Clinical and Translational Challenges in Gene Therapy of Cardiovascular Diseases

Pankajakshan, Divya; Agrawal, Devendra K.

doi:10.5772/54075

Cited by 5 publications

(6 citation statements)

References 174 publications

(200 reference statements)

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“…Other experimental therapeutic approaches include gene therapy to knock down low-density lipoprotein receptors (LDLR) to minimize intracellular cholesterol accumulation and use of recombinant retroviruses to express antioxidants thereby reducing reactive oxygen species (ROS) mediated atherogenesis. However, stability of the vectors, scalability issues, and cost of these methods have limited their clinical translation [3]. To overcome these limitations, other approaches for foam cell targeting and atherosclerosis regression that could be used in conjunction or as an alternative to current therapeutic approaches are being investigated.…”

Section: Introductionmentioning

confidence: 99%

Cyclodextrin conjugated ferritin nanocages reduce intracellular cholesterol level in foam cells

Ravishankar

Lim

2019

Nano Res.

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Accumulation of lipid-laden macrophages (foam cells) is characteristic of atherosclerosis development in the arterial walls. Ferritin nanocages have been found to passively accumulate in the atherosclerotic plaque. Ferritin has been actively investigated as a carrier for contrast agents in atherosclerosis diagnosis. We demonstrate the potential of ferritin as a carrier for therapeutic molecules to mediate cholesterol reduction from foam cells. Cyclodextrin molecules are chemically conjugated to the ferritin nanocages surface or encapsulated within the nanocages using metal co-loading methods. The cyclodextrin-conjugated ferritin has nanomolar affinity to cholesterol molecules. Treatment of foam cells with the conjugates shows decreased levels of intracellular accumulated cholesterol. The preferential localization of ferritin to foam cells is due to transferrin receptor-mediated endocytosis process. These findings show that ferritin nanocages as carriers localize cyclodextrin molecules to foam cells which mediate intracellular cholesterol reduction, thus highlighting its potential use as a therapeutic agent.

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Section: Introductionmentioning

confidence: 99%

Cyclodextrin conjugated ferritin nanocages reduce intracellular cholesterol level in foam cells

Ravishankar

Lim

2019

Nano Res.

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“…However, gene therapy using mRNA faces one same major obstacle to success as gene therapy using DNA: simply, there is no safe and effective way to deliver genes into many epithelial and muscle tissues in vivo [ 5 ]. These tissues are affected by various disorders potentially amenable to gene therapy, including cystic fibrosis (CF)—the most common life-shortening monogenetic disorder [ 6 ]—the muscular dystrophies [ 7 ], and cardiovascular disease [ 8 ]. Current gene therapy vectors have drawbacks that preclude their use in targeting these tissues.…”

Section: Introductionmentioning

confidence: 99%

mRNA transfection by a Xentry-protamine cell-penetrating peptide is enhanced by TLR antagonist E6446

et al. 2018

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Messenger RNA (mRNA) transfection is a developing field that has applications in research and gene therapy. Potentially, mRNA transfection can be mediated efficiently by cell-penetrating peptides (CPPs) as they may be modified to target specific tissues. However, whilst CPPs are well-documented to transfect oligonucleotides and plasmids, mRNA transfection by CPPs has barely been explored. Here we report that peptides, including a truncated form of protamine and the same peptide fused to the CPP Xentry (Xentry-protamine; XP), can transfect mRNAs encoding reporter genes into human cells. Further, this transfection is enhanced by the anti-malarial chloroquine (CQ) and the toll-like receptor antagonist E6446 (6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole), with E6446 being >5-fold more potent than CQ at enhancing this transfection. Finally, E6446 facilitated the transfection by XP of mRNA encoding the cystic fibrosis transmembrane regulator, the protein mutated in cystic fibrosis. As such, these findings introduce E6446 as a novel transfection enhancer and may be of practical relevance to researchers seeking to improve the mRNA transfection efficiency of their preferred CPP.

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“…Antioxidants like catalase reduce the ROS thereby decreasing ROS mediated LDL modification and thus reduced intracellular cholesterol uptake. Additionally, vectors are being developed to knock down LDLR receptors to achieve the same effect of reduced intracellular cholesterol accumulation and foam cell formation [72] . Gene therapy has been demonstrated…”

Section: Challenges Of Treatment Methodsmentioning

confidence: 99%

“…However, its clinical translation remains a challenge due to poor efficiency of gene transfer and high cost of largescale production of gene vectors. The stability of vectors in the physiological environment is also a cause of concern, wherein, ectopic expression could result in undesired immunological response [72,73] .…”

Section: Challenges Of Treatment Methodsmentioning

confidence: 99%

“…Other experimental therapeutic approaches include gene therapy to knock down LDLR to minimize intracellular cholesterol accumulation and use of recombinant retroviruses to express antioxidants thereby reducing ROS mediated atherogenesis. However, stability of the vectors, scalability issues, and cost of these methods have limited their clinical translation [72] . To overcome these limitations, other approaches for foam cell targeting and atherosclerosis regression that could be used in conjunction or as an alternative to current therapeutic approaches are being investigated in this thesis.…”

Section: Introductionmentioning

confidence: 99%

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Engineered ferritin nanocage as a cholesterol sequestering agent

Ravishankar¹

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Clinical and Translational Challenges in Gene Therapy of Cardiovascular Diseases

Cited by 5 publications

References 174 publications

Cyclodextrin conjugated ferritin nanocages reduce intracellular cholesterol level in foam cells

Cyclodextrin conjugated ferritin nanocages reduce intracellular cholesterol level in foam cells

mRNA transfection by a Xentry-protamine cell-penetrating peptide is enhanced by TLR antagonist E6446

Engineered ferritin nanocage as a cholesterol sequestering agent

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