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Open AccessArticle

Identification of Autophagy as a Functional Target Suitable for the Pharmacological Treatment of Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN) In Vitro

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Stephanie Ortiz-Collazos

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Pharmaceutics 2023, 15(1), 267; https://doi.org/10.3390/pharmaceutics15010267 - 12 Jan 2023

Viewed by 1531

Abstract

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a relentlessly progressive neurodegenerative disorder caused by mutations in the C19orf12 gene. C19orf12 has been implicated in playing a role in lipid metabolism, mitochondrial function, and autophagy, however, the precise functions remain unknown. To identify new robust [...] Read more.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a relentlessly progressive neurodegenerative disorder caused by mutations in the C19orf12 gene. C19orf12 has been implicated in playing a role in lipid metabolism, mitochondrial function, and autophagy, however, the precise functions remain unknown. To identify new robust cellular targets for small compound treatments, we evaluated reported mitochondrial function alterations, cellular signaling, and autophagy in a large cohort of MPAN patients and control fibroblasts. We found no consistent alteration of mitochondrial functions or cellular signaling messengers in MPAN fibroblasts. In contrast, we found that autophagy initiation is consistently impaired in MPAN fibroblasts and show that C19orf12 expression correlates with the amount of LC3 puncta, an autophagy marker. Finally, we screened 14 different autophagy modulators to test which can restore this autophagy defect. Amongst these compounds, carbamazepine, ABT-737, LY294002, oridonin, and paroxetine could restore LC3 puncta in the MPAN fibroblasts, identifying them as novel potential therapeutic compounds to treat MPAN. In summary, our study confirms a role for C19orf12 in autophagy, proposes LC3 puncta as a functionally robust and consistent readout for testing compounds, and pinpoints potential therapeutic compounds for MPAN. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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Open AccessArticle

PPAR Gamma Agonist Leriglitazone Recovers Alterations Due to Pank2-Deficiency in hiPS-Derived Astrocytes

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Laura Rodríguez-Pascau

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Pharmaceutics 2023, 15(1), 202; https://doi.org/10.3390/pharmaceutics15010202 - 06 Jan 2023

Cited by 3 | Viewed by 895

Abstract

The novel brain-penetrant peroxisome proliferator-activated receptor gamma agonist leriglitazone, previously validated for other rare neurodegenerative diseases, is a small molecule that acts as a regulator of mitochondrial function and exerts neuroprotective, anti-oxidative and anti-inflammatory effects. Herein, we tested whether leriglitazone can be effective [...] Read more.

The novel brain-penetrant peroxisome proliferator-activated receptor gamma agonist leriglitazone, previously validated for other rare neurodegenerative diseases, is a small molecule that acts as a regulator of mitochondrial function and exerts neuroprotective, anti-oxidative and anti-inflammatory effects. Herein, we tested whether leriglitazone can be effective in ameliorating the mitochondrial defects that characterize an hiPS-derived model of Pantothenate kinase-2 associated Neurodegeneration (PKAN). PKAN is caused by a genetic alteration in the mitochondrial enzyme pantothenate kinase-2, whose function is to catalyze the first reaction of the CoA biosynthetic pathway, and for which no effective cure is available. The PKAN hiPS-derived astrocytes are characterized by mitochondrial dysfunction, cytosolic iron deposition, oxidative stress and neurotoxicity. We monitored the effect of leriglitazone in comparison with CoA on hiPS-derived astrocytes from three healthy subjects and three PKAN patients. The treatment with leriglitazone did not affect the differentiation of the neuronal precursor cells into astrocytes, and it improved the viability of PKAN cells and their respiratory activity, while diminishing the iron accumulation similarly or even better than CoA. The data suggest that leriglitazone is well tolerated in this cellular model and could be considered a beneficial therapeutic approach in the treatment of PKAN. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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Open AccessArticle

Targeting OPA1-Mediated Mitochondrial Fusion Contributed to Celastrol’s Anti-Tumor Angiogenesis Effect

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Pharmaceutics 2023, 15(1), 48; https://doi.org/10.3390/pharmaceutics15010048 - 23 Dec 2022

Cited by 1 | Viewed by 899

Abstract

Celastrol, an active triterpenoid extracted from one of the most famous traditional Chinese medicines (TCMs), Tripterygium wilfordii Hook.f., is a novel anti-cancer drug with significant anti-angiogenesis activity. However, the exact molecular mechanisms underlying its anti-tumor angiogenesis effect remain unclear. The process of angiogenesis [...] Read more.

