Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons^™

Genetic Discrimination: Why Bragdondoes Not Ensure Protection, Laura F. Rothstein

Laura Rothstein

No abstract provided.

Survival Advantage Of Both Human Hepatocyte Xenografts And Genome-Edited Hepatocytes For Treatment Of Alpha-1 Antitrypsin Deficiency, Florie Borel, Qiushi Tang, Gwladys Gernoux, Cynthia Greer, Ziqiong Wang, Adi Barzel, Mark A. Kay, Leonard D. Shultz, Dale L. Greiner, Terence R. Flotte, Michael A. Brehm, Christian Mueller

Christian Mueller

Hepatocytes represent an important target for gene therapy and editing of single-gene disorders. In alpha-1 antitrypsin (AAT) deficiency, one missense mutation results in impaired secretion of AAT. In most patients, lung damage occurs due to a lack of AAT-mediated protection of lung elastin from neutrophil elastase. In some patients, accumulation of misfolded PiZ mutant AAT protein triggers hepatocyte injury, leading to inflammation and cirrhosis. We hypothesized that correcting the Z mutant defect in hepatocytes would confer a selective advantage for repopulation of hepatocytes within an intact liver. A human PiZ allele was crossed onto an immune-deficient (NSG) strain to create …

Interventions To Reduce Neonatal Mortality From Neonatal Tetanus In Low And Middle Income Countries - A Systematic Review, Adeel Ahmed Khan, Aysha Zahidie, F. Rabbani

Fauziah Rabbani

Background In 1988, WHO estimated around 787,000 newborns deaths due to neonatal tetanus. Despite few success stories majority of the Low and Middle Income Countries (LMICs) are still struggling to reduce neonatal mortality due to neonatal tetanus. We conducted a systematic review to understand the interventions that have had a substantial effect on reducing neonatal mortality rate due to neonatal tetanus in LMICs and come up with feasible recommendations for decreasing neonatal tetanus in the Pakistani setting. Methods We systemically reviewed the published literature (Pubmed and Pubget databases) to identify appropriate interventions for reducing tetanus related neonatal mortality. A total …

Evolution Of The Alpha-1 Antitrypsin Muscle Gene Therapy: Translation From Clinical Trial To Benchtop And Back Again, Alisha M. Gruntman, Gwladys Gernoux, Gensheng Wang, Janet Benson, Jeff Chulay, Dave Knop, Christian Mueller, Terence R. Flotte

Christian Mueller

Alpha-one antitrypsin (AAT) deficiency is a genetic disease affecting the lungs due to inadequate anti-protease activity in the pulmonary interstitium. On-going human trials use intra-muscular delivery of adeno-associated virus (rAAV1), allowing expressing myofibers to secrete normal (M)AAT protein. In the Phase IIa trial, patients in the highest dose cohort (6x1012vg/kg) were given 100 intra-muscular (IM) injections of undiluted vector, with serum AAT levels still substantially below target levels. Previous work has shown that delivering rAAV vector to the musculature via limb perfusion leads to widespread gene expression in myofibers. We hypothesize that widespread delivery would result in an overall increase …

5 Year Expression And Neutrophil Defect Repair After Gene Therapy In Alpha-1 Antitrypsin Deficiency, Christian Mueller, Gwladys Gernoux, Alisha M. Gruntman, Florie Borel, Emer P. Reeves, Roberto Calcedo, Farshid N. Rouhani, Anthony Yachnis, Margaret Humphries, Martha Campbell-Thompson, Louis M. Messina, Jeffrey D. Chulay, Bruce Trapnell, James M. Wilson, Noel G. Mcelvaney, Terence R. Flotte

Christian Mueller

Alpha-1 antitrypsin deficiency is a monogenic disorder resulting in emphysema due principally to the unopposed effects of neutrophil elastase. We previously reported achieving plasma wild-type alpha-1 antitrypsin concentrations at 2.5%-3.8% of the purported therapeutic level at 1 year after a single intramuscular administration of recombinant adeno-associated virus serotype 1 alpha-1 antitrypsin vector in alpha-1 antitrypsin deficient patients. We analyzed blood and muscle for alpha-1 antitrypsin expression and immune cell response. We also assayed previously reported markers of neutrophil function known to be altered in alpha-1 antitrypsin deficient patients. Here, we report sustained expression at 2.0%-2.5% of the target level from …

Sustained Expression With Partial Correction Of Neutrophil Defects 5 Years After Intramuscular Raav1 Gene Therapy For Alpha-1 Antitrypsin Deficiency, Terence R. Flotte, Christian Mueller, Gwladys Gernoux, Alisha Gruntman, Jeffrey D. Chulay, David R. Knop, Noel G. Mcelvaney, Martha Campbell-Thompson, James M. Wilson

