Progresses towards safe and efficient gene therapy vectors

Chira, Sergiu; Jackson, Carlo Stephan; Oprea, Iulian; Öztürk, Ferhat; Pepper, Michael Sean; Diaconu, Iulia; Braicu, Cornelia; Ráduly, Lajos; Calin, George A.; Berindan‐Neagoe, Ioana

doi:10.18632/oncotarget.5169

Cited by 178 publications

(170 citation statements)

References 240 publications

(256 reference statements)

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“…Despite the excellent transfection efficiency attained with viral-based vectors, several safety concerns remain, including genotoxicity and immunogenicity (32). In addition, viral vectors are difficult to produce and have restricted target-cell specificity (33). Nonviral platforms have thus emerged as viable alternatives for siRNA delivery.…”

Section: Discussionmentioning

confidence: 99%

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Yan

Duan

Pan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

121

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Osteoarthritis (OA) is a major cause of disability and morbidity in the aging population. Joint injury leads to cartilage damage, a known determinant for subsequent development of posttraumatic OA, which accounts for 12% of all OA. Understanding the early molecular and cellular responses postinjury may provide targets for therapeutic interventions that limit articular degeneration. Using a murine model of controlled knee joint impact injury that allows the examination of cartilage responses to injury at specific time points, we show that intraarticular delivery of a peptidic nanoparticle complexed to NF-κB siRNA significantly reduces early chondrocyte apoptosis and reactive synovitis. Our data suggest that NF-κB siRNA nanotherapy maintains cartilage homeostasis by enhancing AMPK signaling while suppressing mTORC1 and Wnt/β-catenin activity. These findings delineate an extensive crosstalk between NF-κB and signaling pathways that govern cartilage responses postinjury and suggest that delivery of NF-κB siRNA nanotherapy to attenuate early inflammation may limit the chronic consequences of joint injury. Therapeutic benefits of siRNA nanotherapy may also apply to primary OA in which NF-κB activation mediates chondrocyte catabolic responses. Additionally, a critical barrier to the successful development of OA treatment includes ineffective delivery of therapeutic agents to the resident chondrocytes in the avascular cartilage. Here, we show that the peptide–siRNA nanocomplexes are nonimmunogenic, are freely and deeply penetrant to human OA cartilage, and persist in chondrocyte lacunae for at least 2 wk. The peptide–siRNA platform thus provides a clinically relevant and promising approach to overcoming the obstacles of drug delivery to the highly inaccessible chondrocytes.

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Section: Discussionmentioning

confidence: 99%

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Yan

Duan

Pan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

119

121

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“…Unfortunately, using modified viral vectors in therapy is still considered controversial by the medical community because of the risk of viral DNA integration into undesirable locations in the host genome, with the resulting transformation of healthy somatic and germ line cells in the body. Also, the level of expression of the exogenous gene is usually too low to mount a full treatment effect [195]. Another method of transferring specific miRNA into the lung tumour tissue is a cationic lipid-based miRNA delivery system, which had good efficiency both in vitro and in vivo, as was reported by Wu et al [189,196].…”

Section: Problems To Overcomementioning

confidence: 99%

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

Florczuk¹,

Szpechcinski²,

Chorostowska‐Wynimko³

2017

Targ Oncol

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Lung cancer is the most common cancer worldwide. Up to 85% of lung cancer cases are diagnosed as nonsmall cell lung cancer (NSCLC). The effectiveness of NSCLC treatment is expected to be improved through the implementation of robust and specific biomarkers. MicroRNAs (miRNAs) are small, non-coding molecules that play a key role in the regulation of basic cellular processes, including differentiation, proliferation and apoptosis, by controlling gene expression at the post-transcriptional level.

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“…One drawback is that these types of vectors are generally less efficient when compared to their viral counterparts. [14] Characteristics that non-viral vectors should have are biocompatibility, biodegradability, non-toxicity, stability, the ability to perform endosomal/lysosomal escape, the ability to protect siRNA, and ease of production. [26] Three general categories for non-viral vectors are lipid-based vectors, non-lipid organic-based vectors, and non-lipid inorganic-based vectors.…”

Section: Non-viral Vectorsmentioning

confidence: 99%

An Overview of Various Carriers for siRNA Delivery

Marquez¹,

Madu²,

Lü³

2018

Oncomedicine

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RNA interference through the use of short interfering molecules known as short interfering RNA (siRNA) has the potential to greatly advance research in treatments for many diseases because it has the ability to silence the expression of specific genes by helping degrade target mRNA. However, challenges to siRNA delivery have made the development of safe and effective delivery systems paramount in siRNA research. Various types of delivery systems have been proposed and investigated for siRNA delivery and therapy. Although viral vectors have been established to be the most effective in delivering siRNA molecules, they also raise many concerns over biosafety, especially concerning immunogenicity. Therefore, many researchers have begun to investigate and study non-viral vectors. Non-viral vectors are studied because they are typically considered to be safer than viral vectors albeit less efficient as well. The three general non-viral vectors that have been studied for siRNA delivery are lipid-based, non-lipid organic-based, and non-lipid inorganic-based carriers. Within those general parameters of non-viral vector classification are subtypes that are each unique with their own characteristic benefits and downsides. Many of these carriers, as well as even naked siRNA, do have the potential to be modified so that siRNA delivery could be further enhanced with benefits such as greater stability and duration. Researchers still must be wary with alterations as to not interfere with siRNA function. Currently, widespread siRNA therapeutics are still out of reach, but as more advancements in siRNA research including research on their delivery mechanisms are established, the goal of integrating siRNA therapy into the treatment of a multitude of diseases becomes increasingly more of a possibility. Researchers are currently investigating how siRNA can be used to not just treat cancer but ocular and neurodegenerative diseases as well as many others. There are still many obstacles to face and overcome before siRNA therapy can be implemented into the treatment of many diseases, and more research must still be conducted concerning siRNA delivery systems. Many advancements pertaining to siRNA carriers have been made, and many more are likely on their way.

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Progresses towards safe and efficient gene therapy vectors

Cited by 178 publications

References 240 publications

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

An Overview of Various Carriers for siRNA Delivery

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