Genetic Regulation of Surfactant Deficiency

NCT00828243 | Completed DMC FDA Drug

• 2 other identifiers: 07-0156R01HL082747
• Study Type: observational
• Target: 525
• Locations: 1 country
• Sites: 1

Brief Summary

Inherited deficiencies in any one of 3 genes (surfactant protein B, surfactant protein C, and ATP-binding cassette transporter A3) can cause neonatal respiratory distress syndrome by disrupting metabolism of the pulmonary surfactant. The investigators will use state of the art methods to link specific changes in the genetic code of each of these genes with disruption of discrete steps in the metabolism of the pulmonary surfactant in human newborn infants. These studies will lead to improved diagnostic capabilities and suggest novel strategies to correct surfactant deficiency in newborn infants.

Conditions

Respiratory Distress Syndrome, Newborn

Keywords

Pulmonary surfactants; Pulmonary surfactant associated protein B; Pulmonary surfactant associated protein C; ATP-binding cassette protein sub member family A3

Outcome Measures

Primary Outcomes (1)

• Association of specific variants or interactions among variants in SFTPB, SFTPC, and ABCA3 with neonatal respiratory distress syndrome

  Statistical association of increased risk of neonatal respiratory distress in term or near term infants with specific genomic variants in SFTPB, SFTPC, and ABCA3

  1 week

Secondary Outcomes (1)

• Association of specific variants or interactions among variants in SFTPB, SFTPC, and ABCA3 with fractional synthetic rate and/or fractional catabolic rate of surfactant phospholipids, surfactant protein-B, and surfactant protein-C

  1 week

Study Arms (2)

Genetic association

Infants with and without neonatal respiratory distress syndrome undergo surfactant gene sequencing to identify genomic variants associated with neonatal respiratory distress syndrome

Nutrient

To newborn infants with respiratory distress syndrome, we administer stable isotopically labeled nutrients (precursors of surfactant phospholipids or proteins) to permit mass spectrometry-based comparison of surfactant phospholipid and protein turnover.

Drug: Nutrient

Interventions

Nutrient DRUG

We administer stable isotopically labeled precursors of surfactant phospholipids (\[1-13C1\] acetate) and of surfactant protein-B (\[5,5,5-2H3\] leucine) to infants with neonatal respiratory distress syndrome. Using mass spectrometry, we measure incorporation of stable isotopically labeled precursors in tracheal aspirates and compare surfactant phospholipid and surfactant protein-B turnover.

Also known as: [1-13C1] acetate, [5,5,5-2H3] leucine

Nutrient

Eligibility Criteria

• Age: 1 Day - 6 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

The study population includes infants with and without neonatal respiratory distress syndrome (N=513) and infants with varying severity of neonatal respiratory distress syndrome (N=12).

You may qualify if:

• Newborn infants with respiratory distress syndrome who require mechanical ventilation via endotracheal tube or tracheostomy in the first 6 months of life

You may not qualify if:

• Infants with conditions likely to cause imminent death

Sponsors & Collaborators

• Washington University School of Medicine: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

St. Louis Children's Hospital

St Louis, Missouri, 63110, United States

Location

Related Publications (13)

• Tomazela DM, Patterson BW, Hanson E, Spence KL, Kanion TB, Salinger DH, Vicini P, Barret H, Heins HB, Cole FS, Hamvas A, MacCoss MJ. Measurement of human surfactant protein-B turnover in vivo from tracheal aspirates using targeted proteomics. Anal Chem. 2010 Mar 15;82(6):2561-7. doi: 10.1021/ac1001433.

  PMID: 20178338 BACKGROUND

• Hamvas A, Heins HB, Guttentag SH, Wegner DJ, Trusgnich MA, Bennet KW, Yang P, Carlson CS, An P, Cole FS. Developmental and genetic regulation of human surfactant protein B in vivo. Neonatology. 2009;95(2):117-24. doi: 10.1159/000153095. Epub 2008 Sep 6.

  PMID: 18776725 BACKGROUND

• Hamvas A, Nogee LM, Wegner DJ, Depass K, Christodoulou J, Bennetts B, McQuade LR, Gray PH, Deterding RR, Carroll TR, Kammesheidt A, Kasch LM, Kulkarni S, Cole FS. Inherited surfactant deficiency caused by uniparental disomy of rare mutations in the surfactant protein-B and ATP binding cassette, subfamily a, member 3 genes. J Pediatr. 2009 Dec;155(6):854-859.e1. doi: 10.1016/j.jpeds.2009.06.006. Epub 2009 Aug 3.

  PMID: 19647838 RESULT

• McBee AD, Wegner DJ, Carlson CS, Wambach JA, Yang P, Heins HB, Saugstad OD, Trusgnich MA, Watkins-Torry J, Nogee LM, Henderson H, Cole FS, Hamvas A. Recombination as a mechanism for sporadic mutation in the surfactant protein-C gene. Pediatr Pulmonol. 2008 May;43(5):443-50. doi: 10.1002/ppul.20782.

  PMID: 18383112 RESULT

• Garmany TH, Wambach JA, Heins HB, Watkins-Torry JM, Wegner DJ, Bennet K, An P, Land G, Saugstad OD, Henderson H, Nogee LM, Cole FS, Hamvas A. Population and disease-based prevalence of the common mutations associated with surfactant deficiency. Pediatr Res. 2008 Jun;63(6):645-9. doi: 10.1203/PDR.0b013e31816fdbeb.

  PMID: 18317237 RESULT

• Wambach JA, Yang P, Wegner DJ, An P, Hackett BP, Cole FS, Hamvas A. Surfactant protein-C promoter variants associated with neonatal respiratory distress syndrome reduce transcription. Pediatr Res. 2010 Sep;68(3):216-20. doi: 10.1203/PDR.0b013e3181eb5d68.

  PMID: 20539253 RESULT

• Anadkat JS, Kuzniewicz MW, Chaudhari BP, Cole FS, Hamvas A. Increased risk for respiratory distress among white, male, late preterm and term infants. J Perinatol. 2012 Oct;32(10):780-5. doi: 10.1038/jp.2011.191. Epub 2012 Jan 5.

  PMID: 22222548 RESULT

• Agrawal A, Hamvas A, Cole FS, Wambach JA, Wegner D, Coghill C, Harrison K, Nogee LM. An intronic ABCA3 mutation that is responsible for respiratory disease. Pediatr Res. 2012 Jun;71(6):633-7. doi: 10.1038/pr.2012.21. Epub 2012 Feb 15.

  PMID: 22337229 RESULT

• Bereman MS, Tomazela DM, Heins HS, Simonato M, Cogo PE, Hamvas A, Patterson BW, Cole FS, MacCoss MJ. A method to determine the kinetics of multiple proteins in human infants with respiratory distress syndrome. Anal Bioanal Chem. 2012 Jun;403(8):2397-402. doi: 10.1007/s00216-012-5953-3. Epub 2012 Apr 14.

  PMID: 22526637 RESULT

• Wambach JA, Wegner DJ, Depass K, Heins H, Druley TE, Mitra RD, An P, Zhang Q, Nogee LM, Cole FS, Hamvas A. Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome. Pediatrics. 2012 Dec;130(6):e1575-82. doi: 10.1542/peds.2012-0918. Epub 2012 Nov 19.

  PMID: 23166334 RESULT

• Wambach JA, Wegner DJ, Heins HB, Druley TE, Mitra RD, Hamvas A, Cole FS. Synonymous ABCA3 variants do not increase risk for neonatal respiratory distress syndrome. J Pediatr. 2014 Jun;164(6):1316-21.e3. doi: 10.1016/j.jpeds.2014.02.021. Epub 2014 Mar 20.

  PMID: 24657120 RESULT

• Wambach JA, Casey AM, Fishman MP, Wegner DJ, Wert SE, Cole FS, Hamvas A, Nogee LM. Genotype-phenotype correlations for infants and children with ABCA3 deficiency. Am J Respir Crit Care Med. 2014 Jun 15;189(12):1538-43. doi: 10.1164/rccm.201402-0342OC.

  PMID: 24871971 RESULT

• Jackson T, Wegner DJ, White FV, Hamvas A, Cole FS, Wambach JA. Respiratory failure in a term infant with cis and trans mutations in ABCA3. J Perinatol. 2015 Mar;35(3):231-2. doi: 10.1038/jp.2014.236.

  PMID: 25712598 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

DNA samples and tracheal aspirate samples

MeSH Terms

Conditions

Respiratory Distress Syndrome, Newborn

Interventions

Nutrients; Acetates; Leucine

Condition Hierarchy (Ancestors)

Respiratory Distress Syndrome; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Infant, Premature, Diseases; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Food; Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids; Amino Acids, Branched-Chain; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Essential

Study Officials

• F. S. Cole, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 22, 2009
• First Posted: January 23, 2009
• Study Start: November 1, 2007
• Primary Completion: March 1, 2013
• Study Completion: March 1, 2013
• Last Updated: June 7, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)