Christian Mueller

Alpha-1 antitrypsin (AAT) deficiency is a common monogenic disorder resulting in emphysema, which is currently treated with weekly infusions of protein replacement. We previously reported achieving plasma wild-type (M) AAT concentrations at 2.5-3.8% of the therapeutic level at 1 year after intramuscular (IM) administration of 6×1012vg/kg of a recombinant adeno-associated virus serotype 1 (rAAV1)-AAT vector in AAT-deficient patients, with an associated regulatory T cell (Treg) response to AAV1 capsid epitopes in the absence of any exogenous immune suppression. Here, we report sustained expression at greater than 2% of the therapeutic level for 5 years after one-time treatment with rAAV1-AAT in …

Geographic Distribution Of Infant Death During Birth Hospitalization And Maternal Group B Streptococcus Colonization: Eastern Wisconsin, Jessica J.F. Kram, Dennis J. Baumgardner, Kiley A. Bernhard, Melissa A. Lemke

Dennis J. Baumgardner, MD

Background: Neonatal death rate in the United States is 4/1,000 live births; infant death rate is 6/1,000. Group B Streptococcus (GBS) may be transmitted from a colonized mother (rates vary from 15% to 35%) to the newborn during a vaginal delivery, and may contribute to neonatal death.

Purpose: To explore the geographic distribution and associated risk factors for maternal GBS colonization and infant death prior to discharge in eastern Wisconsin births.

Methods: Retrospective study of institutional data from PeriData.net, a comprehensive birth registry, utilizing data from 2007 through 2013 at all Aurora medical centers. Categorical variables were analyzed with chi-square …

Posterior Lenticonus In The Dog, Gustavo D. Aguirre, Stephen I. Bistner

Gustavo D. Aguirre, VMD, PhD

Posterior lenticonus is a congenital defect of the posterior lenticular surface. The posterior cortical and capsular regions of the lens have a circumscribed conelike or globular protrusion of variable size. Opacities may be present in the region of the conus. The defect has been reported in man, rabbits, calves and mice. This report documents 2 cases in unrelated dogs. The possible mechanism for the formation of this defect is discussed.

Canine Rd3 Mutation Establishes Rod-Cone Dysplasia Type 2 (Rcd2) As Ortholog Of Human And Murine Rd3, Anna V. Kukekova, Orly Goldstein, Jennifer L. Johnson, Malcolm A. Richardson, Susan E. Pearce-Kelling, Anand Swaroop, James S. Friedman, Gustavo D. Aguirre, Gregory M. Acland

Gustavo D. Aguirre, VMD, PhD

Rod-cone dysplasia type 2 (rcd2) is an autosomal recessive disorder that segregates in collie dogs. Linkage disequilibrium and meiotic linkage mapping were combined to take advantage of population structure within this breed and to fine map rcd2 to a 230-kb candidate region that included the gene C1orf36 responsible for human and murine rd3, and within which all affected dogs were homozygous for one haplotype. In one of three identified canine retinal RD3 splice variants, an insertion was found that cosegregates with rcd2 and is predicted to alter the last 61 codons of the normal open reading frame and further extend …

Col9a2 And Col9a3 Mutations In Canine Autosomal Recessive Oculoskeletal Dysplasia, Orly Goldstein, Richard Guyon, Anna Kukekova, Tatyana N. Kuznetsova, Susan E. Pearce-Kelling, Jennifer Johnson, Gustavo D. Aguirre, Gregory M. Acland

Gustavo D. Aguirre, VMD, PhD

Oculoskeletal dysplasia segregates as an autosomal recessive trait in the Labrador retriever and Samoyed canine breeds, in which the causative loci have been termed drd1 and drd2, respectively. Affected dogs exhibit short-limbed dwarfism and severe ocular defects. The disease phenotype resembles human hereditary arthro-ophthalmopathies such as Stickler and Marshall syndromes, although these disorders are usually dominant. Linkage studies mapped drd1 to canine chromosome 24 and drd2 to canine chromosome 15. Positional candidate gene analysis then led to the identification of a 1-base insertional mutation in exon 1 of COL9A3 that cosegregates with drd1 and a 1,267-bp deletion mutation in the …

Canine And Human Visual Cortex Intact And Responsive Despite Early Retinal Blindness From Rpe65 Mutation, Geoffrey K. Aguirre, András M. Komáromy, Artur V. Cideciyan, David H. Brainard, Tomas S. Aleman, Alejandro J. Roman, Brian B. Avants, James C. Gee, Marc Korczykowski, William W. Hauswirth, Gregory M. Acland, Gustavo D. Aguirre, Samuel G. Jacobson

