Biology subjects

Matson, J.

Publications and source records attributed to Matson, J..

3 recordsLinked to original sources

bioRxiv2026

Systemic and Local Delivery of siRNA to the CNS and Periphery via Anti-IGF1R Antibody Conjugation

siRNA delivery platforms capable of accessing both central and peripheral tissues are critically needed to expand the therapeutic potential of oligonucleotides. To address this, we developed a novel siRNA-antibody conjugate by attaching an Hprt-targeting siRNA to an engineered antibody shuttle. This shuttle targets the insulin-like growth factor 1 receptor (IGF1R) using a fused antibody fragment (Clone F) and utilizes an antibody backbone with no tissue-relevant binding in this study. The resulting conjugate, designated Clone F-Hprt, demonstrated robust in vivo knockdown across multiple tissues. Clone F-Hprt demonstrated enhanced penetration into central nervous system (CNS) tissues compared to unconjugated siRNA following intracerebroventricular (ICV) and intravenous (IV) administration. In peripheral tissues, Clone F-Hprt achieved widespread knockdown in muscle, heart, and lung, consistent with IGF1R expression. The conjugate was well tolerated across all routes, including with repeated dosing. Although several receptor-mediated approaches for CNS delivery are progressing to the clinic (e.g., targeting the transferrin receptor), clinical validation remains to be demonstrated. Our findings highlight IGF1R as an alternative receptor capable of supporting delivery across both central and peripheral tissues, offering a complementary strategy for expanding the therapeutic landscape of oligonucleotide delivery.

neuroscience↗

bioRxiv2025

Tie2-Dependent Mechanisms Promote Leptomeningeal Collateral Remodeling and Reperfusion Following Stroke

Leptomeningeal collaterals are distal pial arterial anastomotic vessels that provide an alternative route for redistributing cerebral blood flow following arterial obstruction, thereby limiting tissue damage. However, the regulatory mechanisms and strategies to enhance this adaptive response remain under investigation. This study explored the pharmacological effects of Tie2 receptor activation, using the peptide agonist Vasculotide, following permanent middle cerebral artery occlusion (pMCAO). Vasculotide improved collateral growth and remodeling, which correlated with reduced infarct volume, enhanced blood flow, and functional recovery within 24hrs post-pMCAO. In contrast, collateral growth was attenuated in Tie2 and EphA4/Tie2 double knockdown mice, while the loss of EphA4 increased Tie2 and Ang-1 expression and mimicked the positive effects of Vasculotide following stroke. Furthermore, bulk RNA sequencing of meningeal tissue identified key transcriptomic changes, including alterations in AJ-associated transcripts, such as Krt5, Krt14, and Col17a1, in the ipsilateral meninges of both endothelial cell-specific EphA4 knockout and Vasculotide-treated mice. Krt5 expression was found upregulated on meningeal arterial vascular network in injured KO mice, highlighting a potential new mediator of meningeal vascular remodeling. These findings illustrate that EphA4 and Tie2 play opposing roles in collateral remodeling, including the regulation of Krt5. Modulating their activity could potentially enhance the collateral response to stroke.

neuroscience↗

bioRxiv2020

The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing the field to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal, and non-neuronal cells. Therefore, it is critically important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and robust activity throughout the CNS in neurons, oligodendrocytes, astrocytes, and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.

neuroscience↗