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      A Step toward Treating a Lethal Neonatal Lung Disease. STAT3 and Alveolar Capillary Dysplasia

      editorial
      , M.D. 1 , , M.D. 2
      American Journal of Respiratory and Critical Care Medicine
      American Thoracic Society

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          Abstract

          Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) is a rare lethal lung developmental disorder in which the majority of affected infants present with neonatal respiratory failure and severe pulmonary hypertension that is refractory to treatment (1, 2). Pathologically, the disease is characterized by a paucity of distal capillaries and the presence of “misaligned” veins—pulmonary veins located within the same bronchovascular sheath as the pulmonary artery and airway (2). Recently, it has been shown that these misaligned veins are actually anastomotic shunt vessels (3). Most affected infants also have abnormalities in other organ systems, including the cardiac, gastrointestinal, and genitourinary systems (2, 4). Over the past several years, children with milder forms of ACDMPV who present later and survive longer with anti–pulmonary hypertensive therapies have been increasingly recognized, although the prognosis is still poor, with lung transplantation being the only available long-term therapy (5, 6). A breakthrough in understanding the cause of ACDMPV came with the discovery that genic deletions of and mutations in the FOXF1 (forkhead box F1) gene account for the majority of ACDMPV cases (7). FOXF1 is a transcription factor essential for vascular development. Homozygous foxf1-null mice are embryonic lethal because of abnormal vascular development of the allantois and yolk sac (8). Haploinsufficient foxf1 +/− mice recapitulate some of the features of ACDMPV, with affected animals having lung hypoplasia and reduced angiogenesis, abnormal gall bladder morphogenesis, and increased (but not universal) perinatal mortality. Interestingly the pathology of foxf1 +/− mice does not include findings of misaligned pulmonary veins, as seen in the human disorder (8). Haploinsufficiency is the presumed mechanism for FOXF1 mutations causing human lung disease, as disease results from monoallelic gene deletions and null (nonsense and frameshift) mutations (4, 7). Regulation of FOXF1 is complex, as disease-associated mutations are clustered within the DNA-binding domain of FOXF1, and deletions in the 5′ untranslated region involving two long noncoding RNAs also result in the phenotype of ACDMPV (9). In this issue of the Journal, Pradhan and colleagues (pp. 1045–1056) expand our knowledge of the molecular mechanisms by which FOXF1 mutations cause disease and offer a glimmer of hope for treatment for this universally fatal disorder (10). They selected for study a mutation identified in an infant with ACDMPV that resulted in the substitution of phenylalanine for S52F (serine in codon 52). The S52F mutation is located within an evolutionary conserved, frequently mutated, computationally predicted SH2-binding domain important for interactions with the protein STAT3 (signal transducer and activator of transcription 3). The authors demonstrated that the S52F-FOXF1 protein did not bind STAT3 in vitro, indicating the importance of the serine at position 52 in the interaction of FOXF1 and STAT3, although several other FOXF1 mutations within another computationally predicted SH2 binding domain (Y284A, I285Q, S291*) did not disrupt FOXF1’s interaction with STAT3. They then used CrispR/Cas9 to generate a mouse model with one allele expressing the S52F mutation. Perinatal mortality was increased in the wild type (WT)/S52F mice, although, similar to foxf1 +/− mice, it was not uniformly lethal, and the reasons some WT/S52F pups survive remains unclear. However, this murine model largely recapitulates the histopathology of the human phenotype, including pulmonary hypoplasia, misaligned pulmonary veins, pulmonary arterial hypertrophy, and alveolar simplification. Furthermore, decreased transcription of both the FOXF1 and STAT3 genes, as well as decreased transcription of additional downstream target genes important in endothelial cell proliferation and angiogenesis, was observed in the lungs of WT/S52F mice. Finally, they used nanoparticles to deliver STAT3 complementary DNA intravascularly into newborn WT/S52F mice and demonstrated efficient targeting of lung endothelial cells with increased STAT3 protein and phosphorylation, increased expression of endothelial cell markers indicating improved angiogenesis, improved alveogenesis, and decreased inflammation. Whether there was increased survival or improved lung function in treated mice was unaddressed. Although ACDMPV is a rare disease, with the recognition of the causative role of FOXF1 mutations and deletions, clinical genetic testing is now routinely available, allowing for noninvasive diagnosis. As a result, the number of identified cases has increased dramatically in recent years, as exemplified by the additional 28 cases included in the report (10). Could delivery of STAT3 complementary DNA using nanoparticles, which are being used in clinical trials for human malignancies, be used to treat human infants with ACDMPV? There are several important potential limitations and barriers to this approach. First, it is not clear how many other FOXF1 mutations disrupt interactions with STAT3 and are associated with decreased STAT3 signaling, as the authors’ data with respect to several other mutations indicated that they did not interfere with FOXF1–STAT3 interactions. Interestingly, decreased phosphorylated STAT3 was observed in human lung tissue from an infant with an unrelated FOXF1 frameshift mutation downstream of the first STAT3 consensus binding sequence. Augmenting STAT3 signaling might thus be an effective approach for some FOXF1 mutations, as well as an approach that could be applied to augment other downstream signaling critical for angiogenesis. A more practical barrier is that ACDMPV usually arises as a sporadic disorder due to de novo mutations (4, 9). Although familial cases are recognized and prenatal diagnosis has been performed (11), these cases are the exceptions. Most infants present after birth with respiratory failure and persistent pulmonary hypertension, which may result from other disease mechanisms. Even if the diagnosis is suspected initially, confirmatory genetic studies may take several weeks, and affected infants may die before a diagnosis is confirmed. By the time the diagnosis is established for surviving infants, secondary lung damage from oxygen toxicity and ventilator-induced injury will have complicated the infant’s course. Lung biopsy may allow for more rapid diagnosis, but some infants with histologic ACDMPV do not have FOXF1 mutations or deletions (9). Finally, gain-of-function mutations in STAT3 cause an autoimmune disease that can affect the lungs (12), so dosing considerations will be critical so as not to replace one disease with another. Despite these practical limitations, Pradhan and colleagues have generated an important animal model and an important advance in understanding the molecular pathogenesis of ACDMPV, and they suggest a path forward for the treatment of this devastating disorder.

