Splice-Modulating Antisense Oligonucleotides as Therapeutics for Inherited Metabolic Diseases

BioDrugs, Journal Year: 2024, Volume and Issue: 38(2), P. 177 - 203

Published: Jan. 22, 2024

The last decade (2013-2023) has seen unprecedented successes in the clinical translation of therapeutic antisense oligonucleotides (ASOs). Eight such molecules have been granted marketing approval by United States Food and Drug Administration (US FDA) during decade, after first ASO drug, fomivirsen, was approved much earlier, 1998. Splice-modulating ASOs also developed for therapy inborn errors metabolism (IEMs), due to their ability redirect aberrant splicing caused mutations, thus recovering expression normal transcripts, correcting deficiency functional proteins. feasibility treating IEM patients with splice-switching supported FDA permission (2018) "N-of-1" study milasen, an investigational drug Batten disease. Although IEM, owing rarity individual disease and/or pathogenic mutation, only a low number may be treated that specifically suppress pattern mutant precursor mRNA (pre-mRNA), represent superior individualized molecular therapeutics IEM. In this work, we summarize technology respect its mechanisms action, chemical modifications nucleotides, rational design modified oligonucleotides; following that, precisely provide review current understanding developing splice-modulating ASO-based concluding section, suggest potential ways improve optimize development targeting

Language: Английский

---

Amphiphilic Block Copolymer Nanostructures as a Tunable Delivery Platform: Perspective and Framework for the Future Drug Product Development

Biomacromolecules, Journal Year: 2024, Volume and Issue: 25(2), P. 541 - 563

Published: Jan. 19, 2024

Nanoformulation of active payloads or pharmaceutical ingredients (APIs) has always been an area interest to achieve targeted, sustained, and efficacious delivery. Various delivery platforms have explored, but loading APIs challenging because the chemical structural properties these molecules. Polymersomes made from amphiphilic block copolymers (ABCPs) shown enormous promise as a tunable API platform confer multifold advantages over lipid-based systems. For example, COVID booster vaccine comprising polymersomes encapsulating spike protein (ACM-001) recently completed Phase I clinical trial provides case for developing safe drug products based on ABCP platforms. However, several limitations need be resolved before they can reach their full potential. In this Perspective, we would like highlight such aspects requiring further development translating ABCP-based proof concept viable commercial product.

Language: Английский

---

Biomaterial‐based gene therapy

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: June 1, 2023

Gene therapy, a medical approach that involves the correction or replacement of defective and abnormal genes, plays an essential role in treatment complex refractory diseases, such as hereditary cancer, rheumatic immune diseases. Nucleic acids alone do not easily enter target cells due to their easy degradation vivo structure cell membranes. The introduction genes into biological is often dependent on gene delivery vectors, adenoviral which are commonly used therapy. However, traditional viral vectors have strong immunogenicity while also presenting potential infection risk. Recently, biomaterials attracted attention for use efficient vehicles, because they can avoid drawbacks associated with vectors. Biomaterials improve stability nucleic efficiency intracellular delivery. This review focused biomaterial-based systems therapy disease treatment. Herein, we recent developments modalities Additionally, discuss acid strategies, focus systems. Furthermore, current applications summarized.

Language: Английский

---

Enhancing the Effectiveness of Oligonucleotide Therapeutics Using Cell-Penetrating Peptide Conjugation, Chemical Modification, and Carrier-Based Delivery Strategies

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(4), P. 1130 - 1130

Published: April 3, 2023

Oligonucleotide-based therapies are a promising approach for treating wide range of hard-to-treat diseases, particularly genetic and rare diseases. These involve the use short synthetic sequences DNA or RNA that can modulate gene expression inhibit proteins through various mechanisms. Despite potential these therapies, significant barrier to their widespread is difficulty in ensuring uptake by target cells/tissues. Strategies overcome this challenge include cell-penetrating peptide conjugation, chemical modification, nanoparticle formulation, endogenous vesicles, spherical nucleic acids, smart material-based delivery vehicles. This article provides an overview strategies efficient oligonucleotide drugs, as well safety toxicity considerations, regulatory requirements, challenges translating from laboratory clinic.

Language: Английский

---

Engineering biomaterials to tailor the microenvironment for macrophage–endothelium interactions

Nature Reviews Materials, Journal Year: 2023, Volume and Issue: 8(10), P. 688 - 699

Published: Sept. 4, 2023

Language: Английский

---

Exploring precision treatments in immune‐mediated inflammatory diseases: Harnessing the infinite potential of nucleic acid delivery

Exploration, Journal Year: 2024, Volume and Issue: unknown

Published: May 24, 2024

Immune-mediated inflammatory diseases (IMIDs) impose an immeasurable burden on individuals and society. While the conventional use of immunosuppressants disease-modifying drugs has provided partial relief control, their inevitable side effects limited efficacy cast a shadow over finding cure. Promising nucleic acid have shown potential to exert precise at molecular level, with different classes acids having regulatory functions through varying mechanisms. For better delivery acids, safe effective viral vectors non-viral systems (including liposomes, polymers, etc.) been intensively explored. Herein, after describing range categories vectors, we focus application therapeutic in various IMIDs, including rheumatoid arthritis, bowel disease, psoriasis, multiple sclerosis, asthma, ankylosing spondylitis, systemic lupus erythematosus, uveitis. Molecules implicated inflammation immune dysregulation are abnormally expressed series meticulous modulation therapy results degrees remission improvement these diseases. By synthesizing findings centered specific targets, this review delivers systematic elucidation perspective towards advancing utilization therapeutics for managing IMIDs.

