels of the mutant huntingtin protein in cerebrospinal fluid of 46 patients with early Huntington’s diseasein a dose dependent manner.9 The trial has not been published, and it is too early to know whether longer term therapy will improve symptoms and survival. However, if this were shown to work clinically it would be truly transformational.

Promise for the future

Finally, genome editing holds great promise. We now have the ability to edit DNA to remove a mutation, correct a mutation, or alter the sequence of a gene at a precise location in the genome by using engineered nucleases such as the CRISPR-Cas9 system.10 Genome editing of embryos is already possible, as highlighted by a recent study in which a mutation in the MYBPC3 gene (which causes hypertrophic cardiomyopathy) was repaired.11 Changes in the genome can be passed from one generation to another. This brings up ethical challenges, with (perhaps unfounded) fears that it could pave the way to the development of “designer babies.” Another concern relates to the specificity of the CRISPR-Cas9 system and whether it may produce unintended “off-target” mutations.10

Somatic gene therapy is perhaps less of a concern ethically and is already finding application in malignancies. T cell therapies using chimeric antigen receptors (CAR) have been used successfully in malignancies such as acute lymphoblastic leukaemia, leading to the first FDA approval of such treatments. Tisagenlecleucel, a CAR-T cell therapy targeting the CD19 lymphocyte antigen, has a list price of $475 000 for a one time infusion.12

Advances in nucleic acid based therapies over the past few years have been remarkable, providing treatments for serious diseases that have had few or even no satisfactory therapeutic options. But it is important not to overhype the promise of these technologies. We need a realistic approach that allows proper assessment of efficacy and development of monitoring strategies to assess long term safety, especially since only small numbers of patients are likely to be treated, at least initially. A key challenge will be affordability of these new therapies, particularly since many may not be cost effective in conventional health economic models.


I thank the MRC Centre for Drug Safety Science, the NIHR CLAHRC North West Coast, and Wolfson Foundation for support.


  • Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.

  • Provenance and peer review: Commissioned; not externally peer reviewed.


View Abstract