Celastrol, an active triterpenoid extracted from one of the most famous traditional Chinese medicines (TCMs), Tripterygium wilfordii Hook.f., is a novel anti-cancer drug with significant anti-angiogenesis activity. However, the exact molecular mechanisms underlying its anti-tumor angiogenesis effect remain unclear. The process of angiogenesis needs lots of energy supply, which mostly derives from mitochondria, the “energy factory” in our body. This study shows that celastrol exerts visible suppression on tumor growth and angiogenesis in a cell-derived xenograft (CDX). Likewise, it reduced the tube formation and migration of human umbilical vein endothelial cells (HUVECs), suppressed the energy metabolism of mitochondria in the Seahorse XF Mito Stress Test, and triggered mitochondrial fragmentation and NF-κB activation. Mechanically, celastrol downregulated the expression of mitochondrial-sharping protein optic atrophy protein 1 (OPA1), which was further estimated by the OPA1 knockdown model of HUVECs. Specifically, celastrol directly suppressed OPA1 at the mRNA level by inhibiting the phosphorylation of STAT3, and stattic (STAT3 inhibitor) showed the same effects on OPA1 suppression and anti-angiogenesis activity. Overall, this study indicates that celastrol inhibits tumor angiogenesis by suppressing mitochondrial function and morphology via the STAT3/OPA1/P65 pathway and provides new insight for mitochondrion-targeted cancer therapy. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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Open AccessArticle

Determination of Metabolomics Profiling in BPA-Induced Impaired Metabolism

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Maria Alvi

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Kanwal Rehman

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Muhammad Sajid Hamid Akash

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Azka Yaqoob

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Syed Muhammad Shoaib

Pharmaceutics 2022, 14(11), 2496; https://doi.org/10.3390/pharmaceutics14112496 - 17 Nov 2022

Viewed by 1351

Abstract

Exposure to bisphenol A (BPA) is unavoidable and it has far-reaching negative effects on living systems. This study aimed to explore the toxic effects of BPA in an experimental animal model through a metabolomics approach that is useful in measuring small molecule perturbations. [...] Read more.

Exposure to bisphenol A (BPA) is unavoidable and it has far-reaching negative effects on living systems. This study aimed to explore the toxic effects of BPA in an experimental animal model through a metabolomics approach that is useful in measuring small molecule perturbations. Beside this, we also examined the ameliorative effects of resveratrol (RSV) against BPA-induced disturbances in experimental mice. This study was conducted for 28 days, and the results showed that BPA indeed induced an impairment in amino acid metabolism, taking place in the mitochondria by significantly (p < 0.05) decreasing the levels of certain amino acids, i.e., taurine, threonine, asparagine, leucine, norleucine, and glutamic acid in the mice plasma. However, the administration of RSV did prove effective against the BPA-induced intoxication and significantly (p < 0.05) restored the level of free amino acids. Lipid metabolites, L-carnitine, sphinganine, phytosphingosine, and lysophosphatidylcholine were also determined in the mice serum. A significant (p < 0.05) decline in glutathione peroxidase (GPx), superoxide dismutase (SOD,) glutathione, and catalase levels and an elevation in malondialdehyde level in the BPA group confirmed the generation of oxidative stress and lipid peroxidation in experimental mice exposed to BPA. The expression of Carnitine palmitoyltransferase I (CPT-I), carnitine palmitoyltransferase II (CPT-II), lecithin–cholesterol acyltransferase (LCAT), carnitine O-octanoyltransferase (CROT), carnitine-acylcarnitine translocase (CACT), and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) genes was significantly upregulated in the liver tissue homogenates of experimental mice exposed to BPA, although RSV regulated the expression of these genes when compared with BPA treated experimental mice. CPT-I, CPT-II, and CACT genes are located in the mitochondria and are involved in the metabolism and transportation of carnitine. Hence, this study confirms that BPA exposure induced oxidative stress, upregulated gene expression, and impaired lipid and amino acid metabolism in experimental mice. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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Open AccessArticle

BK_Ca Activator NS1619 Improves the Structure and Function of Skeletal Muscle Mitochondria in Duchenne Dystrophy

