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

Metabolic Stability and Targeted Delivery of Oligonucleotides: Advancing RNA Therapeutics Beyond The Liver DOI Creative Commons

Puneet Anand,

Yu Zhang,

Suraj Patil

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Oligonucleotides have emerged as a formidable new class of nucleic acid therapeutics. Fully modified oligonucleotides exhibit enhanced metabolic stability and display successful clinical applicability for targets formerly considered "undruggable". Accumulating studies show that conjugation to targeting modalities stabilized oligonucleotides, especially small interfering RNAs (siRNAs), has enabled robust delivery intended cells/tissues. However, the major challenge in field been targeted (siRNAs antisense (ASOs)) extrahepatic tissues. In this Perspective, we review chemistry innovations emerging approaches revolutionized oligonucleotide drug discovery development. We explore findings from both academia industry highlight potential indications involving different organs─including skeletal muscles, brain, lungs, skin, heart, adipose tissue, eyes. all, continued advances coupled with conjugation-based or novel administration routes will further advance

Language: Английский

Citations

1
A combination of systemic mannitol administration and mannitol-modified polyester nanoparticles facilitate gene delivery to the brain through caveolae-mediated endocytosis DOI Creative Commons
Benjamin Gilbert,

Chirag Miglani,

Arundhati Karmakar

et al.

Molecular Therapy — Nucleic Acids, Journal Year: 2025, Volume and Issue: 36(1), P. 102480 - 102480

Published: Feb. 7, 2025

Overcoming the blood-brain barrier (BBB) remains a significant challenge for nucleic acid delivery to brain. We have explored combination of mannitol-modified poly (β-amino ester) (PBAE) nanoparticles and systemic mannitol injection crossing BBB. incorporated in PBAE polymer caveolae targeting selected monomers that may help avoid liver. also induced at BBB through order create an opportunity caveolae-targeting (M30 D90) containing plasmid DNA cross When clinically relevant dose was administered intravenously this induction model, M30 D90 demonstrated transgene expression reporter brain, with selective uptake by neuronal cells minimal liver accumulation. demonstrate modulation using administration designed are necessary efficient This platform offers simple, scalable, controlled solution holds promise treating brain diseases functional targets.

Language: Английский

Citations

1
A brain-targeted and ROS-responsive natural polysaccharide nanogel for enhancing antidepressant therapy DOI
Dong Xu,

Tao Qiao,

Yan-Ming Zhou

et al.

Chemical Engineering Journal, Journal Year: 2025, Volume and Issue: unknown, P. 160719 - 160719

Published: Feb. 1, 2025

Language: Английский

Citations

1
Durable suppression of seizures in a preclinical model of KCNT1 genetic epilepsy with divalent small interfering RNA DOI Creative Commons

Benjamin J. Andreone,

Jennifer S Lin,

Jenna Tocci

et al.

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
Molecular and cellular characteristics of cerebrovascular cell types and their contribution to neurodegenerative diseases DOI Creative Commons
F. García, Myriam Heiman

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 29, 2025

Language: Английский

Citations

0
Assessing central nervous system drug delivery DOI Creative Commons
Margareta Hammarlund‐Udenaes, Irena Loryan

Expert Opinion on Drug Delivery, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 2, 2025

Delivering drugs to the central nervous system (CNS) remains a major challenge due blood-brain barrier, restricting entry of into brain. This limitation contributes ongoing lack effective treatments for CNS diseases. To improve process drug discovery and development, it is crucial streamline methods that measure clinically relevant parameters, allowing good selection candidates. In this paper, we discuss essential prerequisites successful delivery review methods. We emphasize need closer collaboration between in vitro vivo scientists relevance these increase success rate developing therapies. While our focus on small molecule drugs, also touch some aspects larger molecules. Significant progress has been made recent years method development their application. However, there still work be done before use silico models, cell systems, AI can consistently offer meaningful correlations relationships clinical data. gap partly limited patient data, but lot achieved through research animal models.

