Preterm labor (PTL) and birth of low birth weight (LBW) infants are athe most significant causes of perinatal morbidity and mortality in the US. Annually, prematurity represents 11% of all live births, while about 7% of babies are of LBW. These data translate into nearby $5 billion spent annually to meet the immediate health care needs of premature, LBW infants. Obstetricians are hampered in their efforts to treat PTL due to the lack of medications which are efficacious and safe for another and fetus. This STTR project represents a novel therapeutic approach for tocolysis, utilizing antisense oligonucleotide technology. Antisense oligonucleotides (S-oligos) have been synthesized which bind to and inactivate the messenger RNA (mRNA) encoding cyclooxygenase-2), the rate-limiting enzyme in prostaglandin (PG) biosynthesis, which is part of the pathophysiology of PTL. In theory, since COX-2 mRNA is rendered inactive by the antisense S- oligos, no COX-2 enzyme is expressed, PGs are not synthesized, and the mechanisms driving PTL are not invoked. In Phase I, we demonstrated the scientific feasibility of this strategy and provided in vivo evidence that S-oligos can suppress COX-2 expression within intrauterine tissues. In Phase I, we will further evaluate the S-oligos and test: (i) Efficacy in vivo; (ii) pharmacokinetics and biodistribution; (iii) safety in vivo; and (iv) lack of immune system impairment. These four areas of investigation will serve to provide part of the necessary preclinical validation of the efficacy and safety of the antisense S-oligos directed against COX-2 for the eventual submission of an IND, clinical evaluation and commercialization.
The antisense drugs under development will replace or augment current tocolytics used to treat PTL. PTL affects approx. 350,000 pregnancies in the US at an annual cost of approx. $6 billion. Many human diseases could be potential targets for these antisense therapeutics directed against cox-2 to block inflammation. The potential market size could approach that of the traditional NSAIDs.
