PAPPA2 as a Therapeutic Modulator of IGF-I Bioavailability: in Vivo and in Vitro Evidence

Pregnancy-associated plasma protein A2 (PAPPA2) is a protease that cleaves IGF-binding protein (IGFBP)-3 and IGFBP-5, liberating free IGF-I. Five patients from two families with genetic mutations in PAPPA2 presented with growth retardation, elevated total IGF-I, and IGFBP-3 but decreased free IGF-I.To determine whether plasma transfusion or recombinant human (rh)PAPPA2 could increase free IGF-I in patients with PAPPA2 deficiency or idiopathic short stature (ISS).Single patient interventional study combined with in vitro experimentation.Academic medical center.Three siblings with PAPPA2 deficiency and four patients with ISS.An adult female with PAPPA2 deficiency received a 20 mL/kg plasma transfusion. PAPPA2, intact IGFBP-3, and free and total IGF-I levels were monitored during 2 weeks. rhPAPPA2 was added to serum from patients with PAPPA2 deficiency and ISS in vitro for 4 hours. Intact IGFBP-3 and free IGF-I levels were assayed via ELISA.Free IGF-I concentrations.Plasma transfusion resulted in a 2.5-fold increase of free IGF-I levels on day 1 posttransfusion with a return to baseline during a 2-week period. In vitro studies demonstrated a dose-dependent increase in free IGF-I and decrease in intact IGFBP-3 after the addition of rhPAPPA2. The increase in free IGF-I was more pronounced in patients with PAPPA2 deficiency compared with those with ISS.PAPPA2 plays a key role in regulation of IGF-I bioavailability. rhPAPPA2 is a promising therapy to increase free IGF-I levels both in patients with PAPPA2 deficiency as well as in patients with ISS.