Language: Английский

Citations

0
Running Up that Hill: An Interview with Carole Ho, Denali Therapeutics DOI
Carole Ho, Kevin Davies

GEN Biotechnology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Language: Английский

Citations

0
Fc-engineered large molecules targeting blood-brain barrier transferrin receptor and CD98hc have distinct central nervous system and peripheral biodistribution DOI Creative Commons

Nathalie Khoury,

Michelle E. Pizzo,

Claire B. Discenza

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 20, 2025

Blood brain barrier-crossing molecules targeting transferrin receptor (TfR) and CD98 heavy chain (CD98hc) are widely reported to promote enhanced delivery of therapeutics. Here, we provide a comprehensive unbiased biodistribution characterization TfR CD98hc antibody transport vehicles (ATVTfR ATVCD98hc) compared control IgG. Mouse whole-body tissue clearing reveals distinct organ localization for each molecule. In the brain, ATVTfR ATVCD98hc achieve exposure parenchymal distribution even when exposures matched between ATV IgG in bulk tissue. Using combination cell sorting single-cell RNAseq, reveal that is nearly absent from cells distributed primarily perivascular leptomeningeal cells. contrast, exhibit broad unique cell-type distribution. Finally, profile detail region-specific cynomolgus monkey spinal cord. Taken together, this in-depth multiscale will guide platform selection therapeutic targets interest.

Language: Английский

Citations

0
Comparative Radiotracing Quantifies Brain Cellular Uptake and Catabolism of Bispecific Antibodies Targeting Transferrin Receptor and CD98hc DOI Creative Commons

Jacob L. Veire,

Michael J. Lucas,

Layne G. Bond

et al.

ACS Chemical Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: March 12, 2025

Bispecific antibodies (bAbs) that engage cerebrovascular targets, induce transport across the blood-brain barrier (BBB), and redistribute to secondary targets within brain parenchyma have potential transform diagnosis treatment of a wide range central nervous system disorders. Full understanding pharmacokinetics (PK) these agents, including their for delivering cargo into parenchymal cells, is key priority development numerous therapeutic applications. To date, PK bAbs target transferrin receptor (TfR-1) CD98 heavy chain (CD98hc) has been characterized using techniques incapable distinguishing between CNS clearance intact protein from uptake catabolism by cells. Herein, we address this knowledge gap via comparative radiotracing strategy two radioisotopes with distinct residualizing properties, iodine-125 (I-125) zirconium-89 (Zr-89). We first identify reaction conditions tetravalent chelator modification Zr-89 radiolabeling do not adversely affect in vitro or vivo function. then use define TfR-1 CD98hc targeted without target, generating quantitative evidence TfR-1-mediated cellular implicates processes previously reported differences retention IgGs shuttled BBB pathways. Finally, perform on bAb an internalizing neuronal (TrkB), demonstrating rapid divergence I-125 curves, > 30-fold difference content radioisotopes. Together, results establish as valuable technique identifying quantifying extent timing following engagement.

Language: Английский

Citations

0
Targeting Neuroinflammation in Central Nervous System Diseases by Oral Delivery of Lipid Nanoparticles DOI Creative Commons
Yuan Zou, Jing Zhang, Longmin Chen

et al.

Pharmaceutics, Journal Year: 2025, Volume and Issue: 17(3), P. 388 - 388

Published: March 18, 2025

Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson’s disease, Alzheimer’s disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation immune cells results in massive release pro-inflammatory cytokines, which subsequently induce neuronal death accelerate progression neurodegeneration. Therefore, mitigating neuroinflammation has emerged promising strategy for treatment diseases. Despite advancements drug discovery development novel therapeutics, effective delivery these agents to remains serious challenge due restrictive nature blood–brain barrier (BBB). This underscores need develop system. Recent studies have identified oral lipid nanoparticles (LNPs) approach efficiently deliver drugs across BBB treat neurological review aims comprehensively summarize recent LNPs designed controlled therapeutic modulation diseases through administration. Furthermore, this addresses mechanisms by overcome biological barriers evaluate their clinical implications efficacy context systems. Specifically, it focuses on LNP formulations that facilitate administration, exploring potential enhance bioavailability, improve targeting precision, alleviate or manage symptoms associated with range

Language: Английский

Citations

0