Review
Abstract
Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: the first establishes a vulnerable bronchoalveolar epithelium, and the second triggers mechanisms that reprogram distal epithelia to initiate and perpetuate a profibrotic phenotype. While vulnerability of the bronchoalveolar epithelia is most often driven by common or rare genetic variants, subsequent injury of the bronchoalveolar epithelia results in persistent changes in cell biology that disrupt tissue homeostasis and activate fibroblasts. The dynamic biology of IPF can best be contextualized etiologically and temporally, including stages of vulnerability, early disease, and persistent and progressive lung fibrosis. These dimensions of IPF highlight critical mechanisms that adversely disrupt epithelial function, activate fibroblasts, and lead to lung remodeling. Together with better recognition of early disease, this conceptual approach should lead to the development of novel therapeutics directed at the etiologic and temporal drivers of lung fibrosis that will ultimately transform the care of patients with IPF from palliative to curative.
Authors
James P. Bridges, Eszter K. Vladar, Jonathan S. Kurche, Andrei Krivoi, Ian T. Stancil, Evgenia Dobrinskikh, Yan Hu, Sarah K. Sasse, Joyce S. Lee, Rachel Z. Blumhagen, Ivana V. Yang, Anthony N. Gerber, Anna L. Peljto, Christopher M. Evans, Elizabeth F. Redente, David W.H. Riches, David A. Schwartz
Abstract
The pursuit of a vaccine against the human cytomegalovirus (HCMV) has been ongoing for more than 50 years. HCMV is the leading infectious cause of birth defects, including damage to the brain, and is a common cause of complications in organ transplantation. The complex biology of HCMV has made vaccine development difficult, but a recent meeting sponsored by the National Institute of Allergy and Infectious Diseases in September of 2023 brought together experts from academia, industry, and federal agencies to discuss progress in the field. The meeting reviewed the status of candidate HCMV vaccines under study and the challenges in clinical trial design in demonstrating efficacy against congenital CMV infection or the reduction of HCMV disease following solid organ transplantation or hematopoietic stem cell transplantation. Discussion in the meeting revealed that, with the numerous candidate vaccines that are under study, it is clear that a safe and effective HCMV vaccine is within reach. Meeting attendees achieved a consensus opinion that even a partially effective vaccine would have a major effect on the global health consequences of HCMV infection.
Authors
Sallie R. Permar, Mark R. Schleiss, Stanley A. Plotkin
Abstract
Acute myocardial infarction (MI) is a leading cause of death worldwide. Although with current treatment, acute mortality from MI is low, the damage and remodeling associated with MI are responsible for subsequent heart failure. Reducing cell death associated with acute MI would decrease the mortality associated with heart failure. Despite considerable study, the precise mechanism by which ischemia and reperfusion (I/R) trigger cell death is still not fully understood. In this Review, we summarize the changes that occur during I/R injury, with emphasis on those that might initiate cell death, such as calcium overload and oxidative stress. We review cell-death pathways and pathway crosstalk and discuss cardioprotective approaches in order to provide insight into mechanisms that could be targeted with therapeutic interventions. Finally, we review cardioprotective clinical trials, with a focus on possible reasons why they were not successful. Cardioprotection has largely focused on inhibiting a single cell-death pathway or one death-trigger mechanism (calcium or ROS). In treatment of other diseases, such as cancer, the benefit of targeting multiple pathways with a “drug cocktail” approach has been demonstrated. Given the crosstalk between cell-death pathways, targeting multiple cardiac death mechanisms should be considered.
Authors
Yusuf Mastoor, Elizabeth Murphy, Barbara Roman
Abstract
As epigenetic therapies continue to gain ground as potential treatment strategies for cancer and other diseases, compounds that target histone lysine methylation and the enzyme complexes represent a major frontier for therapeutic development. Clinically viable therapies targeting the activities of histone lysine methyltransferases (HKMT) and demethylases (HKDMs) have only recently begun to emerge following FDA approval of the EZH2 inhibitor tazemetostat in 2020 and remain limited to compounds targeting the well-studied SET domain–containing HKMTs and their opposing HKDMs. These include the H3K27 methyltransferases EZH2/EZH1, the singular H3K79 methyltransferase DOT1L, and the H3K4 methyltransferase MLL1/COMPASS as well as H3K9 and H3K36 methyltransferases. They additionally include the H3K4/9-preferential demethylase LSD1 and the H3K4-, H3K27-, and H3K36-preferential KDM5, KDM6, and KDM2 demethylase subfamilies, respectively. This Review discusses the results of recent clinical and preclinical studies relevant to all of these existing and potential therapies. It provides an update on advancements in therapeutic development, as well as more basic molecular understanding, within the past 5 years approximately. It also offers a perspective on histone lysine methylation that departs from the long-predominant “histone code” metaphor, emphasizing complex-disrupting inhibitors and proximity-based approaches rather than catalytic domain inhibitors in the outlook for future therapeutic development.
Authors
Sarah Gold, Ali Shilatifard
Abstract
Substance use disorders (SUDs) are highly prevalent and associated with excess morbidity, mortality, and economic costs. Thus, there is considerable interest in the early identification of individuals who may be more susceptible to developing SUDs and in improving personalized treatment decisions for those who have SUDs. SUDs are known to be influenced by both genetic and environmental factors. Polygenic scores (PGSs) provide a single measure of genetic liability that could be used as a biomarker in predicting disease development, progression, and treatment response. Although PGSs are rapidly being integrated into clinical practice, there is little information to guide clinicians in their responsible use and interpretation. In this Review, we discuss the potential benefits and pitfalls of the use of PGSs in the clinical care of SUDs, highlighting current research. We also provide suggestions for important considerations prior to implementing the clinical use of PGSs and recommend future directions for research.