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Mikhail V. Dubinin

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Vlada S. Starinets

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Natalia V. Belosludtseva

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Irina B. Mikheeva

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Yuliya A. Chelyadnikova

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Anastasia D. Igoshkina

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Aliya B. Vafina

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Alexander A. Vedernikov

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Konstantin N. Belosludtsev

Pharmaceutics 2022, 14(11), 2336; https://doi.org/10.3390/pharmaceutics14112336 - 29 Oct 2022

Cited by 4 | Viewed by 1571

Abstract

Duchenne muscular dystrophy (DMD) is a progressive hereditary disease caused by the absence of the dystrophin protein. This is secondarily accompanied by a dysregulation of ion homeostasis, in which mitochondria play an important role. In the present work, we show that mitochondrial dysfunction [...] Read more.

Duchenne muscular dystrophy (DMD) is a progressive hereditary disease caused by the absence of the dystrophin protein. This is secondarily accompanied by a dysregulation of ion homeostasis, in which mitochondria play an important role. In the present work, we show that mitochondrial dysfunction in the skeletal muscles of dystrophin-deficient mdx mice is accompanied by a reduction in K⁺ transport and a decrease in its content in the matrix. This is associated with a decrease in the expression of the mitochondrial large-conductance calcium-activated potassium channel (mitoBK_Ca) in the muscles of mdx mice, which play an important role in cytoprotection. We observed that the BK_Ca activator NS1619 caused a normalization of mitoBK_Ca expression and potassium homeostasis in the muscle mitochondria of these animals, which was accompanied by an increase in the calcium retention capacity, mitigation of oxidative stress, and improvement in mitochondrial ultrastructure. This effect of NS1619 contributed to the reduction of degeneration/regeneration cycles and fibrosis in the skeletal muscles of mdx mice as well as a normalization of sarcomere size, but had no effect on the leakage of muscle enzymes and muscle strength loss. In the case of wild-type mice, we noted the negative effect of NS1619 manifested in the inhibition of the functional activity of mitochondria and disruption of their structure, which, however, did not significantly affect the state of the skeletal muscles of the animals. This article discusses the role of mitoBK_Ca in the development of DMD and the prospects of the approach associated with the correction of its function in treatments of this secondary channelopathy. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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Review

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Open AccessReview

Recent Advances in Mitochondrial Fission/Fusion-Targeted Therapy in Doxorubicin-Induced Cardiotoxicity

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Chayodom Maneechote

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Siriporn C. Chattipakorn

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Nipon Chattipakorn

Pharmaceutics 2023, 15(4), 1182; https://doi.org/10.3390/pharmaceutics15041182 - 07 Apr 2023

Viewed by 639

Abstract

Doxorubicin (DOX) has been recognized as one of the most effective chemotherapies and extensively used in the clinical settings of human cancer. However, DOX-mediated cardiotoxicity is known to compromise the clinical effectiveness of chemotherapy, resulting in cardiomyopathy and heart failure. Recently, accumulation of [...] Read more.

Doxorubicin (DOX) has been recognized as one of the most effective chemotherapies and extensively used in the clinical settings of human cancer. However, DOX-mediated cardiotoxicity is known to compromise the clinical effectiveness of chemotherapy, resulting in cardiomyopathy and heart failure. Recently, accumulation of dysfunctional mitochondria via alteration of the mitochondrial fission/fusion dynamic processes has been identified as a potential mechanism underlying DOX cardiotoxicity. DOX-induced excessive fission in conjunction with impaired fusion could severely promote mitochondrial fragmentation and cardiomyocyte death, while modulation of mitochondrial dynamic proteins using either fission inhibitors (e.g., Mdivi-1) or fusion promoters (e.g., M1) can provide cardioprotection against DOX-induced cardiotoxicity. In this review, we focus particularly on the roles of mitochondrial dynamic pathways and the current advanced therapies in mitochondrial dynamics-targeted anti-cardiotoxicity of DOX. This review summarizes all the novel insights into the development of anti-cardiotoxic effects of DOX via the targeting of mitochondrial dynamic pathways, thereby encouraging and guiding future clinical investigations to focus on the potential application of mitochondrial dynamic modulators in the setting of DOX-induced cardiotoxicity. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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Open AccessReview

The Mitochondrion: A Promising Target for Kidney Disease

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Pharmaceutics 2023, 15(2), 570; https://doi.org/10.3390/pharmaceutics15020570 - 08 Feb 2023

Viewed by 998

Abstract

Mitochondrial dysfunction is important in the pathogenesis of various kidney diseases and the mitochondria potentially serve as therapeutic targets necessitating further investigation. Alterations in mitochondrial biogenesis, imbalance between fusion and fission processes leading to mitochondrial fragmentation, oxidative stress, release of cytochrome c and [...] Read more.

Mitochondrial dysfunction is important in the pathogenesis of various kidney diseases and the mitochondria potentially serve as therapeutic targets necessitating further investigation. Alterations in mitochondrial biogenesis, imbalance between fusion and fission processes leading to mitochondrial fragmentation, oxidative stress, release of cytochrome c and mitochondrial DNA resulting in apoptosis, mitophagy, and defects in energy metabolism are the key pathophysiological mechanisms underlying the role of mitochondrial dysfunction in kidney diseases. Currently, various strategies target the mitochondria to improve kidney function and kidney treatment. The agents used in these strategies can be classified as biogenesis activators, fission inhibitors, antioxidants, mPTP inhibitors, and agents which enhance mitophagy and cardiolipin-protective drugs. Several glucose-lowering drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1-RA) and sodium glucose co-transporter-2 (SGLT-2) inhibitors are also known to have influences on these mechanisms. In this review, we delineate the role of mitochondrial dysfunction in kidney disease, the current mitochondria-targeting treatment options affecting the kidneys and the future role of mitochondria in kidney pathology. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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Open AccessReview

Targeting Mitochondria to Control Ageing and Senescence

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Margherita Protasoni

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Manuel Serrano

Pharmaceutics 2023, 15(2), 352; https://doi.org/10.3390/pharmaceutics15020352 - 20 Jan 2023

Cited by 1 | Viewed by 2038

Abstract

Ageing is accompanied by a progressive impairment of cellular function and a systemic deterioration of tissues and organs, resulting in increased vulnerability to multiple diseases. Here, we review the interplay between two hallmarks of ageing, namely, mitochondrial dysfunction and cellular senescence. The targeting [...] Read more.

Ageing is accompanied by a progressive impairment of cellular function and a systemic deterioration of tissues and organs, resulting in increased vulnerability to multiple diseases. Here, we review the interplay between two hallmarks of ageing, namely, mitochondrial dysfunction and cellular senescence. The targeting of specific mitochondrial features in senescent cells has the potential of delaying or even reverting the ageing process. A deeper and more comprehensive understanding of mitochondrial biology in senescent cells is necessary to effectively face this challenge. Here, we discuss the main alterations in mitochondrial functions and structure in both ageing and cellular senescence, highlighting the differences and similarities between the two processes. Moreover, we describe the treatments available to target these pathways and speculate on possible future directions of anti-ageing and anti-senescence therapies targeting mitochondria. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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Open AccessReview

The Therapeutic Strategies Targeting Mitochondrial Metabolism in Cardiovascular Disease

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Pharmaceutics 2022, 14(12), 2760; https://doi.org/10.3390/pharmaceutics14122760 - 09 Dec 2022

Cited by 3 | Viewed by 1224

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Cardiovascular disease (CVD) is a group of systemic disorders threatening human health with complex pathogenesis, among which mitochondrial energy metabolism reprogramming has a critical role. Mitochondria are cell organelles that fuel the energy essential for biochemical reactions and maintain normal physiological functions of [...] Read more.

Cardiovascular disease (CVD) is a group of systemic disorders threatening human health with complex pathogenesis, among which mitochondrial energy metabolism reprogramming has a critical role. Mitochondria are cell organelles that fuel the energy essential for biochemical reactions and maintain normal physiological functions of the body. Mitochondrial metabolic disorders are extensively involved in the progression of CVD, especially for energy-demanding organs such as the heart. Therefore, elucidating the role of mitochondrial metabolism in the progression of CVD is of great significance to further understand the pathogenesis of CVD and explore preventive and therapeutic methods. In this review, we discuss the major factors of mitochondrial metabolism and their potential roles in the prevention and treatment of CVD. The current application of mitochondria-targeted therapeutic agents in the treatment of CVD and advances in mitochondria-targeted gene therapy technologies are also overviewed. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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Open AccessReview

