Development of quantitative molecular clinical end points for siRNA clinical trials

Robyn P. Hickerson, Sancy A. Leachman, Lana N. Pho, Emilio Gonzalez-Gonzalez, Frances J.D. Smith, W. H.Irwin McLean, Christopher H. Contag, Devin Leake, Leonard M. Milstone, Roger L. Kaspar

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


RNA interference (RNAi) is an evolutionarily conserved mechanism that results in specific gene inhibition at the mRNA level. The discovery that short interfering RNAs (siRNAs) are selective, potent, and can largely avoid immune surveillance has resulted in keen interest to develop these inhibitors as therapeutics. A single nucleotide-specific siRNA (K6a-513a.12, also known as TD101) was recently evaluated in a phase 1b clinical trial for the rare skin disorder, pachyonychia congenita (PC). To develop a clinical trial molecular end point for this type of trial, methods were developed to: (1) isolate total RNA containing amplifiable mRNA from human skin and callus material; (2) quantitatively distinguish the single-nucleotide mutant mRNA from wild-type K6a mRNA in both patient-derived keratinocytes and patient callus; and (3) demonstrate that repeated siRNA treatment results in sustained inhibition of mutant K6a mRNA in patient-derived keratinocyte cultures. These methods allow noninvasive sampling and monitoring of gene expression from patient-collected shavings and may be useful in evaluating the effectiveness of RNAi-based therapeutics, including inhibitors that specifically target single-nucleotide mutations.

Original languageEnglish (US)
Pages (from-to)1029-1036
Number of pages8
JournalJournal of Investigative Dermatology
Issue number5
StatePublished - May 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology


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