Discovery and development of therapeutic aptamers.

Therapeutic aptamers are single-stranded structured oligonucleotides that bind to protein targets with high affinity and specificity and modulate protein function. Aptamers are discovered by iterative rounds of selection for binding to the target protein, partitioning, and amplification of binding clones from a diverse starting library (SELEX). Postselection optimization of clones using chemical modification is directed at improving affinity, potency, and metabolic stability. A key attribute of therapeutic aptamers is the ability to tailor the pharmacokinetic profile by modulating the degree of metabolic stability and modulating renal clearance and rate of distribution by conjugation to various sizes of polyethylene glycol (PEG). In toxicology studies, therapeutic aptamers have been largely devoid of the previously reported oligonucleotide class effects of immune stimulation, complement activation, and anticoagulation; and the principal finding is the histologically visible accumulation of drug-related material in mononuclear phagocytes, a finding generally not considered an adverse effect. Good safety margins between the pharmacologically effective dose and toxicologically established no-adverse-effect levels have been observed consistently. There are presently seven aptamers either on the market or in clinical trials, but there is still much to be demonstrated in terms of chronic systemic use to fully realize the potential of this promising new class of drugs.