Pappalysin 2 (PAPP-A2) Enzyme Replacement

Cincinnati Children's Hospital Medical Center

Status and phase: Completed; Phase 1

Conditions: Short Stature, Idiopathic

Treatments: Other: Fresh Frozen Plasma

Study type: Interventional

Funder types: Other

Identifiers

NCT02412943

PAPPA2 Replacement

Details and patient eligibility

About

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.

Full 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.

Enrollment: 1 patient

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

• Homozygous for a defect in PAPPA2.

Exclusion Criteria: None

Trial design

Primary purpose: Basic Science

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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1 participants in 1 patient group

PAPP-A2 Enzyme Replacement

Experimental group

Description:

A 20 cc/kg transfusion of Fresh Frozen Plasma will be given over 3 hours on day 0.

Treatment:

Other: Fresh Frozen Plasma