Transcatheter delivery of c-myc antisense oligomers reduces neointimal formation in a porcine model of coronary artery balloon injury.

BACKGROUND: Smooth muscle cell proliferation and extracellular matrix accumulation are the principal mechanisms leading to vascular restenosis. We have previously demonstrated the growth-inhibitory effect of antisense oligomers targeting the c-myc proto-oncogene in human smooth muscle cells. The goal of this study was to investigate whether c-myc antisense oligomers reduce neointimal formation in balloon-denuded porcine coronary arteries. METHODS AND RESULTS: First, type I collagen synthesis, which reflects synthetic function, was markedly reduced following c-myc antisense oligomers in porcine vascular smooth muscle cells independent of the growth inhibition. These effects in vitro provided the rationale for assessing c-myc antisense oligomers in the prevention of neointima in vivo. Second, the efficiency of single transcatheter delivery of oligomers into denuded porcine coronary arteries was determined. Despite rapid plasma clearance following local delivery, oligomers persisted at the site of injection for at least 3 days, exceeding by severalfold their concentration in peripheral organs. Third, morphometric analyses were carried out in balloon-denuded coronary arteries at 1 month after transcatheter c-myc antisense oligomer administration. Maximal neointimal area was reduced from 0.80 +/- 0.17 mm2 in the control group (n = 12) to 0.24 +/- 0.06 mm2 in the antisense-treated group (n = 13, P < .01). Likewise, a significant reduction in maximal neointimal thickness was observed in the antisense-treated group (P < .01). These changes in vascular remodeling following denuding injury resulted in an increase in residual lumen from 64 +/- 6% in the control group to 81 +/- 5% in the antisense-treated group (P < .05). CONCLUSIONS: (1) Single transcatheter administration allowed for endoluminal delivery of oligomers to the site of coronary arterial injury. (2) C-myc antisense oligomers reduced the formation of neointima in denuded coronary arteries, implying a therapeutic potential of this approach for the prevention of coronary restenosis. (3) It is postulated that the c-myc proto-oncogene is involved in the process of vascular remodeling, regulating smooth muscle cell proliferation and extracellular matrix synthesis.

Embryonic and larval development of the sonic motor nucleus in the oyster toadfish.

The sonic motor nucleus (SMN), a likely homologue of the hypoglossal nucleus, provides the final common pathway for sound production in the oyster toadfish (Opsanus tau). SMN neurons increase in size and number for 7-8 years postnatally, and the swimbladder-sonic muscle complex grows throughout life. This study describes the normal embryonic and larval development of the SMN from its initial differentiation on about day 19 through day 40, when the yolk sac is resorbed and the fish is free swimming. In contrast to the rapid development of CNS nuclei in mammals, the SMN gradually increased in maturity with more active growth at the beginning and end of the observation period and a relatively static period in the middle. Consistent with a hypoglossal homology, the SMN differentiated within the spinal cord, added cells rostrally, and eventually extended into the medulla. Immature neurons appeared to originate from precursor cells in the ventral portion of the ventricular zone of the central canal. Such cells were initially round with little cytoplasmic development and later added processes and Nissl substance. The number of neurons increased 10-fold from a median of 35 to 322 cells, and no evidence of cell death was observed. Soma area approximately doubled from 20.6 to 41.2 micron 2, and cell nucleus area followed a similar pattern. [3H]-thymidine autoradiography demonstrated that neurons were added continuously throughout the nucleus during embryonic and larval development.