The Use of Oligonucleotide Therapies in Rare Disease Research

Rare disease research is such a complicated area because it involves every therapeutic area individually and sometimes in unique combinations. Being able to develop treatments for these conditions requires a strong knowledge of those areas of the body that are impacted and the way that different drug platforms can influence those functions. 

At Allucent, we believe that rare disease research deserves a closer look. With that in mind, we reviewed an article from Nature (access it here) and began to explore rare disease research (read the article here). Going forward, we looked at some of the different drug development platforms that researchers leverage in rare diseases. We looked at small molecules (read it here), antibody therapy (click here to read the article), and protein replacement therapies (click here). In this article, we continue those efforts with a closer look at oligonucleotide therapies.

What are Oligonucleotide Therapies?

Oligonucleotide therapies interfere at a molecular level to influence gene expression or limit protein function. These drugs have three components. There are the nucleobases, which are often an RNA (ribonucleic acid) sequence, as well as sugar backbones and the linkages between these – phosphodiester bonds. Researchers can mix and match sequences. Oligonucleotide therapies are made from nucleotides which include genetic code so these therapies are very specific and targeted. In some cases, oligonucleotide therapies may be customized at an individual level. Even with such specificity, drugs leveraging this drug class can be developed rapidly.

Clinical Success in Oligonucleotides and Rare Disease Research

Developing drugs on this platform is a challenging process when taken as a whole but the number of drugs from this class has been rising steadily. There are three basic classes of oligonucleotide therapies that have evolved over time. The first is based on “antisense” oligonucleotides or ASOs. They are used to bind messenger RNA (mRNA) and inhibit gene function. The second is synthetic RNAs (siRNAs). These also inhibit and they are more complicated than their ASO counterparts. Most of the drug candidates in this category involve the delivery of the drug to the liver. The third class of oligonucleotide therapies restores gene function instead of inhibiting it and can be used to various effect including gene disfunction.

Strengths and Limitations of the Platform

Oligonucleotide therapies have strong clinical efficacy for certain diseases and conditions. For instance, an ASO was approved for people with AIDS in 1998. Other ways that oligonucleotide therapies are used include genetic diseases, cancers, and infections. This drug development platform also works well in treating neurological conditions, including hereditary transthyretin (TTR)- mediated amyloidosis and SMAQ caused by chromosome mutations. Further, drugs in this class can be highly-personalized and they can be developed fairly quickly in comparison to other drug classes. The development of big data helps.

That said, there are limitations. For one, safety is a major concern. Toxicity can be an issue. Further, personalized treatments may sound appealing and could be life-saving, but they can be expensive – possibly costing far beyond any investment that could be recouped by the developing companies. Plus, there is often a new version that promises lower rates of toxicity or greater effectiveness, and good science can get buried in the hype. 

Answering the Challenge of Rare Disease Research

The field of oligonucleotide therapy has had many setbacks. Moving forward, developments in science and technology may help reduce the costs associated with oligonucleotide therapies and make treatments available on a mass scale – but it will take time.

Please note, this post is the fifth in a series of eight articles centered on trends in rare disease research:

  1. Rare Disease Research
  2. Small Molecules
  3. Antibodies
  4. Protein Replacements
  5. Oligonucleotides
  6. Gene Therapy
  7. Drug Repurposing
  8. The Future of Rare Disease Research

For more information on Allucent’s rare disease experience, visit our website.


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