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Pilot dose-ranging of rhIGF-1/rhIGFBP-3 in a preterm lamb model of evolving bronchopulmonary dysplasia
Kurt H Albertine1, Mar Janna Dahl2, Andrew Rebentisch2
1Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA. kurt.albertine@hsc.utah.edu.
Insights
Low insulin-like growth factor-1 (IGF-1) in preterm infants is linked to bronchopulmonary dysplasia. Repleting IGF-1 in preterm lambs improved lung and heart outcomes without toxicity.
Area of Science:
- Neonatal physiology and respiratory medicine
- Endocrinology and growth factors
- Pulmonary and cardiovascular research
Background:
- Low insulin-like growth factor-1 (IGF-1) levels in preterm infants correlate with bronchopulmonary dysplasia (BPD).
- Mechanical ventilation in preterm infants can exacerbate IGF-1 decline, impacting lung and cardiovascular development.
- Understanding IGF-1's role is crucial for developing therapeutic strategies in preterm neonates.
Purpose of the Study:
- To determine the optimal dosage of recombinant human IGF-1/IGFBP-3 (rhIGF-1/rhIGFBP-3) to achieve physiological plasma levels in preterm lambs.
- To evaluate the efficacy of rhIGF-1/rhIGFBP-3 repletion in improving pulmonary and cardiovascular outcomes in a preterm lamb model of BPD.
Main Methods:
- Established normal plasma IGF-1 levels in unventilated preterm lambs from gestation to 5 months.
- Administered continuous intravenous infusion of rhIGF-1/rhIGFBP-3 at varying dosages (0.5, 1.5, 4.5 mg/kg/day) to mechanically ventilated preterm lambs.
- Identified 1.5 mg/kg/day as the optimal dosage to achieve target plasma IGF-1 levels (~125 ng/mL) and assessed outcomes in six lambs.
Main Results:
- A dosage of 1.5 mg/kg/day rhIGF-1/rhIGFBP-3 successfully attained physiological plasma IGF-1 concentrations in mechanically ventilated preterm lambs.
- This optimal dosage significantly improved certain pulmonary and cardiovascular outcomes compared to controls (p < 0.1).
- No evidence of toxicity to the liver, kidneys, or lungs was observed with rhIGF-1/rhIGFBP-3 administration.
Conclusions:
- Three days of continuous intravenous infusion of rhIGF-1/rhIGFBP-3 at 1.5 mg/kg/day is safe and effective in improving select pulmonary and cardiovascular outcomes.
- This therapeutic approach holds promise for managing BPD and associated complications in preterm infants.
- Maintaining physiological IGF-1 levels may be a viable strategy to mitigate adverse effects of preterm birth on organ development.
Background:
Low levels of insulin-like growth factor-1 (IGF-1) protein in preterm human infants are associated with bronchopulmonary dysplasia (BPD). We used our preterm lamb model of BPD to determine (1) dosage of recombinant human (rh) IGF-1 bound to binding protein-3 (IGFBP-3) to reach infant physiologic plasma levels; and (2) whether repletion of plasma IGF-1 improves pulmonary and cardiovascular outcomes.
Methods:
Group 1: normal, unventilated lambs from 128 days gestation through postnatal age 5 months defined normal plasma levels of IGF-1. Group 2: continuous infusion of rhIGF-1/rhIGFBP-3 (0.5, 1.5, or 4.5 mg/kg/day; n = 2) for 3 days in mechanically ventilated (MV) preterm lambs determined that 1.5 mg/kg/day dosage attained physiologic plasma IGF-1 concentration of ~125 ng/mL, which was infused in four more MV preterm lambs.
Results:
Group 1: plasma IGF-1 protein increased from ~75 ng/mL at 128 days gestation to ~220 ng/L at 5 months. Group 2: pilot study of the optimal dosage (1.5 mg/kg/day rhIGF-1/rhIGFBP-3) in six MV preterm lambs significantly improved some pulmonary and cardiovascular outcomes (p < 0.1) compared to six MV preterm controls. RhIGF-1/rhIGFBP-3 was not toxic to the liver, kidneys, or lungs.
Conclusions:
Three days of continuous iv infusion of rhIGF-1/rhIGFBP-3 at 1.5 mg/kg/day improved some pulmonary and cardiovascular outcomes without toxicity.
Impact:
Preterm birth is associated with rapid decreases in serum or plasma IGF-1 protein level. This decline adversely impacts the growth and development of the lung and cardiovascular system. For this pilot study, continuous infusion of optimal dosage of rhIGF-1/rhIGFBP-3 (1.5 mg/kg/day) to maintain physiologic plasma IGF-1 level of ~125 ng/mL during mechanical ventilation for 3 days statistically improved some structural and biochemical outcomes related to the alveolar formation that would favor improved gas exchange compared to vehicle-control. We conclude that 3 days of continuous iv infusion of rhIGF-1/rhIGFBP-3 improved some physiological, morphological, and biochemical outcomes, without toxicity, in mechanically ventilated preterm lambs.
