Nucleic acid aptamers against ADAMTS as a new therapeutic approach against degenerative disc disease

Abstract

ADAMTS-5 is a key protein involved in cartilage degradation and the progress of degenerative disc disease (DDD). It has previously been shown that mice deficient in the catalytic domain of ADAMTS-5 are protected from cartilage degradation. In humans, an unanswered question is the contribution of both ADAMTS-4 and ADAMTS-5 to cartilage maintenance. It is likely that ADAMTS-4 and ADAMTS-5 are good therapeutic targets for diseases of cartilage degradation, including DDD and osteoarthritis. Aptamers are 15-40 base single-stranded nucleic acids sequences which bind to their targets through conformational complementarity with high specificity and affinity, that are proven therapeutic agents used clinically. However, no therapeutic agents based on aptamers have yet been developed for a disease of bone or cartilage. In this study, we express and purify the catalytic domains of human ADAMTS-4 and -5 in different expression systems to enable the development of aptamers specific against each ADAMTS. Aptamers will then be selected and evolved (by Systematic Evolution of Ligands by EXponential enrichment, SELEX) against each target with corresponding counterselection to evolve specificity. The highly specific independent aptamers against ADAMTS-4 or ADAMTS-5 will then be used both individually and in parallel to dissect the biological functions of ADAMTS and will be a foundation for further therapeutic development.