Mitochondrion-targeted RNA therapies as a potential treatment strategy for mitochondrial diseases

Chernega, T.; Choi, Ji Soo; Salmena, Leonardo; Andreazza, Ana Cristina

doi:10.1016/j.omtn.2022.10.012

Cited by 12 publications

(8 citation statements)

References 180 publications

(299 reference statements)

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“…We live in an exciting era. RNA/DNA therapies like antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), gene replacement therapies, and genome editing are entering the clinical realm with proven therapeutic benefit and life extension for rare, previously fatal Mendelian diseases [ 140 , 141 ]. Yet with ∼20,000 protein-coding genes and the considerable genetic heterogeneity of mitochondrial neurodevelopmental disorders, RNA/DNA therapeutics will remain inaccessible to most patients.…”

Section: Small Molecule Therapeutics In Mitochondrial Neurodevelopmen...mentioning

confidence: 99%

Functional genomics and small molecules in mitochondrial neurodevelopmental disorders

Calame,

Emrick

2024

Neurotherapeutics

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Section: Small Molecule Therapeutics In Mitochondrial Neurodevelopmen...mentioning

confidence: 99%

Functional genomics and small molecules in mitochondrial neurodevelopmental disorders

Calame,

Emrick

2024

Neurotherapeutics

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“… 1 , 3 , 4 , 5 , 6 However, due to the complexity of the body, it is almost impossible to cure such diseases in adults. 1 , 2 , 3 , 7 , 8 Therefore, if mitochondria with pathogenic genes can be removed or replaced in germ cells or early embryos through assisted reproductive technology, this will effectively block the inheritance of such diseases in offspring. 9 …”

Section: Introductionmentioning

confidence: 99%

“…The mtDNA mutations will accumulate in cells with the increasing age of the carriers, which will lead to energy metabolism disorders, including abnormalities in respiratory chain, reduced adenosine triphosphate synthesis, and increased reactive oxygen species production, and eventually induce diabetes, neurodegenerative diseases, and cardiovascular‐related diseases 1,3–6 . However, due to the complexity of the body, it is almost impossible to cure such diseases in adults 1–3,7,8 . Therefore, if mitochondria with pathogenic genes can be removed or replaced in germ cells or early embryos through assisted reproductive technology, this will effectively block the inheritance of such diseases in offspring 9 …”

Section: Introductionmentioning

confidence: 99%

“…1,[3][4][5][6] However, due to the complexity of the body, it is almost impossible to cure such diseases in adults. [1][2][3]7,8 Therefore, if mitochondria with pathogenic genes can be removed or replaced in germ cells or early embryos through assisted reproductive technology, this will effectively block the inheritance of such diseases in offspring. 9 In recent years, a new therapeutic strategy, mitochondrial replacement (MR), has been used to transfer the nuclear genetic materials (spindle [SP], first/second polar body [PB1/PB2], and pronucleus) of oocytes with pathogenic mitochondria into a healthy enucleated oocyte (reconstructed oocyte/zygote).…”

Section: Introductionmentioning

confidence: 99%

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Earlier second polar body transfer and further mitochondrial carryover removal for potential mitochondrial replacement therapy

Liao

Lin

et al. 2023

MedComm

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The second polar body (PB2) transfer in assisted reproductive technology is regarded as the most promising mitochondrial replacement scheme for preventing the mitochondrial disease inheritance owing to its less mitochondrial carryover and stronger operability. However, the mitochondrial carryover was still detectable in the reconstructed oocyte in conventional second polar body transfer scheme. Moreover, the delayed operating time would increase the second polar body DNA damage. In this study, we established a spindle‐protrusion‐retained second polar body separation technique, which allowed us to perform earlier second polar body transfer to avoid DNA damage accumulation. We could also locate the fusion site after the transfer through the spindle protrusion. Then, we further eliminated the mitochondrial carryover in the reconstructed oocytes through a physically based residue removal method. The results showed that our scheme could produce a nearly normal proportion of normal‐karyotype blastocysts with further reduced mitochondrial carryover, both in mice and humans. Additionally, we also obtained mouse embryonic stem cells and healthy live‐born mice with almost undetectable mitochondrial carryover. These findings indicate that our improvement in the second polar body transfer is conducive to the development and further mitochondria carryover elimination of reconstructed embryos, which provides a valuable choice for future clinical applications of mitochondrial replacement.

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“…[ 18,19 ] In the past few years, several polymer‐ and lipid‐based NPs such as MITO‐Porter have been developed for mitochondria‐targeted siRNA delivery. [ 19,20 ] Although these delivery systems have shown promising results in vitro, their in vivo gene silencing efficacy remains unknown. To achieve effective in vivo siRNA delivery into the mitochondria for cancer therapy, an ideal delivery system at least shows the following features: i) long blood circulation and high tumor accumulation; ii) efficient escape from the endosomes into the cytoplasm; iii) strong ability to target the mitochondria; iv) efficient penetration of mitochondrial membrane; and v) good biocompatibility and robust formulation processes that are easy to scale‐up.…”

Section: Introductionmentioning

confidence: 99%

Remodeling of Mitochondrial Metabolism by a Mitochondria‐Targeted RNAi Nanoplatform for Effective Cancer Therapy

Xu,

Huang,

Liu

et al. 2023

Small

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Emerging evidence has demonstrated the significant contribution of mitochondrial metabolism dysfunction to promote cancer development and progression. Aberrant expression of mitochondrial genome (mtDNA)‐encoded proteins widely involves mitochondrial metabolism dysfunction, and targeted regulation of their expression can be an effective strategy for cancer therapy, which however is challenged due to the protection by the mitochondrial double membrane. Herein, a mitochondria‐targeted RNAi nanoparticle (NP) platform for effective regulation of mitochondrial metabolism and breast cancer (BCa) therapy is developed. This nanoplatform is composed of a hydrophilic polyethylene glycol (PEG) shell, a hydrophobic poly(2‐(diisopropylamino)ethyl methacrylate) (PDPA) core, and charged‐mediated complexes of mitochondria‐targeting and membrane‐penetrating peptide amphiphile (MMPA) and small interfering RNA (siRNA) embedded in the core. After tumor accumulation and internalization by tumor cells, these NPs can respond to the endosomal pH to expose the MMPA/siRNA complexes, which can specifically transport siRNA into the mitochondria to down‐regulate mtDNA‐encoded protein expression (e.g., ATP6 and CYB). More importantly, because ATP6 down‐regulation can suppress ATP production and enhance reactive oxygen species (ROS) generation to induce mitochondrial damage and mtDNA leakage into tumor tissues, the NPs can combinatorially inhibit tumor growth via suppressing ATP production and repolarizing tumor‐associated macrophages (TAMs) into tumor‐inhibiting M1‐like macrophages by mtDNA.

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Mitochondrion-targeted RNA therapies as a potential treatment strategy for mitochondrial diseases

Cited by 12 publications

References 180 publications

Functional genomics and small molecules in mitochondrial neurodevelopmental disorders

Functional genomics and small molecules in mitochondrial neurodevelopmental disorders

Earlier second polar body transfer and further mitochondrial carryover removal for potential mitochondrial replacement therapy

Remodeling of Mitochondrial Metabolism by a Mitochondria‐Targeted RNAi Nanoplatform for Effective Cancer Therapy

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