Aptamers as therapeutics

Abstract

Nucleic acid aptamers can be selected from pools of random-sequence oligonucleotides to bind a wide range of biomedically relevant proteins with affinities and specificities that are comparable to antibodies. Aptamers exhibit significant advantages relative to protein therapeutics in terms of size, synthetic accessibility and modification by medicinal chemistry. Despite these properties, aptamers have been slow to reach the marketplace, with only one aptamer-based drug receiving approval so far. A series of aptamers currently in development may change how nucleic acid therapeutics are perceived. It is likely that in the future, aptamers will increasingly find use in concert with other therapeutic molecules and modalities.

Figure 1. Aptamer modifications.

a | Nucleotides can be modified by replacing the 2′ position with either a fluoro- (F), amino- (NH₂) or O-methyl (OCH₃) group for enhanced nuclease resistance. These modified nucleotides can be introduced either chemically or enzymatically. b | Bridging phosphorothioates can be incorporated enzymatically. c | End caps that involve reversing the polarity of the chain can be incorporated during chemical synthesis. d | Linkers are often inserted at the 5′-ends of aptamers by either chemical or enzymatic means to provide handles for conjugation or to alter pharmacokinetic properties. B, base; PEG, polyethylene glycol.

Figure 2. The pharmacokinetics of aptamers conjugated to different molecular mass PEGs.

Pharmacokinetic profiles of 39-mer 2′-deoxy purine, 2′-O-methyl pyrimidine composition aptamers. These aptamers were unconjugated or conjugated to either 20 kDa polyethylene glycol (PEG) or 40 kDa PEG and administered intravenously to CD-1 mice (n = 3 per time point) at 10 mg per kg. Data redrawn from Ref. .

Figure 3. Crystal structure of the all-DNA parent of ARC1779 bound to the A1 domain of von Willebrand factor.

Figure 4. Aptamer architectures for therapy.

a | OX40-specific aptamers were hybridized to an 'organizer' consisting of two antisense oligonucleotides separated by a polyethylene glycol (PEG) spacer^,. b | Prostate-specific membrane antigen (PSMA)-specific aptamer A9 and 27-mer small interfering RNAs (siRNAs) were biotinylated (B) and conjugated to streptavidin (SA). c | PSMA-specific aptamer A10 was extended with a sequence that promoted hybridization to the guide strand of a siRNA. The processed extension of the aptamer can then participate in gene silencing. d | PSMA-specific aptamer A10 was extended with a short hairpin RNA-like sequence. Processing again leads to gene silencing.