Intracellular delivery of therapeutic antisense oligonucleotides targeting mRNA coding mitochondrial proteins by cell-penetrating peptides

Cerrato, Carmine Pasquale; Kivijärvi, Tove; Tozzi, Roberta; Lehto, Tõnis; Gestin, Maxime; Langel, Ülo

doi:10.1039/d0tb01106a

Cited by 23 publications

(14 citation statements)

References 64 publications

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“…In the last decade, there has been a crescendo of interest in the development of suitable nano-delivery systems to carry genetic content into the proximity of mitochondria and ensure its long-term expression, a strategy to deal with diseases related to mtDNA mutations [19,20,[40][41][42][43][44]. In this work, peptide/pND1 complexes have been developed aiming to target mitochondria and deliver pND1 plasmid into this organelle, as the first step for efficient mitochondrial gene expression.…”

Section: Pnd1 Complexation Capacitymentioning

confidence: 99%

“…In the past few years, several research studies have demonstrated efficient mitochondria targeting [19,40,43,44,[50][51][52] The efforts in the development of delivery systems displaying this capacity have been fruitful, with various reports on biomolecules or gene delivery into mitochondria [19,39,[53][54][55]. Despite this achieved progress, to date, few works have demonstrated effective long-term mitochondrial transgene expression [52].…”

Section: Mitochondria Targeting Abilitymentioning

confidence: 99%

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Development of Peptide-Based Nanoparticles for Mitochondrial Plasmid DNA Delivery

et al. 2021

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A mitochondrion is a cellular organelle able to produce cellular energy in the form of adenosine triphosphate (ATP). As in the nucleus, mitochondria contain their own genome: the mitochondrial DNA (mtDNA). This genome is particularly susceptible to mutations that are at the basis of a multitude of disorders, especially those affecting the heart, the central nervous system and muscles. Conventional clinical practice applied to mitochondrial diseases is very limited and ineffective; a clear need for innovative therapies is demonstrated. Gene therapy seems to be a promising approach. The use of mitochondrial DNA as a therapeutic, optimized by peptide-based complexes with mitochondrial targeting, can be seen as a powerful tool in the reestablishment of normal mitochondrial function. In line with this requirement, in this work and for the first time, a mitochondrial-targeting sequence (MTS) has been incorporated into previously researched peptides, to confer on them a targeting ability. These peptides were then considered to complex a plasmid DNA (pDNA) which contains the mitochondrial gene ND1 (mitochondrially encoded NADH dehydrogenase 1 protein), aiming at the formation of peptide-based nanoparticles. Currently, the ND1 plasmid is one of the most advanced bioengineered vectors for conducting research on mitochondrial gene expression. The formed complexes were characterized in terms of pDNA complexation capacity, morphology, size, surface charge and cytotoxic profile. These data revealed that the developed carriers possess suitable properties for pDNA delivery. Furthermore, in vitro studies illustrated the mitochondrial targeting ability of the novel peptide/pDNA complexes. A comparison between the different complexes revealed the most promising ones that complex pDNA and target mitochondria. This may contribute to the optimization of peptide-based non-viral systems to target mitochondria, instigating progress in mitochondrial gene therapy.

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Section: Pnd1 Complexation Capacitymentioning

confidence: 99%

Section: Mitochondria Targeting Abilitymentioning

confidence: 99%

Development of Peptide-Based Nanoparticles for Mitochondrial Plasmid DNA Delivery

et al. 2021

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“…The results showed that the vaccine augments Th1 (type 1 helper T-cell)-biased CD4 T-cell responses. Additionally, undetectable or very low Th2 or CD8 T-cell responses were noted ( 132 ).…”