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          Most cited references11

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          Alveolar capillary dysplasia.

          Alveolar capillary dysplasia with misalignment of the pulmonary veins (ACD/MPV) is a rare, fatal developmental lung disorder of neonates and infants. This review aims to address recent findings in the etiology and genetics of ACD/MPV and to raise awareness of this poorly known disease, which may also present as milder, unclassified forms. Successively discussed are what is known about the epidemiology, pathogenesis, pathophysiology, diagnostic indicators and approaches, genetic testing, treatment, and cases of delayed onset. The review concludes with suggestions for future directions to answer the many unknowns about this disorder.
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            Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

            Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis. © 2013 Wiley Periodicals, Inc.
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              Defects in pulmonary vasculature and perinatal lung hemorrhage in mice heterozygous null for the Forkhead Box f1 transcription factor.

              Decreased pulmonary expression of Forkhead Box f1 (Foxf1) transcription factor was associated with lethal alveolar hemorrhage in 55% of the Foxf1 +/- newborn mice. The severity of the pulmonary abnormalities correlates with the levels of Foxf1 mRNA. Defects in alveolarization and vasculogenesis were observed in subsets of the Foxf1 +/- mice with relatively low levels of expression from the normal Foxf1 allele. Lung hemorrhage was coincident with disruption of the mesenchymal-epithelial cell interfaces in the alveolar and bronchiolar regions of the lung parenchyma and was associated with increased apoptosis and reduced surfactant protein B (SP-B) expression. Finally, the lung defect associated with the Foxf1 +/- mutation was accompanied by reduced expression of vascular endothelial growth factor (VEGF), the VEGF receptor 2 (Flk-1), bone morphogenetic protein 4 (Bmp-4), and the transcription factors of the Brachyury T-Box family (Tbx2-Tbx5) and Lung Kruppel-like Factor. Reduction in the level of Foxf1 caused neonatal pulmonary hemorrhage and abnormalities in alveologenesis, implicating this transcription factor in the regulation of mesenchyme-epithelial interaction critical for lung morphogenesis. Copyright 2001 Academic Press.
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                Author and article information

                Journal
                Am J Respir Crit Care Med
                Am. J. Respir. Crit. Care Med
                ajrccm
                American Journal of Respiratory and Critical Care Medicine
                American Thoracic Society
                1073-449X
                1535-4970
                15 October 2019
                15 October 2019
                15 October 2019
                15 October 2019
                : 200
                : 8
                : 961-962
                Affiliations
                [ 1 ]Department of Pediatrics

                St. Louis Children’s Hospital and Washington University in St. Louis

                St. Louis, Missouri

                and
                [ 2 ]Department of Pediatrics

                Johns Hopkins University School of Medicine

                Baltimore, Maryland
                Article
                201906-1102ED
                10.1164/rccm.201906-1102ED
                6794102
                31343895
                277a21cc-e36c-4019-9e72-adbf1b6000d3
                Copyright © 2019 by the American Thoracic Society

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 ( http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ( dgern@ 123456thoracic.org ).

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