Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 378, P. 1 - 17
Published: Dec. 7, 2024
Language: Английский
International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(22), P. 12284 - 12284
Published: Nov. 15, 2024
RNA therapeutics have undergone remarkable evolution since their inception in the late 1970s, revolutionizing medicine by offering new possibilities for treating previously intractable diseases. The field encompasses various modalities, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), and messenger (mRNAs), each with unique mechanisms applications. foundation was laid 1978 discovery that synthetic could inhibit viral replication, followed pivotal developments such as interference's 1998. COVID-19 pandemic marked a crucial turning point, demonstrating potential of mRNA vaccines accelerating interest RNA-based approaches. However, significant challenges remain, stability issues, delivery to target tissues, off-target effects, immunogenicity concerns. Recent advancements chemical modifications, systems, integration AI technologies are addressing these challenges. has seen notable successes, approved treatments spinal muscular atrophy hereditary transthyretin-mediated amyloidosis. Looking ahead, show promise personalized approaches, particularly genetic disorders cancer. continued this field, driven technological innovations deeper understanding biology, suggests transformative impact on future medical treatments. purpose review is provide comprehensive overview evolution, current state, prospects therapeutics.
Language: Английский
Citations
6
Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15
Published: July 24, 2024
ATP-binding cassette (ABC) transporters are transmembrane proteins expressed commonly in metabolic and excretory organs to control xenobiotic or endobiotic disposition maintain their homeostasis. Changes ABC transporter expression may directly affect the pharmacokinetics of relevant drugs involving absorption, distribution, metabolism, excretion (ADME) processes. Indeed, overexpression efflux cancer cells bacteria limits drug exposure causes therapeutic failure that is known as multidrug resistance (MDR). With discovery functional noncoding microRNAs (miRNAs) produced from genome, many miRNAs have been revealed govern posttranscriptional gene regulation transporters, which shall improve our understanding complex mechanism behind linked MDR. In this article, we first overview localization important human tissues clinical importance regarding ADME well Further, summarize miRNA-controlled effects on Additionally, discuss development utilization novel bioengineered miRNA agents modulate subsequent influence cellular accumulation chemosensitivity. Findings not only mechanisms variable but also provide insight into developing new means towards rational more effective pharmacotherapies.
Language: Английский
Citations
4
Epilepsia, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 27, 2025
Abstract Objective Gain‐of‐function variants in the KCNT1 gene, which encodes a sodium‐activated potassium ion channel, drive severe early onset developmental epileptic encephalopathies including epilepsy of infancy with migrating focal seizures and sleep‐related hypermotor epilepsy. No therapy provides more than sporadic or incremental improvement. Here, we report suppression genetic mouse model by reducing Kcnt1 transcript divalent small interfering RNA (siRNA), an emerging variant oligonucleotide technology developed for central nervous system. Methods The ATL‐201 molecule is two identical synthetic double‐stranded siRNAs, covalently linked, 100% nucleotide base pair match to sequence present both human that does not contain any known pathogenic variant. activity was tested cortical neurons cultured from wild‐type mice homozygous Kcnt1‐Y777H , ortholog KCNT1‐Y796H missense Seizures nest‐building behavior were measured freely behaving mice. number duration electrocorticography dosed phosphate‐buffered saline 6‐month durability study 2‐month dose–efficacy study. Results In vitro, reduced whole‐cell lysate eliminated currents channels heterologous expression. also recorded individual neurons. vivo, suppressed dose‐dependent manner near‐complete 2 weeks at least 4 months. had defects nest building, whereas ATL‐201‐treated building equivalent Significance Patients KCNT1‐driven experience up hundreds per day have impairment cognitive, motor, language development high mortality. efficacy long show promise as disease‐modifying treatment
Language: Английский
Citations
0
Journal of Pharmaceutical and Biomedical Analysis Open, Journal Year: 2025, Volume and Issue: unknown, P. 100057 - 100057
Published: Jan. 1, 2025
Language: Английский
Citations
0
Journal of Chromatography B, Journal Year: 2025, Volume and Issue: 1254, P. 124505 - 124505
Published: Feb. 4, 2025
Language: Английский
Citations
0
Gut, Journal Year: 2025, Volume and Issue: unknown, P. gutjnl - 331742
Published: Feb. 23, 2025
RNA-based therapeutics have rapidly emerged over the past decade, offering a new class of medicines that differ significantly from conventional drugs. These therapies can be programmed to target or restore defective genes, allowing for more personalised treatments and reducing side effects. Notably, RNA made significant progress in treatment genetic liver diseases, exemplified by small interfering hereditary transthyretin amyloidosis, which use liver-targeting strategies such as GalNAc conjugation improve efficacy safety. gene-editing technologies, base editor prime clustered regularly interspaced short palindromic repeats systems, also show promise with their ability minimise genomic rearrangements cancer risk. While offer high precision, challenges remain optimising delivery methods ensuring long-term safety efficacy. Lipid nanoparticle-mRNA therapeutics, particularly protein replacement rare gained support preclinical successes. Compared viral gene therapies, mRNA present safer profile reduced risks integration oncogene activation. However, clinical trials, especially face limitations sample sizes observation periods. Further studies, including non-human primates, will essential refining trial designs. Despite potential, costs pose challenge require cost–utility models guide pricing accessibility. Here, we discuss fundamental aspects showcase most relevant developments metabolic diseases.
