Use of antisense oligonucleotides to treat rare diseases

By Rosie Davies


A rare disease is a disorder that affects less than 5 in 10,000 of the general population. Although individually rare, as a whole, there are up to 8000 known rare diseases, affecting approximately 3.5 million people in the UK[1]and impacts tens of millions of individuals globally. Moreover, the number of newly published rare diseases is increasing at a rate of about five a week[1]. This is partly due to a revolutionary method of diagnosis by use of next generation technologies to detect detrimental changes in DNA. Despite better diagnosis and, with it, expanding knowledge about these conditions, there are very few therapeutic options available for patients with ultra-rare diseases.

In recent years however, development of a group of small molecules to target and treat genetic diseases has emerged. Antisense oligonucleotides (AONs, or less commonly ASOs) are short, synthetic, single stranded molecules that are designed to specifically bind to DNA targets and change downstream expression. They can work through a variety of mechanisms, either to reduce expression of mutant proteins by breakdown of the targeted transcript or restore protein expression through interference with pre-mRNA splicing[2].

AONs have been engineered with the intention of manipulating disease since 1978[3] with the first FDA approved AON therapy to treat cytomegalovirus retinitis in AIDS patients in 1998*[4]. However, the recent success of AON therapies is best illustrated in rare diseases. Key examples where these molecules have been approved by the FDA as investigational new drugs (INDs) for rare diseases include eteplirsen for Duchene Muscular Dystrophy[5], SPINRAZA for treatment of spinal muscular atrophy (SMA)[6] and QR-110 for Leber Congenital Amaurosis (LCA)[7]. And these small molecule drugs are on the rise; out of 59 new molecular entities being FDA approved in 2018, 64% of therapies were small molecule drugs, such as AONs[8]. The numbers are a reflection of pharmaceutical companies’ new interest in creating therapies to tackle rare, genetic diseases.

A recent success story occurred within just a year from first patient contact to launching of a tailormade treatment. The patient, a 6-year-old girl, was treated with a new AON therapy that appeared to halt progression of the neurodegenerative disorder, Batten’s Disease[9]. Batten’s Disease is a recessively inherited, progressive and fatal disorder caused by dysfunctional lysosomes and subsequent build-up of fatty substances in the cells of the brain, central nervous system and retina. Affecting 100-150 children in the UK, usually there are few treatment options. Now, a group at Boston Children’s Hospital have been able to engineer the first patient specific therapy for a mutation in CLN7, a key lysosomal gene. The mutation, a maternally inherited retrotransposon inserted into an intron of CLN7, was first identified through whole genome sequencing and RNA-sequencing. This insertion led to an additional fragment of DNA being incorporated into the downstream mRNA and subsequent gene inactivation[9]; essentially, it was as if the gene was not present in the patient at all.

Scientists at Boston Children’s Hospital designed the AON to ignore the genetic change and rectify the defect, initially in the patient’s cells in vitro, where it was shown to reverse lysosomal dysfunction and produce a functioning CLN7protein. The first in human trial is ongoing in the patient after being approved as an IND by the FDA under the drug name Milsen and early results have reported to arrest further clinical deterioration and reduce seizure intensity and frequency. Furthermore, no safety or tolerability issues have risen[9].

This study and development of other AON therapies discussed here illustrates an end-to-end pathway from genomic diagnosis to individualised, precision therapy. Although this treatment cannot be used to treat every genetic disease – successful AONs must be tailormade to each individual mutation and fulfil criteria to be specific, stable and able to trigger changes in gene expression to remedy the disease – they do open up possibilities and avenues for development of new treatments for rare, genetic diseases where they did not exist before. This work contributes towards the overall goal of helping alleviate the burden of rare diseases.

*This AON was later voluntarily withdrawn from market due to improvements in other HIV/AIDS medications.


  2. Rinaldi and Wood, 2017.
  3. Stephenson ML, Zamecnik PC. 1073/pnas.75.1.285
  4. Roehr B (1998) Fomivirsen approved for CMV retinitis. J Int Assoc Physicians AIDS Care
  5. Charleston et al., 2018. 10.1212/WNL.0000000000005680
  6. Scoto et al., 2018.
  7. Dulla et al., 2018.
  8. Jarvis, 2019, Chemical & Engineering News.
  9. Yu et al., 2018.

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