Pappalysin 2 (PAPP-A2) Enzyme Replacement

Short Stature, Idiopathic Clinical Trial

Official title:

PAPP-A2 Enzyme Replacement Therapy Using Plasma Transfusion

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02412943
• Other study ID #: PAPPA2 Replacement
• Status: Completed
• Phase: Phase 1
• First received: April 1, 2015
• Last updated: May 27, 2015
• Start date: April 2015
• Est. completion date: May 2015

Study information

• Verified date: May 2015
• Source: Children's Hospital Medical Center, Cincinnati
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

This study evaluates the transfusion of fresh frozen plasma containing the enzyme PAPP-A2 into the a female adult. This female adult has a mutated version of PAPP-A2 that prevents the unbinding of IGF-1 from IGF binding proteins. The investigator's hypothesize that transfusion of plasma with donor PAPP-A2 will lead to the unbinding of IGF-1 from its binding proteins and that they will be able to measure free IGF-1 in the blood of this female adult.

Description:

PAPP-A2 is a plasma protease that is known to cleave IGFBP-3 and IGFBP-5. It is thought that this cleavage frees up IGF-1 from its bound form allowing it to become the active free IGF-1. The participant has short stature accompanied with elevated plasma levels of both IGF-1 and IGF binding protein 3 (IGFBP-3). Genetic analysis of the participant identified a novel missense mutation in PAPPA2 (Ala1033Val). This gene is a perfect candidate to explain our patients' phenotype. The investigators' hypothesis is that loss of activity of PAPP-A2 leads to an inability to cleave the IGF binding proteins and thus an overall elevation in IGFBP-3 and consequent elevation in total IGF-1. However, this IGF-1 cannot be freed up and is thus not able to be active leading to short stature. The patient's missense variant is predicted to be damaging by in silicon prediction models such as Polyphen2. Furthermore, two knock out mouse models of PAPPA2 as well as a zebrafish knock out exist, all showing growth retardation (post-natally in the mice). Taken together, this is definitive evidence that the patients' mutation in PAPPA2 is responsible for their short stature phenotype.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1
• Est. completion date: May 2015
• Est. primary completion date: May 2015
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Homozygous for a defect in PAPPA2.

Exclusion Criteria: None

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Dwarfism
• Short Stature, Idiopathic

Intervention

Other:
• Fresh Frozen Plasma
Liquid portion of human blood that was centrifuged, separated, and frozen solid within 6 hours of collection

Locations

Country	Name	City	State
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Children's Hospital Medical Center, Cincinnati

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Decrease in IGF-1	Decrease in either total IGF-1 or IGFBP-3 of 20% or greater as a clinically meaningful decrease in levels	5 minutes	No
Secondary	Length of decrease in IGF-1		up to 30 days	No