Dr. Wahlestedt’s laboratory pursues drug discovery and evaluation of combination therapies for various cancers. His team has been successful in identifying and bringing forward – towards testing in human – several novel inhibitors of epigenetic and other drug targets. They are also conducting personalized ex vivo drug screening (with the cancer patient’s own cells) to aid optimized treatment.
RNA targeted gene upregulation and therapeutic combination strategies
Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Oligonucleotides can be utilized not only to reduce gene expression but also to achieve gene upregulation through targeting of various categories of RNAs associated with gene expression. Notably, perturbation of endogenous noncoding natural antisense transcripts (NATs; a sub-class of long noncoding RNAs) by AntagoNAT oligonucleotides, in vitro or in vivo, typically reveals discordant inhibitory regulation and results in locus specific up-regulation of conventional (protein-coding) gene expression. AntagoNATs are oligonucleotides that antagonize NATs either by blocking or cleaving them.
In the past, we identified AntagoNATs for upregulation of some 100 human protein coding genes of medical interest. Notably, one clinical stage project is based on targeting a NAT controlling the expression of a brain sodium channel, SCN1A, with an AntagoNAT designed to restore haploinsufficient channel function in Dravet disease, a severe form of childhood epilepsy.
This lecture will describe a few novel aspects of gene upregulation technologies and assess synergies of combinatorial strategies with AntagoNATs and other oligonucleotides having distinct RNA targets and mechanisms of action.