Mitochondrial Dysfunction: Pathophysiology and Mitochondria-Targeted Drug Delivery Approaches

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Pharmaceutics 2022, 14(12), 2657; https://doi.org/10.3390/pharmaceutics14122657 - 30 Nov 2022

Cited by 1 | Viewed by 1537

Abstract

Mitochondria are implicated in a wide range of functions apart from ATP generation, and, therefore, constitute one of the most important organelles of cell. Since healthy mitochondria are essential for proper cellular functioning and survival, mitochondrial dysfunction may lead to various pathologies. Mitochondria [...] Read more.

Mitochondria are implicated in a wide range of functions apart from ATP generation, and, therefore, constitute one of the most important organelles of cell. Since healthy mitochondria are essential for proper cellular functioning and survival, mitochondrial dysfunction may lead to various pathologies. Mitochondria are considered a novel and promising therapeutic target for the diagnosis, treatment, and prevention of various human diseases including metabolic disorders, cancer, and neurodegenerative diseases. For mitochondria-targeted therapy, there is a need to develop an effective drug delivery approach, owing to the mitochondrial special bilayer structure through which therapeutic molecules undergo multiple difficulties in reaching the core. In recent years, various nanoformulations have been designed such as polymeric nanoparticles, liposomes, inorganic nanoparticles conjugate with mitochondriotropic moieties such as mitochondria-penetrating peptides (MPPs), triphenylphosphonium (TPP), dequalinium (DQA), and mitochondrial protein import machinery for overcoming barriers involved in targeting mitochondria. The current approaches used for mitochondria-targeted drug delivery have provided promising ways to overcome the challenges associated with targeted-drug delivery. Herein, we review the research from past years to the current scenario that has identified mitochondrial dysfunction as a major contributor to the pathophysiology of various diseases. Furthermore, we discuss the recent advancements in mitochondria-targeted drug delivery strategies for the pathologies associated with mitochondrial dysfunction. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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Open AccessReview

Muscle Delivery of Mitochondria-Targeted Drugs for the Treatment of Sarcopenia: Rationale and Perspectives

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Francesco Bellanti

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Aurelio Lo Buglio

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Gianluigi Vendemiale

Pharmaceutics 2022, 14(12), 2588; https://doi.org/10.3390/pharmaceutics14122588 - 24 Nov 2022

Cited by 1 | Viewed by 897

Abstract

An impairment in mitochondrial homeostasis plays a crucial role in the process of aging and contributes to the incidence of age-related diseases, including sarcopenia, which is defined as an age-dependent loss of muscle mass and strength. Mitochondrial dysfunction exerts a negative impact on [...] Read more.

An impairment in mitochondrial homeostasis plays a crucial role in the process of aging and contributes to the incidence of age-related diseases, including sarcopenia, which is defined as an age-dependent loss of muscle mass and strength. Mitochondrial dysfunction exerts a negative impact on several cellular activities, including bioenergetics, metabolism, and apoptosis. In sarcopenia, mitochondria homeostasis is disrupted because of reduced oxidative phosphorylation and ATP generation, the enhanced production of reactive species, and impaired antioxidant defense. This review re-establishes the most recent evidence on mitochondrial defects that are thought to be relevant in the pathogenesis of sarcopenia and that may represent promising therapeutic targets for its prevention/treatment. Furthermore, we describe mechanisms of action and translational potential of promising mitochondria-targeted drug delivery systems, including molecules able to boost the metabolism and bioenergetics, counteract apoptosis, antioxidants to scavenge reactive species and decrease oxidative stress, and target mitophagy. Even though these mitochondria-delivered strategies demonstrate to be promising in preclinical models, their use needs to be promoted for clinical studies. Therefore, there is a compelling demand to further understand the mechanisms modulating mitochondrial homeostasis, to characterize powerful compounds that target muscle mitochondria to prevent sarcopenia in aged people. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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Open AccessReview

Prospects for the Development of Pink1 and Parkin Activators for the Treatment of Parkinson’s Disease

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Alexandra A. Melnichenko

Pharmaceutics 2022, 14(11), 2514; https://doi.org/10.3390/pharmaceutics14112514 - 19 Nov 2022

Viewed by 1167

Abstract

Impaired mitophagy is one of the hallmarks of the pathogenesis of Parkinson’s disease, which highlights the importance of the proper functioning of mitochondria, as well as the processes of mitochondrial dynamics for the functioning of dopaminergic neurons. At the same time, the main [...] Read more.

