Until recently, children and adults with devastating genetic conditions like Duchenne muscular dystrophy (DMD) or spinal muscular atrophy (SMA) had no choice but to accept their fate: that their condition was incurable and ‘undruggable’ – meaning that the management options available were woefully inadequate.
DMD, for one, is a devastating genetic condition where mutations in the dystrophin-encoding DMD gene cause progressive muscle weakening and death. From the onset of symptoms at age one to three years old, patients progress rapidly to wheelchair then ventilation dependency, before premature death in their 20s and 30s.
Before PTC Therapeutics’ Translarna (ataluren) was approved in the European Union in 2014, there were no disease-modifying treatments available to treat the condition. A more recent treatment for DMD, Sarepta Therapeutics’ Exondys 51 (eteplirsen), was then approved in the US in 2016, offering patients a precision medicine in the form of an oligonucleotide-based therapy, an innovative therapeutic modality that employs a novel mechanism of action. Exondys works by interfering in the translation of the mutated DMD gene, causing the translation to ‘skip’ a step and thus produce a shorter but functional dystrophin protein. Although not a cure, this should delay disease progression.
Oligonucleotides are essentially short DNA or RNA molecules that function in the regulation of gene expression, and can be synthesised in the lab. The novel mode of action of oligonucleotide-based therapies offers hope for many patients and their families, who may now receive adequate treatment for their ‘undruggable’ conditions – so called because they are refractory to standard drug therapies.
Advanced analytics from bench to bedside
However, the complexity of oligonucleotides raises challenges for manufacturing and regulation. While chemically synthesised in a similar manner to that of traditional small-molecule drugs, their diverse mode of action at the cellular level better resemble those of biologic therapies. This lack of a ready categorisation as a small or large molecule means that regulatory authorities have had to devote special attention to this new therapeutic modality.
To help meet these challenges, analytical technologies have advanced in parallel with those of synthetic oligonucleotide science. The quantification and characterisation of synthesised oligonucleotide product is essential in drug discovery, development and manufacture – to analyse, characterise and ensure the stability, purity, efficacy and safety profile of the drug. Mass spectrometry and capillary electrophoresis methodologies are now the preferred solutions for analysing oligonucleotides.
With other approved oligonucleotide-based drugs, such as Biogen’s Spinraza (nusinersen) and Jazz Pharmaceuticals’ Defitelio (defibrotide), and several other oligonucleotide therapies in research pipelines, quantitation scientists are refining these methodologies to be more efficient, sensitive, specific and robust.
By engaging with biomedical scientists in open collaboration, they ensure these advances address real-world challenges in drug development and commercialisation. This translates into accelerated drug development and manufacture, so that the promise of oligonucleotide therapies can be more quickly realised time and time again for patients with rare undruggable disorders.
Mani Krishnan is vice president of Global Biopharma and Capillary Electrophoresis at SCIEX
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