Chemically modified in-vitro-transcribed mRNA encoding thrombopoietin stimulates thrombopoiesis in mice

Xi, Xiaodong; Yu, Hang; Yang, Liuyan; Lin, Jinzhong; Yang, Wen; Liu, Junling; Fan, Xing; Xu, Yingjie

doi:10.1016/j.omtn.2022.08.017

Cited by 7 publications

(6 citation statements)

References 54 publications

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“…Moreover, mRNA-based synthesis of therapeutic proteins confers distinct advantages, such as highly controlled translational kinetics and a minimized risk of insertional mutagenesis. Zhang et al executed a study wherein chemically modified thrombopoietin (TPO) mRNA was synthesized via in vitro transcription and subsequently administered in vivo utilizing LNPs (Figure a) . Upon intravenous administration of TPO mRNA in murine models, circulating TPO protein concentrations escalated in a dose-responsive manner, surpassing baseline physiological levels by over a 1000-fold.…”

Section: Chemical Modifications On Rna Molecules In Preclinical Researchmentioning

confidence: 99%

Section: Chemical Modifications On Rna Molecules In Preclinical Researchmentioning

confidence: 99%

“…Zhang et al executed a study wherein chemically modified thrombopoietin (TPO) mRNA was synthesized via in vitro transcription and subsequently administered in vivo utilizing LNPs (Figure 32a). 437 Upon intravenous administration of TPO mRNA in murine models, circulating TPO protein concentrations escalated in a dose-responsive manner, surpassing baseline physiological levels by over a 1000-fold. Intriguingly, a solitary intravenous infusion of LNP-encapsulated TPO mRNA precipitated a marked elevation in both reticulated and aggregate platelet enumerations, corroborating the functional competency of TPO protein synthesized from the exogenously delivered mRNA (Figure 32b).…”

Section: Chemical Modifications On Mrnamentioning

confidence: 99%

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Chemically Modified Platforms for Better RNA Therapeutics

Shi,

Zhen,

Zhang

et al. 2024

Chem. Rev.

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RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential in disease prevention and treatment. However, despite their remarkable achievements, these therapies encounter substantial challenges including low stability, susceptibility to degradation by nucleases, and a prominent negative charge, thereby hindering further development. Chemically modified platforms have emerged as a strategic innovation, focusing on precise alterations either on the RNA moieties or their associated delivery vectors. This comprehensive review delves into these platforms, underscoring their significance in augmenting the performance and translational prospects of RNA-based therapeutics. It encompasses an in-depth analysis of various chemically modified delivery platforms that have been instrumental in propelling RNA therapeutics toward clinical utility. Moreover, the review scrutinizes the rationale behind diverse chemical modification techniques aiming at optimizing the therapeutic efficacy of RNA molecules, thereby facilitating robust disease management. Recent empirical studies corroborating the efficacy enhancement of RNA therapeutics through chemical modifications are highlighted. Conclusively, we offer profound insights into the transformative impact of chemical modifications on RNA drugs and delineates prospective trajectories for their future development and clinical integration. CONTENTS1. Introduction 930 2. Current Status and Challenges of RNA Therapeutics in Clinics 933 2.1. Molecular Mechanisms and Clinical Research Progress of RNAs 934 2.1.1. ASO 934 2.1.2. siRNA 934 2.1.3. Aptamer 936 2.1.4. mRNA 936 2.1.5. RNA Therapeutics on the Cusp of Clinical Breakthroughs 938 2.2. Major Challenges of Current RNA Therapeutics in Clinics 940 2.

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Section: Chemical Modifications On Rna Molecules In Preclinical Researchmentioning

confidence: 99%

Section: Chemical Modifications On Rna Molecules In Preclinical Researchmentioning

confidence: 99%

Section: Chemical Modifications On Mrnamentioning

confidence: 99%

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Chemically Modified Platforms for Better RNA Therapeutics

Shi,

Zhen,

Zhang

et al. 2024

Chem. Rev.

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“…There are also pre-clinical studies for hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) [ 165 ]. However, for IVT-mRNA-mediated therapy to be considered as a long-term PRT of monogenic disorders, repeated administrations of the IVT-mRNA should be applied [ 166 ].…”