Section: Covid-19 Mrna Vaccinesmentioning

confidence: 99%

From COVID-19 to Cancer mRNA Vaccines: Moving From Bench to Clinic in the Vaccine Landscape

et al. 2021

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Recently, mRNA vaccines have become a significant type of therapeutic and have created new fields in the biopharmaceutical industry. mRNA vaccines are promising next-generation vaccines that have introduced a new age in vaccinology. The recent approval of two COVID-19 mRNA vaccines (mRNA-1273 and BNT162b2) has accelerated mRNA vaccine technology and boosted the pharmaceutical and biotechnology industry. These mRNA vaccines will help to tackle COVID-19 pandemic through immunization, offering considerable hope for future mRNA vaccines. Human trials with data both from mRNA cancer vaccines and mRNA infectious disease vaccines have provided encouraging results, inspiring the pharmaceutical and biotechnology industries to focus on this area of research. In this article, we discuss current mRNA vaccines broadly in two parts. In the first part, mRNA vaccines in general and COVID-19 mRNA vaccines are discussed. We presented the mRNA vaccine structure in general, the different delivery systems, the immune response, and the recent clinical trials for mRNA vaccines (both for cancer mRNA vaccines and different infectious diseases mRNA vaccines). In the second part, different COVID-19 mRNA vaccines are explained. Finally, we illustrated a snapshot of the different leading mRNA vaccine developers, challenges, and future prospects of mRNA vaccines.

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“…A bit earlier, Szeto and Schiller introduced cell-permeable, mitochondrial-targeted peptides [129,130], which were grafted onto different polymer-based nanoparticles, but not onto PBNs. Based on the Szeto-Schiller peptide SS-31, Prof. Langel's group developed a set of mitochondrialpenetrating peptides based on the covalent fusion of PF14 and mtCPP1 [131] for antisense oligonucleotide (ASO) delivery [132]. In this report, the specific delivery of peptide/oligonucleotide nano-complexes were shown as proof-of-principle for the potent therapeutic application to patients with mitochondrial diseases.…”

Section: Organelle Targetingmentioning

confidence: 99%

Peptide-Based Nanoparticles for Therapeutic Nucleic Acid Delivery

et al. 2021

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Gene therapy offers the possibility to skip, repair, or silence faulty genes or to stimulate the immune system to fight against disease by delivering therapeutic nucleic acids (NAs) to a patient. Compared to other drugs or protein treatments, NA-based therapies have the advantage of being a more universal approach to designing therapies because of the versatility of NA design. NAs (siRNA, pDNA, or mRNA) have great potential for therapeutic applications for an immense number of indications. However, the delivery of these exogenous NAs is still challenging and requires a specific delivery system. In this context, beside other non-viral vectors, cell-penetrating peptides (CPPs) gain more and more interest as delivery systems by forming a variety of nanocomplexes depending on the formulation conditions and the properties of the used CPPs/NAs. In this review, we attempt to cover the most important biophysical and biological aspects of non-viral peptide-based nanoparticles (PBNs) for therapeutic nucleic acid formulations as a delivery system. The most relevant peptides or peptide families forming PBNs in the presence of NAs described since 2015 will be presented. All these PBNs able to deliver NAs in vitro and in vivo have common features, which are characterized by defined formulation conditions in order to obtain PBNs from 60 nm to 150 nm with a homogeneous dispersity (PdI lower than 0.3) and a positive charge between +10 mV and +40 mV.

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Intracellular delivery of therapeutic antisense oligonucleotides targeting mRNA coding mitochondrial proteins by cell-penetrating peptides

Abstract: Cell-penetrating peptides are a promising therapeutic strategy for a wide variety of degenerative diseases, ageing, and cancer. Among the multitude of cell-penetrating peptides, PepFect14 has been preferentially used in our...

Cited by 23 publications

References 64 publications

Development of Peptide-Based Nanoparticles for Mitochondrial Plasmid DNA Delivery

Development of Peptide-Based Nanoparticles for Mitochondrial Plasmid DNA Delivery

From COVID-19 to Cancer mRNA Vaccines: Moving From Bench to Clinic in the Vaccine Landscape

Peptide-Based Nanoparticles for Therapeutic Nucleic Acid Delivery

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