Authors
Rachel L. Kember, Christal N. Davis, Kyra L. Feuer, Henry R. Kranzler
Abstract
Cannabis has been legalized for medical and recreational purposes in multiple countries. A large number of people are using cannabis and some will develop cannabis use disorder (CUD). There is a growing recognition that CUD requires specific interventions. This Review will cover this topic from a variety of perspectives, with a particular emphasis on neurobiological findings and innovative treatment approaches that are being pursued. We will first describe the epidemiology and burden of disease of CUD, including risk factors associated with CUD (both in terms of general risk and genetic risk variants). Neurobiological alterations identified in brain imaging studies will be presented. Several psychosocial interventions that are useful for the management of CUD, including motivational enhancement therapy, behavioral and cognitive therapy, and contingency management, will be covered. Although no pharmacological interventions are yet approved for CUD, we present the most promising pharmacological interventions being tested.
Authors
Bernard Le Foll, Victor M. Tang, Sergio Rueda, Leanne V. Trick, Isabelle Boileau
Abstract
Opioid misuse, addiction, and associated overdose deaths remain global public health crises. Despite the tremendous need for pharmacological treatments, current options are limited in number, use, and effectiveness. Fundamental leaps forward in our understanding of the biology driving opioid addiction are needed to guide development of more effective medication-assisted therapies. This Review focuses on the omics-identified biological features associated with opioid addiction. Recent GWAS have begun to identify robust genetic associations, including variants in OPRM1, FURIN, and the gene cluster SCAI/PPP6C/RABEPK. An increasing number of omics studies of postmortem human brain tissue examining biological features (e.g., histone modification and gene expression) across different brain regions have identified broad gene dysregulation associated with overdose death among opioid misusers. Drawn together by meta-analysis and multi-omic systems biology, and informed by model organism studies, key biological pathways enriched for opioid addiction–associated genes are emerging, which include specific receptors (e.g., GABAB receptors, GPCR, and Trk) linked to signaling pathways (e.g., Trk, ERK/MAPK, orexin) that are associated with synaptic plasticity and neuronal signaling. Studies leveraging the agnostic discovery power of omics and placing it within the context of functional neurobiology will propel us toward much-needed, field-changing breakthroughs, including identification of actionable targets for drug development to treat this devastating brain disease.
Authors
Eric O. Johnson, Heidi S. Fisher, Kyle A. Sullivan, Olivia Corradin, Sandra Sanchez-Roige, Nathan C. Gaddis, Yasmine N. Sami, Alice Townsend, Erica Teixeira Prates, Mirko Pavicic, Peter Kruse, Elissa J. Chesler, Abraham A. Palmer, Vanessa Troiani, Jason A. Bubier, Daniel A. Jacobson, Brion S. Maher
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a previously unrecognized, potent, age-related, and common risk factor for atherosclerosis. Somatic mutations in certain known leukemia driver genes give rise to clones of mutant cells in peripheral blood. The increased risk of developing hematologic malignancy does not, on its own, explain excess mortality in individuals with CHIP. Cardiovascular disease accounts for much of this gap. Experimental evidence supports the causality of certain CHIP mutations in accelerated atherosclerosis. CHIP due to mutations in different driver genes varies in their promotion of atherosclerotic events and in the region of augmented atherosclerotic involvement. For example, CHIP due to mutations in DNMT3a appears less atherogenic than CHIP that arises from TET2 or JAK2, forms of CHIP that incite inflammation. The recognition of certain CHIP mutations as promoters of atherosclerotic risk has opened new insights into understanding of the pathophysiology of this disease. The accentuated cardiovascular risk and involvement of distinct pathways of various forms of CHIP also inform novel approaches to allocation of targeted therapies, affording a step toward personalized medicine.
Authors
Ohad Oren, Aeron M. Small, Peter Libby
Abstract
Therapy-related clonal hematopoiesis (t-CH) is defined as clonal hematopoiesis detected in individuals previously treated with chemotherapy and/or radiation therapy. With the increased use of genetic analysis in oncological care, the detection of t-CH among cancer patients is becoming increasingly common. t-CH arises through the selective bottleneck imposed by chemotherapies and potentially through direct mutagenesis from chemotherapies, resulting in a distinct mutational landscape enriched with mutations in DNA damage-response pathway genes such as TP53, PPM1D, and CHEK2. Emerging evidence sheds light on the mechanisms of t-CH development and potential strategies to mitigate its emergence. Due to its unique characteristics that predominantly affect cancer patients, t-CH has clinical implications distinct from those of CH in the general population. This Review discusses the potential mechanisms of t-CH development, its mutational landscape, mutant-drug relationships, and its clinical significance. We highlight the distinct nature of t-CH and call for intensified research in this field.
Authors
Koichi Takahashi, Daisuke Nakada, Margaret Goodell
Abstract
Clonal hematopoiesis (CH), the expansion of hematopoietic stem cells and their progeny driven by somatic mutations in leukemia-associated genes, is a common phenomenon that rises in prevalence with advancing age to affect most people older than 70 years. CH remains subclinical in most carriers, but, in a minority, it progresses to a myeloid neoplasm, such as acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm. Over the last decade, advances in our understanding of CH, its molecular landscape, and the risks associated with different driver gene mutations have culminated in recent developments that allow for a more precise estimation of myeloid neoplasia risk in CH carriers. In turn, this is leading to the development of translational and clinical programs to intercept and prevent CH from developing into myeloid neoplasia. Here, we give an overview of the spectrum of CH driver mutations, what is known about their pathophysiology, and how this informs the risk of incident myeloid malignancy.
Authors
William G. Dunn, Matthew A. McLoughlin, George S. Vassiliou
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