Language: Английский

---

Integrating Machine Learning-Based Approaches into the Design of ASO Therapies

Genes, Journal Year: 2025, Volume and Issue: 16(2), P. 185 - 185

Published: Feb. 2, 2025

Rare diseases impose a significant burden on affected individuals, caregivers, and healthcare systems worldwide. Developing effective therapeutics for these small patient populations presents substantial challenges. Antisense oligonucleotides (ASOs) have emerged as promising therapeutic approach that targets the underlying genetic cause of disease at RNA level. Several ASOs gained FDA approval treatment conditions, including use in personalized N-of-1 trials. However, despite their potential, often exhibit limited clinical efficacy, optimizing design is complex process influenced by numerous factors. Machine learning-based platforms, eSkip-Finder ASOptimizer, been developed to address challenges predicting optimal ASO sequences chemical modifications enhance efficacy. focuses exon-skipping applications, while ASOptimizer aims optimize degradation. Preliminary vitro results demonstrated predictive power platforms. limitations remain, generalizability alternative gaps consideration all factors influencing efficacy safety. Continued advancements machine learning models, alongside efforts incorporate additional features affecting safety, hold promise field. These platforms potential streamline development, reduce associated costs, improve outcomes, positioning key tool future therapeutics.

Language: Английский

---

Removing the stumbling block of exosome applications in clinical and translational medicine: expand production and improve accuracy

Stem Cell Research & Therapy, Journal Year: 2023, Volume and Issue: 14(1)

Published: April 1, 2023

Abstract Although the clinical application and transformation of exosomes are still in exploration stage, prospects promising have a profound impact on future medicine exosomes. However, due to limitation production poor targeting ability exosomes, extensive rich biological functions restricted, potential is limited. The current research committed solving above problems expanding value, but it lacks an extensive, multi-angle, comprehensive systematic summary prospect. Therefore, we reviewed optimization strategies medical applications, including exogenous treatment parent cells improvement extraction methods, compared their advantages disadvantages. Subsequently, was improved by carrying drugs engineering structure solve problem transformation. In addition, discussed other that may exist exploratory drug delivery, diagnosis treatment, regenerative medicine.

Language: Английский

---

Therapeutic Antisense Oligonucleotides in Oncology: From Bench to Bedside

Cancers, Journal Year: 2024, Volume and Issue: 16(17), P. 2940 - 2940

Published: Aug. 23, 2024

Advancements in our comprehension of tumor biology and chemoresistance have spurred the development treatments that precisely target specific molecules within body. Despite expanding landscape therapeutic options, there persists a demand for innovative approaches to address unmet clinical needs. RNA therapeutics emerged as promising frontier this realm, offering novel avenues intervention such interference utilization antisense oligonucleotides (ASOs). ASOs represent versatile class capable selectively targeting messenger RNAs (mRNAs) silencing disease-associated proteins, thereby disrupting pathogenic processes at molecular level. Recent advancements chemical modification carrier molecule design significantly enhanced stability, biodistribution, intracellular uptake ASOs, bolstering their potential. While ASO therapy holds promise across various disease domains, including oncology, coronary angioplasty, neurological disorders, viral, parasitic diseases, review manuscript focuses specifically on application targeted cancer therapies. Through comprehensive examination latest research findings developments, we delve into intricacies ASO-based treatment, shedding light mechanisms action, efficacy, prospects.

Language: Английский

---

The evolving landscape of gene therapy strategies for the treatment of osteoarthritis

Osteoarthritis and Cartilage, Journal Year: 2024, Volume and Issue: 32(4), P. 372 - 384

Published: Jan. 8, 2024

Objectives Significant advances have been made in our understanding of osteoarthritis (OA) pathogenesis; however, no disease-modifying therapies identified. This review will summarize the gene therapy landscape, its initial successes for OA, and possible challenges using recent studies examples clinical trials. Design narrative has three major sections: 1) vector systems OA therapy, 2) current emerging targets 3) considerations future directions. Results Gene is strategy by which nucleic acids are delivered to treat reverse disease progression. Specificity prolonged expression these achieved manipulating promoters, genes, systems. Certain also allow development combinatorial acid strategies that can be a single intraarticular injection – an approach likely required complexity pathogenesis. Several viral non-viral vector-based trials many more being evaluated preclinical arena. Conclusions In post-COVID era, certainly promising; majority validation continues focus heavily on post-traumatic models changes only cartilage subchondral bone. To ensure successful translation, new candidates arena must examined against all joint tissues as well pain diverse injury-, obesity-, age-induced disease. Lastly, consideration given repeat administration cost treatment owing chronic nature OA.

Language: Английский

---