The Emergence of Oligonucleotide Building Blocks in the Multispecific Proximity-Inducing Drug Toolbox of Destruction DOI
K. Zhou, Katherine E. Bujold

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 20, 2024

Oligonucleotides are a rapidly emerging class of therapeutics. Their most well-known examples informational drugs that modify gene expression by binding mRNA. Despite inducing proximity between biological machinery and mRNA when applied to modulating expression, oligonucleotides not typically labeled as "proximity-inducing" in literature. Yet, they have recently been explored building blocks for multispecific proximity-inducing (MPIDs). MPIDs unique because can direct endogenous destroy targeted molecules cells, contrast traditional inhibit only their functions. The mechanism action has enabled the targeting previously "undruggable" molecular entities cannot be effectively inhibited. However, development must ensure these will selectively potent, destruction-based toward intended targets over healthy tissues avoid causing life-threatening toxicities. emerged promising design sequence-controlled rationally designed program interactions. In this Review, we examine emergence oligonucleotide-containing induction space, which dominated antibody small molecule MPID modalities. Moreover, developed candidates immunotherapy protein degradation discussed demonstrate utility expanding scope selectivity toolbox. Finally, discuss programming "AND" gates into oligonucleotide scaffolds encode conditional responses potential incorporated MPIDs, further enhance selectivity, thus increasing drug category.

Language: Английский

Skeletal muscle effects of antisense oligonucleotides targeting glycogen synthase 1 in a mouse model of Pompe disease DOI Creative Commons
Lan Weiss, Michele Carrer, Alyaa Shmara

et al.

Clinical and Translational Medicine, Journal Year: 2025, Volume and Issue: 15(4)

Published: April 1, 2025

Abstract Pompe disease (PD) is a progressive myopathy caused by the aberrant accumulation of glycogen in skeletal and cardiac muscle resulting from deficiency enzyme acid alpha‐glucosidase (GAA). Administration recombinant human GAA as replacement therapy (ERT) works well alleviating manifestations PD but loses sustained benefit ameliorating pathology. The limited efficacy ERT partially attributable to its inability curb new produced synthase 1 (GYS1). Substrate reduction therapies aimed at knocking down GYS1 expression represent promising avenue improve myopathy. However, finding specific inhibitors for challenging given presence highly homologous GYS2 liver. Antisense oligonucleotides (ASOs) are chemically modified oligomers that hybridise their complementary target RNA induce degradation with exquisite specificity. In present study, we show ASO‐mediated Gys1 knockdown Gaa −/− mouse model led robust muscle. addition, combining ASO slightly further reduced content muscle, eliminated autophagic buildup lysosomal dysfunction, improved motor function mice. Our results provide strong foundation validation use ASO, alone or combination ERT, PD. We propose early administration may be key preventative treatment options Key points oligonucleotide (ASO) achieves reduces Combination improves performance compared disease.

Language: Английский

Citations

0
Unlocking the future: Precision oligonucleotide therapy for targeted treatment of neurodegenerative disorders DOI Creative Commons
Naitik Jain, Amrita Arup Roy,

Geethu Madhusoodanan

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: unknown, P. 143515 - 143515

Published: April 1, 2025

Language: Английский

Citations

0
Long non-coding rnas as key modulators of the immune microenvironment in hepatocellular carcinoma: implications for Immunotherapy DOI Creative Commons
Siqi Zhao, Fei Chen, Lingyu Hu

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 25, 2025

Hepatocellular carcinoma (HCC) represents a major global health challenge, characterized by its complex immune microenvironment that plays pivotal role in tumor progression and therapeutic response. Long non-coding RNAs (lncRNAs) have emerged as critical regulators of various biological processes, including gene expression cell function. This review explores the multifaceted roles lncRNAs modulating HCC. We discuss how influence infiltration activation cells, shape cytokine profiles, regulate checkpoint molecules, thereby affecting tumor’s immunogenicity response to immunotherapy. Furthermore, we highlight specific implicated evasion mechanisms their potential biomarkers targets. By elucidating intricate interplay between landscape HCC, this aims provide insights into novel strategies for enhancing immunotherapeutic efficacy improving patient outcomes.

Language: Английский

Citations

0
Bioanalysis of free antisense oligonucleotide payload from antibody–oligonucleotide conjugate by hybridization LC-MS/MS DOI Creative Commons
Di Jiang, Pei Li, Long Yuan

et al.

