Review
Abstract
Muscular dystrophies are a heterogeneous group of genetic diseases, characterized by progressive degeneration of skeletal and cardiac muscle. Despite the intense investigation of different therapeutic options, a definitive treatment has not been yet developed for this debilitating class of pathologies. Cell-based therapies in muscular dystrophies have been pursued experimentally for the last three decades. Several cell types with different characteristics and tissues of origin, including myogenic stem and progenitor cells, stromal cells, and pluripotent stem cells, have been investigated over the years and have recently entered in the clinical arena with mixed results. In this review, we will do a roundup of the past attempts and describe the updated status of cell-based therapies aimed at counteracting the skeletal and cardiac myopathy present in dystrophic patients. We will present current challenges, summarize recent progresses, and make recommendations for future research and clinical trials.
Authors
Stefano Biressi, Antonio Filareto, Thomas A. Rando
Abstract
Pulmonary hypertension (PH) is characterized by pulmonary artery remodeling that can subsequently culminate in right heart failure and premature death. Emerging evidence suggests that Hypoxia Inducible Factor (HIF) signaling plays a fundamental and pivotal role in the pathogenesis of PH. This review summarizes the regulation of HIF isoforms and their impact in various PH subtypes, as well as the elaborate conditional and cell specific knockout mouse studies that brought the role of this pathway to light. We also discuss the current preclinical status of pan- and isoform-selective HIF inhibitors, and propose new research areas that may facilitate HIF isoform-specific inhibition as a novel therapeutic strategy for PH and right heart failure.
Authors
Soni Savai Pullamsetti, Argen Mamazhakypov, Norbert Weissmann, Werner Seeger, Rajkumar Savai
Abstract
Epithelial cell dysfunction has emerged as a central component in the pathophysiology of diffuse parenchymal diseases including idiopathic pulmonary fibrosis (IPF). Alveolar type 2 (AT2) cells represent a metabolically active lung cell population important for surfactant biosynthesis and alveolar homeostasis. AT2 cells and other distal lung epithelia, like all eukaryotic cells, contain an elegant quality control (QC) network to respond to intrinsic metabolic and biosynthetic challenges imparted by mutant protein conformers, dysfunctional subcellular organelles, and dysregulated telomeres. Failed AT2 QC components (ubiquitin-proteasome system, unfolded protein response, macroautophagy, mitophagy, and telomere maintenance) result in diverse cellular endophenotypes and molecular signatures including ER stress, defective autophagy, mitochondrial dysfunction, apoptosis, inflammatory cell recruitment, profibrotic signaling, and altered progenitor function that ultimately converge to drive downstream fibrotic remodeling in the IPF lung. As this complex network becomes increasingly better understood, opportunities will emerge to identify targets and therapeutic strategies for IPF.
Authors
Jeremy Katzen, Michael F. Beers
Abstract
Hypoxia-inducible factors (HIFs) and the HIF-dependent cancer hallmarks angiogenesis and metabolic rewiring are well-established drivers of breast cancer aggressiveness, therapy resistance, and poor prognosis. Targeting of HIF and its downstream targets in angiogenesis and metabolism has been unsuccessful so far in the breast cancer clinical setting, with major unresolved challenges residing in target selection, development of robust biomarkers for response prediction, and understanding and harnessing escape mechanisms. This Review discusses the pathophysiological role of HIFs, angiogenesis, and metabolism in breast cancer and the challenges of targeting these features in breast cancer patients. Rational therapeutic combinations, especially with immunotherapy and endocrine therapy, seem most promising in the clinical exploitation of the intricate interplay of HIFs, angiogenesis, and metabolism in breast cancer cells and the tumor microenvironment.
Authors
Ellen C. de Heer, Mathilde Jalving, Adrian L. Harris
Abstract
Hypoxia/HIF-1α- and extracellular adenosine/A2-adenosine receptor-mediated immunosuppression protects tissues from collateral damage by anti-pathogen immune cells. However, this mechanism also protects cancerous tissues by inhibiting anti-tumor immune cells in hypoxic and extracellular adenosine-rich tumors that are the most resistant to current therapies. Here, we explain a conceptually novel, anti-immunosuppressive reasoning to justify strategies using respiratory hyperoxia and oxygenation agents in cancer treatment. Earlier attempts to use oxygenation of tumors as a monotherapy or to improve radiotherapy have failed because oxygenation protocols were not combined with immunotherapies of cancer. In contrast, the proposal for therapeutic use of anti-hypoxic oxygenation described here was motivated by the need to prevent the hypoxia/HIF-1α-driven accumulation of extracellular adenosine to (i) unleash anti-tumor immune cells from inhibition by intracellular cAMP and (ii) prevent immunosuppressive transcription of cAMP response element- and hypoxia response element-containing immunosuppressive gene products (e.g. TGF-β. Using oxygenation agents together with inhibitors of the A2A adenosine receptor may be required to enable the most effective cancer immunotherapy. The emerging outcomes from clinical trials of cancer patients refractory to all other treatments provide support for the molecular and immunological mechanism-based approach to cancer immunotherapy described here.
