Engineered bacterial voltage-gated sodium channel platform for cardiac gene therapy

Nguyen, Hung; Wu, Tianyu; Needs, Daniel A.; Zhang, Hengtao; Perelli, Robin M; DeLuca, Sophia; Yang, Rachel; Tian, Michael; Landstrom, Andrew P.; Henriquez, Craig S.; Bursac, Nenad

doi:10.1038/s41467-022-28251-6

Cited by 14 publications

(6 citation statements)

References 96 publications

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“…Action potential propagation was initiated by 2-Hz stimuli from a bipolar point electrode, and the signals were collected by a 19-mm-diameter optical fiber array through a custom 3:1 fiber optic taper. Isochrone map construction and conduction velocity and action potential duration calculations were performed using custom MATLAB software, as previously described ( 97 ).…”

Section: Methodsmentioning

confidence: 99%

Time-dependent effects of BRAF-V600E on cell cycling, metabolism, and function in engineered myocardium

Strash,

DeLuca,

Janer Carattini

et al. 2024

Sci. Adv.

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Candidate cardiomyocyte (CM) mitogens such as those affecting the extracellular signal–regulated kinase (ERK) signaling pathway represent potential targets for functional heart regeneration. We explored whether activating ERK via a constitutively active mutant of B-raf proto-oncogene (BRAF), BRAF-V600E (caBRAF), can induce proproliferative effects in neonatal rat engineered cardiac tissues (ECTs). Sustained CM-specific caBRAF expression induced chronic ERK activation, substantial tissue growth, deficit in sarcomeres and contractile function, and tissue stiffening, all of which persisted for at least 4 weeks of culture. caBRAF-expressing CMs in ECTs exhibited broad transcriptomic changes, shift to glycolytic metabolism, loss of connexin-43, and a promigratory phenotype. Transient, doxycycline-controlled caBRAF expression revealed that the induction of CM cycling is rapid and precedes functional decline, and the effects are reversible only with short-lived ERK activation. Together, direct activation of the BRAF kinase is sufficient to modulate CM cycling and functional phenotype, offering mechanistic insights into roles of ERK signaling in the context of cardiac development and regeneration.

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Section: Methodsmentioning

confidence: 99%

Time-dependent effects of BRAF-V600E on cell cycling, metabolism, and function in engineered myocardium

Strash,

DeLuca,

Janer Carattini

et al. 2024

Sci. Adv.

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“…To determine the functional titer of lentiviruses containing a green fluorescent reporter (GFP) and CAR protein gene, 293T cells were transduced with serial dilutions of the concentrated lentiviral stock. The percentage of transduced cells was then assessed via flow cytometry at 72 h post-transduction [ 28 ]. The functional titer of the lentiviruses was calculated using the following equation: titer (TU/mL) = (F × C/V) × D, where F represents the percentage of GFP-positive cells, C denotes the cell number, V refers to the inoculum volume in milliliters, and D signifies the lentivirus dilution ratio.…”

Section: Methodsmentioning

confidence: 99%

Inhalable CAR-T cell-derived exosomes as paclitaxel carriers for treating lung cancer

et al. 2023

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Background Non-small cell lung cancer (NSCLC) is a worldwide health threat with high annual morbidity and mortality. Chemotherapeutic drugs such as paclitaxel (PTX) have been widely applied clinically. However, systemic toxicity due to the non-specific circulation of PTX often leads to multi-organ damage, including to the liver and kidney. Thus, it is necessary to develop a novel strategy to enhance the targeted antitumor effects of PTX. Methods Here, we engineered exosomes derived from T cells expressing the chimeric antigen receptor (CAR-Exos), which targeted mesothelin (MSLN)-expressing Lewis lung cancer (MSLN-LLC) through the anti-MSLN single-chain variable fragment (scFv) of CAR-Exos. PTX was encapsulated into CAR-Exos (PTX@CAR-Exos) and administered via inhalation to an orthotopic lung cancer mouse model. Results Inhaled PTX@CAR-Exos accumulated within the tumor area, reduced tumor size, and prolonged survival with little toxicity. In addition, PTX@CAR-Exos reprogrammed the tumor microenvironment and reversed the immunosuppression, which was attributed to infiltrating CD8+ T cells and elevated IFN-γ and TNF-α levels. Conclusions Our study provides a nanovesicle-based delivery platform to promote the efficacy of chemotherapeutic drugs with fewer side effects. This novel strategy may ameliorate the present obstacles to the clinical treatment of lung cancer.

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“…The feasibility of this approach has been demonstrated in rodent models, where voltage-gated potassium channels were delivered for the treatment of epilepsy or neuropathic pain [ 99 , 100 ]. Recent and promising developments involving engineered prokaryotic Nav channels for cardiac arrhythmias also illustrate the potential of this concept for clinical applications [ 101 ] and may inform future investigations regarding the delivery of neuronal Nav channels.…”

Section: Therapeutic Potential Of Nav Channels For Admentioning

confidence: 99%

Voltage-Gated Na+ Channels in Alzheimer’s Disease: Physiological Roles and Therapeutic Potential

Baumgartner,

Haghighijoo,

Goode

et al. 2023

Life

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Alzheimer’s disease (AD) is the most common cause of dementia and is classically characterized by two major histopathological abnormalities: extracellular plaques composed of amyloid beta (Aβ) and intracellular hyperphosphorylated tau. Due to the progressive nature of the disease, it is of the utmost importance to develop disease-modifying therapeutics that tackle AD pathology in its early stages. Attenuation of hippocampal hyperactivity, one of the earliest neuronal abnormalities observed in AD brains, has emerged as a promising strategy to ameliorate cognitive deficits and abate the spread of neurotoxic species. This aberrant hyperactivity has been attributed in part to the dysfunction of voltage-gated Na+ (Nav) channels, which are central mediators of neuronal excitability. Therefore, targeting Nav channels is a promising strategy for developing disease-modifying therapeutics that can correct aberrant neuronal phenotypes in early-stage AD. This review will explore the role of Nav channels in neuronal function, their connections to AD pathology, and their potential as therapeutic targets.

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Engineered bacterial voltage-gated sodium channel platform for cardiac gene therapy

Cited by 14 publications

References 96 publications

Time-dependent effects of BRAF-V600E on cell cycling, metabolism, and function in engineered myocardium

Time-dependent effects of BRAF-V600E on cell cycling, metabolism, and function in engineered myocardium

Inhalable CAR-T cell-derived exosomes as paclitaxel carriers for treating lung cancer

Voltage-Gated Na+ Channels in Alzheimer’s Disease: Physiological Roles and Therapeutic Potential

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