Masterarbeit
Oligonucleotide-based Therapeutics, Development and Regulatory Challenges ***
Mariana Lagos Quintana (2016)
Summary
Oligonucleotide-based therapeutics are categorised based on their mode of action, in either (1) antisense oligonucleotides (ASOs), which are inhibitors of RNA activity, namely siRNAs, miRNA mimics, anti-miRs, splicing modulators, RNAse H-dependent mRNA ASOs, and steric blockers of mRNA translation) or (2) modulators of protein activity (aptamers). The understanding of the underlying biological processes and the technology for chemically synthesizing oligonucleotide therapeutics has been developed and advanced along the last four decades. These therapeutics have progressed into the clinic and in 1998 the first nucleotide drug was approved by the FDA. However, to date, there are only four oligonucleotides that have received marketing authorisation, raising the question whether this therapeutic approach will indeed play a role in the future of disease treatment.
The pharmacokinetic characteristics of oligonucleotide drugs with chemical structures similar to that of naturally occurring nucleic acids, makes them poor therapeutic candidates, as they are immediately degraded in vivo by nucleases and do not have adequate pharmacokinetic properties. To overcome these limitations, different chemical modifications are introduced to oligonucleotide chains, which render them nuclease-resistant, increase their RNA-binding affinities, and change their pharmacokinetic properties, including their capacity to enter target cells. As these ever-evolving drug candidates progress along preclinical and clinical development programs, both industry and regulatory agencies representatives have encountered many regulatory challenges, among them the lack of guidance for this unique class of drugs. A group of experts responded by assembling the Oligonucleotide Safety Working Group (OSWG) in a collaborative attempt to create a consensus on how to plan and develop safety testing programs and how to approach regulatory evaluations. Beyond the work of this group, the numerous development programs for oligonucleotide therapeutics have generated a growing amount of data, which although lacking significant post-marketing experience, contributes to the better understanding of the pharmaceutical characteristics of subclasses of oligonucleotides. Lastly, advances on oligonucleotide delivery systems play a game-changing role in turning the field of oligonucleotide therapeutics into a therapeutic reality.
Pages: 48, Annexes 1, Pages: 8