Authors
Stephen M. Hatfield, Michail V. Sitkovsky
Abstract
Hypoxia can be defined as a relative deficiency in the amount of oxygen reaching the tissues. Hypoxia inducible factors (HIFs) are critical regulators of the mammalian response to hypoxia. In normal circumstances, HIF-1α protein turnover is rapid, and hyperglycemia further destabilizes the protein. In addition to their role in diabetes pathogenesis, HIFs are implicated in development of the microvascular and macrovascular complications of diabetes. Improving glucose control in people with diabetes increases HIF-1α protein and has wide-ranging benefits, some of which are at least partially mediated by HIF-1α. Despite this, most strategies to improve diabetes or its complications via regulating HIF-1α have not proven currently clinically useful. The intersection of HIF biology with diabetes is a complex area in which many further questions remain, especially around the well-conducted and clearly-described discrepant effects of different methods of increasing HIF-1α, even within the same tissues. This review will present a brief overview of HIFs, discuss the range of evidence implicating HIFs in β-cell dysfunction, diabetes pathogenesis, and diabetes complications, and examine the differing outcomes of HIF-targeting approaches in these conditions.
Authors
Jenny E. Gunton
Abstract
The liver has strong innate immunity to counteract pathogens from the gastrointestinal tract. During the development of liver cancer, which is typically driven by chronic inflammation, the composition and biological roles of the innate immune cells are extensively altered. Hypoxia is a common finding in all stages of liver cancer development. Hypoxia drives the stabilization of hypoxia-inducible factors (HIFs), which act as central regulators to dampen the innate immunity of liver cancer. HIF signaling in innate immune cells and liver cancer cells together favor the recruitment and maintenance of pro-tumorigenic immune cells and the inhibition of anti-tumorigenic immune cells, promoting immune evasion. HIFs represent attractive therapeutic targets to inhibit the formation of an immunosuppressive microenvironment and growth of liver cancer.
Authors
Vincent Wai-Hin Yuen, Carmen Chak-Lui Wong
Abstract
Intermittent hypoxia (IH) is a hallmark manifestation of obstructive sleep apnea (OSA), a widespread disorder of breathing. This review focuses on the role of hypoxia-inducible factors (HIFs) in hypertension, type 2 diabetes (T2D), and cognitive decline in experimental models of IH patterned after O2 profiles seen in OSA. IH increases HIF-1α and decreases HIF-2α protein levels. Dysregulated HIFs increase reactive oxygen species (ROS) through HIF-1-dependent activation of pro-oxidant enzyme genes in addition to reduced transcription of anti-oxidant genes by HIF-2. ROS in turn activates chemoreflex and suppresses baroreflex, thereby stimulating the sympathetic nervous system and causing hypertension. We will also discuss how increased ROS generation by HIF-1 also contributes to IH-induced insulin resistance and T2D as well as disrupted NMDA receptor signaling in the hippocampus, resulting in cognitive decline.
Authors
Nanduri R. Prabhakar, Ying-Jie Peng, Jayasri Nanduri
Abstract
Pediatric cancers, particularly high-risk solid tumors, urgently need effective and specific therapies. Their outlook has not appreciably improved in decades. Immunotherapies such as immune checkpoint inhibitors offer much promise, but most are only approved for use in adults. Though several hundred clinical trials have tested immune-based approaches in childhood cancers, few have been guided by biomarkers or clinical-grade assays developed to predict patient response and, ultimately, to help select those most likely to benefit. There is extensive evidence in adults to show that immune profiling has substantial predictive value, but few studies focus on childhood tumors, because of the relatively small disease population and restricted use of immune-based therapies. For instance, only one published study has retrospectively examined the immune profiles of pediatric brain tumors after immunotherapy. Furthermore, application and integration of advanced multiplex techniques has been extremely limited. Here, we review the current status of immune profiling of pediatric solid tumors, with emphasis on tumor types that represent enormous unmet clinical need, primarily in the context of immune checkpoint inhibitor therapy. Translating optimized and informative immune profiling into standard practice and access to personalized combination therapy will be critical if childhood cancers are to be treated effectively and affordably.
Authors
Rachael L. Terry, Deborah Meyran, David S. Ziegler, Michelle Haber, Paul G. Ekert, Joseph A. Trapani, Paul J. Neeson
Abstract
Muscular dystrophies are debilitating disorders that result in progressive weakness and degeneration of skeletal muscle. Although the genetic mutations and clinical abnormalities of a variety of neuromuscular diseases are well known, no curative therapies have been developed to date. The advent of genome editing technology provides new opportunities to correct the underlying mutations responsible for many monogenic neuromuscular diseases. For example, Duchenne muscular dystrophy, which is caused by mutations in the dystrophin gene, has been successfully corrected in mice, dogs, and human cells through CRISPR/Cas9 editing. In this Review, we focus on the potential for, and challenges of, correcting muscular dystrophies by editing disease-causing mutations at the genomic level. Ideally, because muscle tissues are extremely long-lived, CRISPR technology could offer a one-time treatment for muscular dystrophies by correcting the culprit genomic mutations and enabling normal expression of the repaired gene.
Authors
Francesco Chemello, Rhonda Bassel-Duby, Eric N. Olson
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Copyright © 2020 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)