Language: Английский
Citations
0
Langmuir, Journal Year: 2025, Volume and Issue: unknown
Published: March 13, 2025
Ribonucleic acid (RNA) nanocarriers, specifically lipid nanoparticles and polymeric nanoparticles, enable RNA transfection both in vitro vivo; however, only a small percentage of endocytosed by cell is delivered to the cytosolic machinery, minimizing its effect. nanocarriers face two major obstacles after endocytosis: endosomal escape release. Overcoming simultaneously challenging because usually achieved using high positive charge disrupt membrane. However, this typically also inhibits release anionic strongly bound nanocarrier electrostatic interactions. Many address one over other despite growing body evidence demonstrating that are crucial for transfection. In review, we survey various strategies have been employed accomplish with focus on nanomaterials. We first consider requirements must achieve delivery including protection from degradation, cellular internalization, escape, then discuss current polymers used examine achieving Finally, review stimuli-responsive While continues be challenge efficient transfection, many new innovations materials elucidated promising strategies.
Language: Английский
Citations
0
ACS Synthetic Biology, Journal Year: 2024, Volume and Issue: 13(6), P. 1906 - 1915
Published: May 11, 2024
Synthetic biology constitutes a scientific domain focused on intentional redesign of organisms to confer novel functionalities or create new products through strategic engineering their genetic makeup. Leveraging the inherent capabilities nature, one may address challenges across diverse sectors including medicine. Inspired by this concept, we have developed an innovative bioengineering platform, enabling high-yield and large-scale production biological small interfering RNA (BioRNA/siRNA) agents via bacterial fermentation. Herein, show that with use tRNA fused pre-miRNA carrier, can produce various forms BioRNA/siRNA within living host cells. We report high-level overexpression nine target molecules at 100% success rate, yielding 3-10 mg per 0.25 L culture high purity (>98%) low endotoxin (<5 EU/μg RNA). Furthermore, demonstrate three representative BioRNA/siRNAs against GFP, BCL2, PD-L1 are biologically active specifically efficiently silence respective targets potential effectively downstream antiproliferation effects PD-L1-siRNA. With these promising results, aim advance field synthetic offering platform bioengineer functional siRNA for research drug development.
Language: Английский
Citations
2
Advanced Functional Materials, Journal Year: 2024, Volume and Issue: unknown
Published: Oct. 31, 2024
Abstract Lipid nanoparticles (LNPs) are the most clinically advanced RNA delivery technology, but their efficiency is limited by low release after endosome disruption. To improve release, an acid‐responsive polymer synthesized with which to formulate LNPs for encapsulation and release. Specifically, three poly(lactic acid)‐ block‐ poly(carboxybetaine) zwitterionic derivatives designed that cationic complexed at pH 7.4, neutral following cleavage endosomal pH, thereby having lower affinity RNA. The polymers formulated into each of approved Onpattro, Moderna, or Pfizer LNP formulations produce hybrid polymer‐lipid (PLNPs). With PLNPs, IC 50 values multiple small interfering RNAs (siRNAs) decreased up 5.4‐fold compared parent in several cell lines. Moreover, messenger (mRNA) transfection increased two fold. PLNPs accounted enhanced as this phenomenon lost acid‐inert polymers. Confocal microscopy confirmed cytosolic concentration using polymers; conversely, uptake escape identical existing LNPs. This due dissociation from its carrier. novel represents a versatile strategy increase
Language: Английский
Citations
1
Non-Coding RNA, Journal Year: 2024, Volume and Issue: 10(6), P. 55 - 55
Published: Nov. 8, 2024
Understanding the structures of noncoding RNAs (ncRNAs) is important for development RNA-based therapeutics. There are inherent challenges in employing current experimental techniques to determine tertiary (3D) with high complexity and flexibility folding, which makes computational methods indispensable. In this study, we compared utilities three advanced tools, namely RNAComposer, Rosetta FARFAR2, latest AlphaFold 3, predict 3D various forms RNAs, including small interfering RNA drug, nedosiran, novel bioengineered (BioRNA) molecule showing therapeutic potential. Our results showed that, while RNAComposer offered a malachite green aptamer structure closer its crystal structure, performances FARFAR2 largely depend upon secondary inputted, predictions might not even recapitulate typical, inverted “L” shape tRNA structure. Overall, integrating molecular dynamics principles into deep learning framework, directly predicted from primary sequence inputs, accepting several common post-transcriptional modifications, closely aligned experimentally determined structures. However, there were significant discrepancies among tools predicting distal loop human pre-microRNA larger BioRNA (tRNA fused pre-miRNA) molecules whose have been characterized experimentally. While show considerable promise, their notable strengths limitations emphasize needs validation besides characterization more
Language: Английский
Citations
0