Emerging therapies: The potential roles SGLT2 inhibitors, GLP1 agonists, and ARNI therapy for ARNI pulmonary hypertension.

Pulmonary hypertension (PH) is a highly morbid condition. PH due to left heart disease (PH-LHD) has no specific therapies and pulmonary arterial hypertension (PAH) has substantial residual risk despite several approved therapies. Multiple lines of experimental evidence link metabolic dysfunction to the pathogenesis and outcomes in PH-LHD and PAH, and novel metabolic agents hold promise to improve outcomes in these populations. The antidiabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP1) agonists targeting metabolic dysfunction and improve outcomes in patients with LHD but have not been tested specifically in patients with PH. The angiotensin receptor/neprilysin inhibitors (ARNIs) produce significant improvements in cardiac hemodynamics and may improve metabolic dysfunction that could benefit the pulmonary circulation and right ventricle function. On the basis of promising preclinical work with these medications and clinical rationale, we explore the potential of SGLT2 inhibitors, GLP1 agonists, and ARNIs as therapies for both PH-LHD and PAH.

Correction of Airway Stem Cells: Genome Editing Approaches for the Treatment of Cystic Fibrosis.

Cystic fibrosis (CF) is an autosomal recessive disease caused by variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although CF affects multiple organs, the primary cause of mortality is respiratory failure resulting from poor clearance of hyperviscous secretions and subsequent airway infection. Recently developed CFTR modulators provide significant therapeutic benefit to the majority of CF individuals. However, treatments directed at the underlying cause are needed for the ∼7% of CF patients who are not expected to be responsive to these modulators. Genome editing can restore the native CFTR genetic sequence and function to mutant cells, representing an approach to establish durable physiologic CFTR correction. Although editing the CFTR gene in various airway cell types may transiently restore CFTR activity, effort is focused on editing airway basal stem/progenitor cells, since their correction would allow appropriate and durable expression of CFTR in stem cell-derived epithelial cell types. Substantial progress has been made to directly correct airway basal cells in vitro, theoretically enabling transplantation of autologous corrected cells to regenerate an airway with CFTR functional cells. Another approach to create autologous, gene-edited airway basal cells is derivation of CF donor-specific induced pluripotent stem cells, correction of the CFTR gene, and subsequent directed differentiation to airway basal cells. Further work is needed to translate these advances by developing effective transplantation methods. Alternatively, gene editing in vivo may enable CFTR correction. However, this approach will require robust delivery methods ensuring that basal cells are efficiently targeted and corrected. Recent advances in gene editing-based therapies provide hope that the genetic underpinning of CF can be durably corrected in airway epithelial stem cells, thereby preventing or treating lung disease in all people with CF.

Two iPSC lines generated from the bone marrow of a relapsed/refractory AML patient display normal karyotypes and myeloid differentiation potential.

Using iPSCs to study cancer has been complicated by the fact that many cancer cells are difficult to reprogram, which has been attributed to the genomic abnormalities present. Acute Myeloid Leukemia (AML) is a complex disease that presents with various types of genomic aberrations that affect prognosis. Here we reprogrammed CD34+ cells from an AML patient containing a rare der(7)t(7;13) translocation associated with poor prognosis, who had relapsed and was refractory to current treatments. The generated AML-iPSCs displayed normal karyotypes and myeloid differentiation potential. These findings have implications for modeling and treating AML disease.