Bioanalysis, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 10

Published: July 23, 2024

Antisense oligonucleotides (ASOs) have been conjugated to various moieties, such as peptides, antibodies or Fab regions of antibodies, enhance their delivery target tissues. The quantitation free ASO (ASO payload) is critical characterize its pharmacokinetics/pharmacodynamics (PK/PD) properties and biodistribution after the peptide/antibody/Fab conjugates.

Language: Английский

Citations

3
Drug Delivery Across the Blood–Brain Barrier: A New Strategy for the Treatment of Neurological Diseases DOI Creative Commons

Jiao Yang,

Lin Yang,

Rujuan Wang

et al.

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(12), P. 1611 - 1611

Published: Dec. 19, 2024

The blood–brain barrier (BBB) serves as a highly selective between the blood and central nervous system (CNS), its main function is to protect brain from foreign substances. This physiological property plays crucial role in maintaining CNS homeostasis, but at same time greatly limits delivery of drug molecules CNS, thus posing major challenge for treatment neurological diseases. Given that high incidence low cure rate diseases have become global public health problem, development effective BBB penetration technologies important enhancing efficiency delivery, reducing systemic toxicity, improving therapeutic outcomes review describes pathological properties BBB, well current challenges trans-BBB detailing structural basis protection. Secondly, this paper reviews strategies recent years, including physical, biological chemical approaches, nanoparticle-based technologies, provides comprehensive assessment effectiveness, advantages limitations these strategies. It hoped will provide valuable references inspiration future researchers studies

Language: Английский

Citations

2
Alzheimer's Targeted Treatments: Focus on Amyloid and Inflammation DOI Creative Commons
Takeshi Iwatsubo,

Michael C. Irizarry,

Joseph W. Lewcock

et al.

Journal of Neuroscience, Journal Year: 2023, Volume and Issue: 43(47), P. 7894 - 7898

Published: Nov. 15, 2023

Alzheimer's disease (AD) is the major cause of dementia that now threatening lives billions elderly people on globe, and recent progress in elucidation pathomechanism AD opening venue to tackle by developing implementing "disease-modifying therapies" directly act pathophysiology slow down progression neurodegeneration. A example success clinical trials anti-amyloid b antibody drugs, whereas other therapeutic targets, e.g., inflammation tau, are being actively investigated. In this dual perspective session, we plan have speakers from leading pharmas field representing distinct investments space, which will be followed comment scientific leadership Association who speak behalf all stakeholders. Neuroscientists participating Society for Neuroscience may able gain insights into cutting edge approaches neurodegenerative disorders, discuss future contribution neuroscience field.

Language: Английский

Citations

4
An AAV capsid reprogrammed to bind human Transferrin Receptor mediates brain-wide gene delivery DOI Creative Commons
Qin Huang, Ken Y. Chan, Shan Lou

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 22, 2023

Developing vehicles that efficiently deliver genes throughout the human central nervous system (CNS) will broaden range of treatable genetic diseases. We engineered an AAV capsid, BI-hTFR1, binds Transferrin Receptor (TfR1), a protein expressed on blood-brain barrier (BBB). BI-hTFR1 was actively transported across brain endothelial cell layer and, relative to AAV9, provided 40-50 times greater reporter expression in CNS

Language: Английский

Citations

4
Intravenous administration of blood–brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system DOI
Chang Wang, Siyu Wang, Yonger Xue

et al.

Nature Biotechnology, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 25, 2024

Language: Английский

Citations

1
Engineering considerations for next-generation oligonucleotide therapeutics DOI
Sasha B. Ebrahimi,

Himanshu Bhattacharjee,

Sujatha Sonti

et al.

Nature Chemical Engineering, Journal Year: 2024, Volume and Issue: 1(12), P. 741 - 750

Published: Dec. 23, 2024

Language: Английский

Citations

1
Towards Aptamer-Targeted Drug Delivery to Brain Tumors: The Synthesis of Ramified Conjugates of an EGFR-Specific Aptamer with MMAE on a Cathepsin B-Cleavable Linker DOI Creative Commons
Vladimir A. Brylev, Ekaterina V. Ryabukhina, Evgeniya V. Nazarova

et al.

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(11), P. 1434 - 1434

Published: Nov. 11, 2024

Targeted delivery of chemotherapeutic agents is a well-established approach to cancer therapy. Antibody-drug conjugates (ADCs) typically carry toxic payloads attached tumor-associated antigen-targeting IgG antibody via an enzyme-cleavable linker that releases the drug inside cell. Aptamers are promising alternative antibodies in terms antigen targeting; however, their polynucleotide nature and smaller size result completely different PK/PD profile compared IgG. This may prove advantageous: owing lower molecular weight, aptamer-drug achieve better penetration solid tumors ADCs.

Language: Английский

Citations

0