Gustavo D. Aguirre, VMD, PhD

Background RPE65 is an essential molecule in the retinoid-visual cycle, and RPE65 gene mutations cause the congenital human blindness known as Leber congenital amaurosis (LCA). Somatic gene therapy delivered to the retina of blind dogs with an RPE65 mutation dramatically restores retinal physiology and has sparked international interest in human treatment trials for this incurable disease. An unanswered question is how the visual cortex responds after prolonged sensory deprivation from retinal dysfunction. We therefore studied the cortex of RPE65-mutant dogs before and after retinal gene therapy. Then, we inquired whether there is visual pathway integrity and responsivity in adult humans …

Cloning Of Canine Galactokinase (Galk1) And Evaluation As A Candidate Gene For Hereditary Cataracts In Labrador Retrievers, Duska J. Sidjanin, John L. Mcelwee, Brian Miller, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

We identified a pedigree of Labrador retrievers (LR) that develop hereditary cataracts between 6 and 18 months of age. In humans, galactokinase deficiency is an autosomal recessive disorder characterized by juvenile onset of cataracts.1 In order to evaluate GALK1 as a candidate gene, we cloned and sequenced the canine GALK1 gene and tested a single nucleotide polymorphism (SNP) in the gene for segregation with cataracts in the LR pedigree.

Blinded By The Light: Retinal Phototoxicity In The Context Of Safety Studies, Maria Cristina De Vera Mudry, Sven Kronenberg, Shun-Ichiro Komatsu, Gustavo D. Aguirre

Gustavo D. Aguirre, VMD, PhD

No abstract provided.

Canine Multifocal Retinopathy In The Australian Shepherd: A Case Report, Ingo Hoffmann, Karina E. Guziewicz, Barbara Zangerl, Gustavo D. Aguirre, Christian Y. Mardin

Gustavo D. Aguirre, VMD, PhD

A 1-year-old Australian Shepherd (AS) was presented for a routine hereditary eye examination. During the examination multiple raised, brown to orange lesions were noted in the fundus, which could not be attributed to a known retinal disease in this breed. As they clinically most closely resembled canine multifocal retinopathy (cmr) and no indication of an acquired condition was found, genetic tests for BEST1 gene mutations were performed. These showed the dog to be homozygous for the cmr1 (C73T/R25X) gene defect. Furthermore, ultrasound (US), electroretinography (ERG), and optical coherence tomography were performed, confirming changes typical for cmr. Subsequently, the AS pedigree …

Rare Case Of Klinefelters Syndrome With 48xxyy, Vasudev G. Magaji Md, Ms, Deborah Feden Crnp, Gretchen Perilli Md

Vasudev G Magaji MD, MS

No abstract provided.

Doença Renal Policística Autossômica Dominante Em Pacientes Em Hemodiálise No Sul Do Brasil; Autosomal Dominant Polycystic Kidney Disease In Hemodialysis Patients In Southern Brazil, Everton Fernando Alves

Everton Fernando Alves

Introdução: A doença renal policística autossômica dominante é a enfermidade renal hereditária mais comum em seres humanos. Objetivo: Analisar a prevalência, características clínicas e laboratoriais de pacientes com rins policísticos e relacionar as manifestações da doença por gênero. Métodos: Trata-se de um estudo observacional e retrospectivo. Foram revisados todos os prontuários médicos de pacientes com rins policísticos admitidos para hemodiálise entre 1995 e 2012, em quatro centros que atendem a área de abrangência da 15ª regional de saúde do Paraná, Brasil. Resultados: Fizeram parte do estudo 48 pacientes com rins policísticos, causa primária da doença renal crônica (DRC) estágio 5. …

Codon Optimization For Alpha 1-Antitrypsin Disease, Timothy Menz, Qiushi Tang, Lina Song, Christian Mueller, Terence R. Flotte

Christian Mueller

Alpha 1-antitrypsin deficiency is a genetic disorder caused by defective production of alpha 1-antitrypsin (AAT). Gene therapy approaches have been conducted in patients with AAT deficiency with successful AAT expression, but not to the therapeutic levels required to reduce the risk of emphysema. Codon optimization, a somewhat new and evolving technique, is used by many scientists to maximize protein expression in living organisms by altering translational and transcriptional efficiency as well as protein refolding. The purpose of this study was to develop single stranded and double stranded AAT gene constructs, test their protein expression in vitro, and compare with those …