Cell and Gene Therapy for Genetic Diseases: Inherited Disorders Affecting the Lung and Those Mimicking Sudden Infant Death Syndrome

Keeler, Allison M.; Flotte, Terence R.

doi:10.1089/hum.2012.087

Cited by 17 publications

(15 citation statements)

References 78 publications

(76 reference statements)

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“…Potential genetic-based treatments for CF lung disease include gene transfer of a wild-type (WT) CFTR cDNA (gene therapy) (4)(5)(6), correction of the CFTR gene sequence (genome editing) (7), repair of CFTR mRNA (8), and stem-cell transplantation to airways (9). Gene-and cell-based approaches have potential for long-lasting benefits and are applicable for all CFTR genotypes, but they are limited by CFTR restoration to a limited number of cells.…”

mentioning

confidence: 99%

Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Shah

Ernst

Tang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cystic fibrosis (CF) is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. Airway disease is the major source of morbidity and mortality. Successful implementation of gene- and cell-based therapies for CF airway disease requires knowledge of relationships among percentages of targeted cells, levels of CFTR expression, correction of electrolyte transport, and rescue of host defense defects. Previous studies suggested that, when ∼10–50% of airway epithelial cells expressed CFTR, they generated nearly wild-type levels of Cl− secretion; overexpressing CFTR offered no advantage compared with endogenous expression levels. However, recent discoveries focused attention on CFTR-mediated HCO3− secretion and airway surface liquid (ASL) pH as critical for host defense and CF pathogenesis. Therefore, we generated porcine airway epithelia with varying ratios of CF and wild-type cells. Epithelia with a 50:50 mix secreted HCO3− at half the rate of wild-type epithelia. Likewise, heterozygous epithelia (CFTR+/− or CFTR+/∆F508) expressed CFTR and secreted HCO3− at ∼50% of wild-type values. ASL pH, antimicrobial activity, and viscosity showed similar relationships to the amount of CFTR. Overexpressing CFTR increased HCO3− secretion to rates greater than wild type, but ASL pH did not exceed wild-type values. Thus, in contrast to Cl− secretion, the amount of CFTR is rate-limiting for HCO3− secretion and for correcting host defense abnormalities. In addition, overexpressing CFTR might produce a greater benefit than expressing CFTR at wild-type levels when targeting small fractions of cells. These findings may also explain the risk of airway disease in CF carriers.

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mentioning

confidence: 99%

Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Shah

Ernst

Tang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…These metabolic disorders, primarily fatty acid oxidation disorders, mimic the presentation of SUID, with little or no clinical prodrome. 45 Medium-chain acyl coenzyme A dehydrogenase deficiency is the most prevalent fatty acid oxidation disorder detected among SUIDs. 44 Newborn screening for medium-chain acyl coenzyme A dehydrogenase led to newborn screening now performed in all states and territories of the United States.…”

Section: Metabolic Disordersmentioning

confidence: 99%

“…1 Although the proportion of unexplained stillbirth varies by classification scheme, a US population-based study did not identify a cause in 24% of stillbirths. 2 There were also 3422 sudden unexpected infant deaths (SUIDs) 3 (87.0/100 000 live births), with 45.6% reported as due to the sudden infant death syndrome (SIDS). SIDS is defined as the sudden and unexpected death of an infant <12 months of age that remains unexplained after a review of the clinical history, complete autopsy, and death scene investigation.…”

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confidence: 99%

Sudden Unexpected Death in Fetal Life Through Early Childhood

2016

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In March 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development held a workshop entitled “Sudden Unexpected Death in Fetal Life Through Early Childhood: New Opportunities.” Its objective was to advance efforts to understand and ultimately prevent sudden deaths in early life, by considering their pathogenesis as a potential continuum with some commonalities in biological origins or pathways. A second objective of this meeting was to highlight current issues surrounding the classification of sudden infant death syndrome (SIDS), and the implications of variations in the use of the term “SIDS” in forensic practice, and pediatric care and research. The proceedings reflected the most current knowledge and understanding of the origins and biology of vulnerability to sudden unexpected death, and its environmental triggers. Participants were encouraged to consider the application of new technologies and “omics” approaches to accelerate research. The major advances in delineating the intrinsic vulnerabilities to sudden death in early life have come from epidemiologic, neural, cardiac, metabolic, genetic, and physiologic research, with some commonalities among cases of unexplained stillbirth, SIDS, and sudden unexplained death in childhood observed. It was emphasized that investigations of sudden unexpected death are inconsistent, varying by jurisdiction, as are the education, certification practices, and experience of death certifiers. In addition, there is no practical consensus on the use of “SIDS” as a determination in cause of death. Major clinical, forensic, and scientific areas are identified for future research.

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“…This process is traditionally the mode of energy generation in most cells. During metabolic stress, fasting, or extensive exercise, cells utilize fatty acid oxidation to break down fat stores for energy production (Keeler and Flotte, 2012). This is particularly prominent in highly oxidative tissues (Goetzman, 2011;Keeler and Flotte, 2012).…”

Section: Lipid Metabolism Disordersmentioning

confidence: 99%

“…During metabolic stress, fasting, or extensive exercise, cells utilize fatty acid oxidation to break down fat stores for energy production (Keeler and Flotte, 2012). This is particularly prominent in highly oxidative tissues (Goetzman, 2011;Keeler and Flotte, 2012). Fatty acid oxidation occurs via b-oxidation within the mitochondria using precursors generated from the esterification of fatty acids by coenzyme-A to produce acyl-CoA.…”

Section: Lipid Metabolism Disordersmentioning

confidence: 99%

Adeno-Associated Virus–Mediated Gene Therapy for Metabolic Myopathy

Mah

Soustek²,

Todd³

et al. 2013

Human Gene Therapy

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Metabolic myopathies are a diverse group of rare diseases in which impaired breakdown of stored energy leads to profound muscle dysfunction ranging from exercise intolerance to severe muscle wasting. Metabolic myopathies are largely caused by functional deficiency of a single gene and are generally subcategorized into three major types of metabolic disease: mitochondrial, lipid, or glycogen. Treatment varies greatly depending on the biochemical nature of the disease, and unfortunately no definitive treatments exist for metabolic myopathy. Since this group of diseases is inherited, gene therapy is being explored as an approach to personalized medical treatment. Adeno-associated virus-based vectors in particular have shown to be promising in the treatment of several forms of metabolic myopathy. This review will discuss the most recent advances in gene therapy efforts for the treatment of metabolic myopathies.

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Cell and Gene Therapy for Genetic Diseases: Inherited Disorders Affecting the Lung and Those Mimicking Sudden Infant Death Syndrome

Cited by 17 publications

References 78 publications

Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Sudden Unexpected Death in Fetal Life Through Early Childhood

Adeno-Associated Virus–Mediated Gene Therapy for Metabolic Myopathy

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Cell and Gene Therapy for Genetic Diseases: Inherited Disorders Affecting the Lung and Those Mimicking Sudden Infant Death Syndrome

Cited by 17 publications

References 78 publications

Relationships among CFTR expression, HCO 3 − secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Relationships among CFTR expression, HCO 3 − secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Sudden Unexpected Death in Fetal Life Through Early Childhood

Adeno-Associated Virus–Mediated Gene Therapy for Metabolic Myopathy

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Product

Resources

About

Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

Relationships among CFTR expression, HCO ₃ ⁻ secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies