There is obvious benefit in having an antidote available to treat the consequences of accidental or deliberate drug overdose, as well as to counter unexpected adverse events. Although specific drug antidotes are available – including flumazenil, which reverses the effects of benzodiazepines and naloxone, which reverses the effects of opioids – these were not generally developed at the same time as the drugs whose effects they counter. Developing antidotes to individual medicines is not a cost-effective process but researchers at Duke University Medical Center have now described an approach that will reverse the effects of an entire drug class.
The team showed that their antidotes could reverse the effects of any of eight aptamers, regardless of sequence or target. Aptamers are highly structured single strands of RNA or DNA that bind to a specific target and offer affinity and selectivity to rival those of antibodies. Aptamers offer advantages over antibodies or small molecule drugs in that they are easy to prepare, can be chemically modified to enhance pharmacokinetic and pharmacodynamic properties, and have little or no immunogenic potential. Unlike other nucleic-acid based therapies, aptamers typically do not affect steps preceding protein synthesis, but directly modulate the activity of the target protein in a similar fashion to antibodies or small molecules. Aptamers targeting a diverse range of proteins have been described and pegaptanib, which targets vascular endothelial growth factor, has been approved by the FDA for the treatment of wet age-related macular degeneration.
The Duke approach exploits the fact that, when a patient receives a therapeutic dose of an aptamer, the drug is the only free extracellular oligonucleotide in the body and can be captured using protein- or polymer-based molecules such as protamine and β-cyclodextrin-containing polycations.
Bleeding is a common problem with anticoagulant therapy used to prevent blood clots during surgery or angioplasty, and the Duke team have just completed a series of successful clinical trials in patients receiving an anticoagulant aptamer and an antidote engineered to reverse the effects of the aptamer.
Since the neutralising polymers can reverse the action of any aptamer, the discovery has broad application and the team believe that further optimisation will improve the efficiency of sequestering aptamers from the circulation, and should spur the development of many new aptamer drugs.
The study is published in the journal Nature Medicine.