Impaired mitophagy is one of the hallmarks of the pathogenesis of Parkinson’s disease, which highlights the importance of the proper functioning of mitochondria, as well as the processes of mitochondrial dynamics for the functioning of dopaminergic neurons. At the same time, the main factors leading to disruption of mitophagy in Parkinson’s disease are mutations in the Pink1 and Parkin enzymes. Based on the characterized mutant forms, the marked cellular localization, and the level of expression in neurons, these proteins can be considered promising targets for the development of drugs for Parkinson’s therapy. This review will consider such class of drug compounds as mitophagy activators and these drugs in the treatment of Parkinson’s disease. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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Open AccessReview

Advancements in Polymeric Nanocarriers to Mediate Targeted Therapy against Triple-Negative Breast Cancer

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Mahak Fatima

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Afsana Sheikh

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Mohammed A. S. Abourehab

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Prashant Kesharwani

Pharmaceutics 2022, 14(11), 2432; https://doi.org/10.3390/pharmaceutics14112432 - 10 Nov 2022

Cited by 4 | Viewed by 1238

Abstract

Triple-negative breast cancer (TNBC) is a destructive disease with a poor prognosis, low survival rate and high rate of metastasis. It comprises 15% of total breast cancers and is marked by deficiency of three important receptor expressions, i.e., progesterone, estrogen, and human epidermal [...] Read more.

Triple-negative breast cancer (TNBC) is a destructive disease with a poor prognosis, low survival rate and high rate of metastasis. It comprises 15% of total breast cancers and is marked by deficiency of three important receptor expressions, i.e., progesterone, estrogen, and human epidermal growth factor receptors. This absence of receptors is the foremost cause of current TNBC therapy failure, resulting in poor therapeutic response in patients. Polymeric nanoparticles are gaining much popularity for transporting chemotherapeutics, genes, and small-interfering RNAs. Due to their exclusive properties such as great stability, easy surface modification, stimuli-responsive and controlled drug release, ability to condense more than one therapeutic moiety inside, tumor-specific delivery of payload, enhanced permeation and retention effect, present them as ideal nanocarriers for increasing efficacy, bioavailability and reducing the toxicity of therapeutic agents. They can even be used as theragnostic agents for the diagnosis of TNBC along with its treatment. In this review, we discuss the limitations of already existing TNBC therapies and highlight the novel approach to designing and the functionalization of polymeric nanocarriers for the effective treatment of TNBC. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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Open AccessReview

Gene Therapy for Mitochondrial Diseases: Current Status and Future Perspective

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Alessia Di Donfrancesco

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Pharmaceutics 2022, 14(6), 1287; https://doi.org/10.3390/pharmaceutics14061287 - 17 Jun 2022

Cited by 4 | Viewed by 3831

Abstract

Mitochondrial diseases (MDs) are a group of severe genetic disorders caused by mutations in the nuclear or mitochondrial genome encoding proteins involved in the oxidative phosphorylation (OXPHOS) system. MDs have a wide range of symptoms, ranging from organ-specific to multisystemic dysfunctions, with different [...] Read more.

Mitochondrial diseases (MDs) are a group of severe genetic disorders caused by mutations in the nuclear or mitochondrial genome encoding proteins involved in the oxidative phosphorylation (OXPHOS) system. MDs have a wide range of symptoms, ranging from organ-specific to multisystemic dysfunctions, with different clinical outcomes. The lack of natural history information, the limits of currently available preclinical models, and the wide range of phenotypic presentations seen in MD patients have all hampered the development of effective therapies. The growing number of pre-clinical and clinical trials over the last decade has shown that gene therapy is a viable precision medicine option for treating MD. However, several obstacles must be overcome, including vector design, targeted tissue tropism and efficient delivery, transgene expression, and immunotoxicity. This manuscript offers a comprehensive overview of the state of the art of gene therapy in MD, addressing the main challenges, the most feasible solutions, and the future perspectives of the field. Full article

(This article belongs to the Special Issue Advances in Mitochondria-Targeted Drug Delivery)

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