Molecular Cardiac Surgery with Recirculating Delivery (MCARD): Procedure and Vector Transfer

Katz, Michael G.; Fargnoli, Anthony S.; Kendle, Andrew P.; Bridges, Charles R.

doi:10.1007/978-1-4939-6588-5_20

Cited by 3 publications

(3 citation statements)

References 15 publications

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“…Preclinical studies with this endovascular device show that it can directly access target tissues, such as the heart, kidney and pancreas, without the need to seal the puncture site 146 . Re-circulation devices, which allow the agent to pass the area of interest multiple times, can enhance transduction efficiency in large animal models 174 . Selective pressure-regulated retroinfusion (SSR) with blockage of the antegrade flow is another promising approach for safe, efficient delivery of various agents, including cDNA, miRNA inhibitors and gene therapeutic agents 175 .…”

Section: Catheter Deliverymentioning

confidence: 99%

Unlocking the promise of mRNA therapeutics

et al. 2022

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z and enhanced catalysis to the ribosomal complex [32][33][34][35][36] . Optimization of the poly(A) tail length (100-300 nucleotides) has proven critical in balancing the synthetic capability of a given mRNA 34,36 . Similarly, improved 5′ cap analogs not only increase translational capacity but also enhance capping efficiency, from 70% to 95%, greatly improving the in vitro transcription process 32,37 . The composition of the 3′ and 5′ UTRs can also be customized for the target cell of interest, increasing the efficiency and tissue specificity of translation 35,38,39 .At present, most mRNA products contain a synthetic UTR sequence from α-globin or β-globin [38][39][40] , but UTR optimization can further improve protein expression by a few fold 41,42 . Careful screening and customization to the target of interest could conceivably offer a wide range of improvements in future UTR sequences, allowing each mRNA to be tailored to the targeted cell and disease-induced microenvironment to maximize protein synthesis per mRNA transcript [41][42][43][44] .Perhaps the most critical advances in mRNA vaccines and therapeutics lie in the discovery that the inclusion of chemically modified nucleosides, particularly in uridine moieties, can markedly increase protein expression after in vitro or in vivo transfection. The chemical modifications of most new RNA formulations to date have been central in intellectual property claims 45,46 . Thus far, over 130 different naturally occurring chemical modifications of RNA have been reported 47,48 . The interest in methylpseudouridine and other modified nucleosides centers on their capacity to greatly reduce (up to 100-fold) detection by the Toll-like receptors of the innate immune system, resulting in an increase in protein expression in vivo compared to unmodified mRNA 40,[49][50][51][52][53] . Combinations of different types of chemical modifications, carriers, for the treatment of chronic conditions. The fifth section provides a comprehensive table and summary of current clinical trends in mRNA therapeutics. Finally, the sixth section considers the scope of mRNA therapeutics and guiding principles for near-term and longer-term clinical development of this novel therapeutic modality.

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Section: Catheter Deliverymentioning

confidence: 99%

Unlocking the promise of mRNA therapeutics

et al. 2022

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“…Summarizing, it has been demonstrated that complete surgical isolation of the heart in situ , using CPB with high-pressure retrograde coronary sinus infusion with multiple-pass recirculation of vector through the heart results in an increase of several orders of magnitude in cardiac marker gene activities compared with controls, receiving retrograde infusion of adenovirus without CPB and without cardiac isolation [ 16 ]. The principal strength of this technology includes a dramatic (>1000-fold) increase in transduction efficiency, the extension of vector residence time, the ability to manipulate endothelial permeability, the avoidance of an immune response to the vector and the ability to washout the vector post gene delivery limiting collateral organ exposure [ 17 ]. “Closed loop” systems such as MCARD can provide robust gene expression with no detectable extra-cardiac transfer and no detrimental effects on major organ function.…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

In Situ Heart Isolation Featuring Closed Loop Recirculation: The Gold Standard for Optimum Cardiac Gene Transfer?

et al. 2017

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The concept of delivering nucleic material encoding a therapeutic gene to the heart has arduously moved from hypothesis to a variety of high potential clinical applications. Despite the promise however, the results achieved have yet to be realized due to several problems that persist in the clinic. One of these identified problems is the need for an efficient delivery method which facilitates complete cardiotropism and minimizes collateral effects. Additional parameters impacting gene delivery that most need to be improved have been identified as follows: (1) Increasing the contact time of vector in coronary circulation permitting transfer, (2) Sustained intravascular flow rate and perfusion pressure to facilitate proper kinetics, (3) Modulation of cellular permeability to increase uptake efficiency, and once in the cells (4) Enhancing transcription and translation within the transfected cardiac cells, and (5) Obtaining the global gene distribution for maximum efficacy. Recently it was hypothesized that use of cardiopulmonary bypass may facilitate cardiac-selective gene transfer and permit vector delivery in the arrested heart in isolated “closed loop” recirculating model. This system was named molecular cardiac surgery with recirculating delivery (MCARD). The key components of this approach include: isolation of the heart from systemic organs, multiple pass recirculation of vector through the coronary vasculature, and removing the residual vector from the coronary circulation to minimize collateral expression. These attributes unique to a surgical approach such as MCARD can effectively increase vector transduction efficiency in coronary vasculature.

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“…Because of its invasiveness, this method is rarely used; see [14] for a detailed description. For reviews describing delivery methods that are suitable for large animal models and humans, see [15-19]. …”

Section: Introductionmentioning

confidence: 99%

AAV Vectors for Efficient Gene Delivery to Rodent Hearts

Lopez-Gordo

Kohlbrenner

Katz

et al. 2019

Methods in Molecular Biology

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Currently, gene therapy is one of the most promising fields in biomedicine, with great therapeutic potential for an array of inherited and acquired diseases. Adeno-associated viral (AAV) vectors have emerged as promising tools to deliver selectively a therapeutic payload to target organs, including the heart. In this chapter, we describe the production and quality control of recombinant AAV (rAAV) vectors of the serotype 9, the most cardiotropic AAV serotype when delivered systemically in rodents. We also describe the systemic administration of rAAV vectors and the local delivery of rAAV vectors by direct intramyocardial injection. Taken together, the methods described in this chapter will allow the reader to deliver efficiently therapeutic genes to the rodent heart, both globally and regionally.

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Molecular Cardiac Surgery with Recirculating Delivery (MCARD): Procedure and Vector Transfer

Cited by 3 publications

References 15 publications

Unlocking the promise of mRNA therapeutics

Unlocking the promise of mRNA therapeutics

In Situ Heart Isolation Featuring Closed Loop Recirculation: The Gold Standard for Optimum Cardiac Gene Transfer?

AAV Vectors for Efficient Gene Delivery to Rodent Hearts

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