Section: Protein Replacement Therapy For Monogenetic Disordersmentioning

confidence: 99%

Protein Transduction Domain-Mediated Delivery of Recombinant Proteins and In Vitro Transcribed mRNAs for Protein Replacement Therapy of Human Severe Genetic Mitochondrial Disorders: The Case of Sco2 Deficiency

et al. 2023

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Mitochondrial disorders represent a heterogeneous group of genetic disorders with variations in severity and clinical outcomes, mostly characterized by respiratory chain dysfunction and abnormal mitochondrial function. More specifically, mutations in the human SCO2 gene, encoding the mitochondrial inner membrane Sco2 cytochrome c oxidase (COX) assembly protein, have been implicated in the mitochondrial disorder fatal infantile cardioencephalomyopathy with COX deficiency. Since an effective treatment is still missing, a protein replacement therapy (PRT) was explored using protein transduction domain (PTD) technology. Therefore, the human recombinant full-length mitochondrial protein Sco2, fused to TAT peptide (a common PTD), was produced (fusion Sco2 protein) and successfully transduced into fibroblasts derived from a SCO2/COX-deficient patient. This PRT contributed to effective COX assembly and partial recovery of COX activity. In mice, radiolabeled fusion Sco2 protein was biodistributed in the peripheral tissues of mice and successfully delivered into their mitochondria. Complementary to that, an mRNA-based therapeutic approach has been more recently considered as an innovative treatment option. In particular, a patented, novel PTD-mediated IVT-mRNA delivery platform was developed and applied in recent research efforts. PTD-IVT-mRNA of full-length SCO2 was successfully transduced into the fibroblasts derived from a SCO2/COX-deficient patient, translated in host ribosomes into a nascent chain of human Sco2, imported into mitochondria, and processed to the mature protein. Consequently, the recovery of reduced COX activity was achieved, thus suggesting the potential of this mRNA-based technology for clinical translation as a PRT for metabolic/genetic disorders. In this review, such research efforts will be comprehensibly presented and discussed to elaborate their potential in clinical application and therapeutic usefulness.

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“…[ 11 ] Chemically modified in vitro‐transcribed mRNA encoding thrombopoietin stimulated thrombopoiesis in a study on mice. [ 12 ] The combined use of epidermal growth factor and hepatocyte growth factor mRNA repaired liver damage in a mouse liver injury model. [ 13 ] Finally, a phase I clinical trial on vascular endothelial growth factor A (VEGF‐A) mRNA‐induced protein replacement therapy in patients with diabetes showed that the therapy can effectively improve peripheral circulation.…”

Section: Introductionmentioning

confidence: 99%

Lipid Nanoparticle Delivery of Chemically Modified NGF^R100W mRNA Alleviates Peripheral Neuropathy

Yang

Xia

et al. 2022

Adv Healthcare Materials

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Messenger RNA (mRNA) carries genetic instructions to the cell machinery for the transient production of antigens or therapeutic proteins and shows enormous potential in vaccine development, cancer immunotherapy, protein replacement therapy, and genome engineering. Here, the synthesis of chemically modified nerve growth factor mutant (NGF R100W ) mRNA through in vitro transcription is described. After the replacement of the original signal peptide sequence with the Ig Kappa leader sequence, codon-optimized NGF R100W mRNA yielded high secretion of mature NGF R100W , which promotes axon growth in PC12 cells. Using lipid nanoparticle (LNP)-delivery of N1-methylpseudouridine-modified mRNA in mice, NGF R100W -mRNA-LNPs result in the successful expression of NGF R100W protein, which significantly reduces nociceptive activity compared to that of NGF WT . This indicates that NGF R100W derived from exogenous mRNA elicited "painless" neuroprotective activity. Additionally, the therapeutic value of NGF R100W mRNA is established in a paclitaxel-induced peripheral neuropathy model by demonstrating the rapid recovery of intraepidermal nerve fibers. The results show that in vitro-transcribed mRNA has significant flexibility in sequence design and fast in vivo functional validation of target proteins. Furthermore, the results highlight the therapeutic potential of mRNA as a supplement to beneficial proteins for preventing or reversing some chronic medical conditions, such as peripheral neuropathy.

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Chemically modified in-vitro-transcribed mRNA encoding thrombopoietin stimulates thrombopoiesis in mice

Cited by 7 publications

References 54 publications

Chemically Modified Platforms for Better RNA Therapeutics

Chemically Modified Platforms for Better RNA Therapeutics

Protein Transduction Domain-Mediated Delivery of Recombinant Proteins and In Vitro Transcribed mRNAs for Protein Replacement Therapy of Human Severe Genetic Mitochondrial Disorders: The Case of Sco2 Deficiency

Lipid Nanoparticle Delivery of Chemically Modified NGF^R100W mRNA Alleviates Peripheral Neuropathy

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Chemically modified in-vitro-transcribed mRNA encoding thrombopoietin stimulates thrombopoiesis in mice

Cited by 7 publications

References 54 publications

Chemically Modified Platforms for Better RNA Therapeutics

Chemically Modified Platforms for Better RNA Therapeutics

Protein Transduction Domain-Mediated Delivery of Recombinant Proteins and In Vitro Transcribed mRNAs for Protein Replacement Therapy of Human Severe Genetic Mitochondrial Disorders: The Case of Sco2 Deficiency

Lipid Nanoparticle Delivery of Chemically Modified NGFR100W mRNA Alleviates Peripheral Neuropathy

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Lipid Nanoparticle Delivery of Chemically Modified NGF^R100W mRNA Alleviates Peripheral Neuropathy