Biology subjects

Solanoy, H.

Publications and source records attributed to Solanoy, H..

7 recordsLinked to original sources

bioRxiv2025

Dual targeting of transferrin receptor and CD98hc enhances brain exposure of large molecules

Targeting proteins highly expressed at the blood-brain barrier, including transferrin receptor (TfR) and CD98hc, is a transformative approach enabling more effective brain delivery of biotherapeutics for treatment of neurological diseases. TfR-mediated delivery promotes rapid, high brain uptake, while CD98hc-mediated delivery is slower with more prolonged exposure. Here, we engineer a huIgG Fc domain to bind both TfR and CD98hc to create a dual transport vehicle (TV) platform that drives distinct brain delivery properties. Dual TVs achieve significantly higher brain concentrations than TVs targeting either TfR or CD98hc alone. Modulation of TfR and CD98hc affinities shifts dual TV brain exposure kinetics and biodistribution. Stronger TfR affinity drives faster brain uptake and clearance, while stronger CD98hc affinity yields higher, more sustained concentrations, likely due to CD98hc affinity-dependent reduction in TfR-mediated neuronal internalization. This dual targeting strategy leverages the complementary properties of TfR and CD98hc-mediated brain exposure to increase optionality for brain delivery of biotherapeutics.

neuroscience↗

bioRxiv2024

Transferrin receptor-mediated transport at the blood-brain barrier is elevated in early development but maintained across adult aging

Transferrin receptor (TfR)-mediated transcytosis across the blood-brain barrier (BBB) is a promising strategy to improve delivery of biologics to the central nervous system (CNS). However, it remains unclear whether age and aging-related diseases impact TfR expression and/or BBB transport capacity. Here, we used the TfR-targeted antibody transport vehicle (ATVTfR) to enhance CNS delivery in healthy mice and in the 5xFAD mouse model of Alzheimers disease (AD). Healthy neonates exhibited the highest vascular TfR expression and ATVTfR brain exposure, whereas BBB transport capacity remained stable across adulthood. Additionally, neither TfR expression nor ATVTfR brain uptake changed significantly in 5xFAD mice. Further, vascular TfR expression in AD patient brains was similar to age-matched controls, suggesting that TfR transport may be conserved for AD in humans. The elevated TfR-mediated brain delivery observed in early mouse development suggests the potential of added efficacy in utilizing TfR platforms for the treatment of early childhood diseases. Preservation of ATVTfR transport in adult mice across healthy aging and in an AD model supports continued application of TfR platforms in age-related diseases.

neuroscience↗

bioRxiv2024

Engineering anti-amyloid antibodies with transferrin receptor targeting improves safety and brain biodistribution

Although the first generation of immunotherapies for Alzheimers disease (AD) are now clinically approved, amyloid-related imaging abnormalities (ARIA) remain a major safety problem for this class of drugs. Here, we report an antibody transport vehicle (ATV) targeting the transferrin receptor (TfR) for brain delivery of amyloid beta (A{beta}) antibodies that significantly reduced ARIA-like lesions and improved plaque target engagement in a mouse model of amyloid deposition. Asymmetrical Fc mutations (ATVcisLALA) allowed the molecule to selectively retain effector function only when bound to A{beta} while mitigating TfR-related hematology liabilities. Mice treated with ATVcisLALA:A{beta} exhibited broad brain parenchymal antibody distribution; in contrast, anti-A{beta} IgG was highly enriched at arterial perivascular spaces where vascular A{beta} localizes and likely plays a role in induction of ARIA. Importantly, ATVcisLALA: A{beta} almost completely eliminated ARIA-like lesions and vascular inflammation associated with anti-A{beta} treatment. Taken together, ATVcisLALA has the potential to significantly improve both safety and efficacy of A{beta} immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.

neuroscience↗

bioRxiv2023

DNL343 is an investigational CNS penetrant eIF2B activator that prevents and reverses the effects of neurodegeneration caused by the Integrated Stress Response

The integrated stress response (ISR) is a conserved pathway in eukaryotic cells that is activated in response to multiple sources of cellular stress. Although acute activation of this pathway restores cellular homeostasis, intense or prolonged ISR activation perturbs cell function and may contribute to neurodegeneration. DNL343 is an investigational CNS-penetrant small molecule ISR inhibitor designed to activate the eukaryotic initiation factor 2B (eIF2B) and suppress aberrant ISR activation. DNL343 reduced CNS ISR activity and neurodegeneration in a dose-dependent manner in two established in vivo models - the optic nerve crush injury and an eIF2B loss of function (LOF) mutant - demonstrating neuroprotection in both and preventing motor dysfunction in the LOF mutant mouse. Treatment with DNL343 at a late stage of disease in the LOF model reversed elevation in plasma biomarkers of neuroinflammation and neurodegeneration and prevented premature mortality. Several proteins and metabolites that are dysregulated in the LOF mouse brains were normalized by DNL343 treatment, and this response is detectable in human biofluids. Several of these biomarkers show differential levels in CSF and plasma from patients with vanishing white matter disease (VWMD), a neurodegenerative disease that is driven by eIF2B LOF and chronic ISR activation, supporting their potential translational relevance. This study demonstrates that DNL343 is a brain penetrant ISR inhibitor capable of attenuating neurodegeneration in mouse models and identifies several biomarker candidates that may be used to assess treatment responses in the clinic.

neuroscience↗

bioRxiv2021

Molecular architecture determines brain delivery of a transferrin-receptor targeted lysosomal enzyme

Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse biotherapeutics to platforms that bind the transferrin receptor (TfR), a brain endothelial cell target, to facilitate receptor-mediated transcytosis across the BBB. Here, we characterized the pharmacological behavior of two distinct TfR-targeted platforms fused to iduronate 2-sulfatase (IDS), a lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared the relative brain exposures and functional activities of both approaches in mouse models. IDS fused to a moderate-affinity, monovalent TfR binding enzyme transport vehicle (ETV:IDS) resulted in widespread brain exposure, internalization by parenchymal cells, and significant substrate reduction in the CNS of an MPS II mouse model. In contrast, IDS fused to a standard high-affinity bivalent antibody (IgG:IDS) resulted in lower brain uptake, limited biodistribution beyond brain endothelial cells, and reduced brain substrate reduction. These results highlight important features likely to impact the clinical development of TfR-targeting platforms in MPS II and potentially other CNS diseases. SummaryBrain delivery, biodistribution and pharmacodynamics of a lysosomal enzyme fused to a moderate-affinity transferrin receptor-directed blood-brain barrier enzyme transport vehicle are superior to a traditional high-affinity anti-TfR monoclonal antibody fusion.

neuroscience↗

bioRxiv2021

Understanding LRRK2 kinase activity in preclinical models and human subjects through quantitative analysis of LRRK2 and pRab10

Variants in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with increased risk for familial and sporadic Parkinsons disease (PD). Pathogenic variants in LRRK2, including the common variant G2019S, result in increased LRRK2 kinase activity, supporting the therapeutic potential of LRRK2 kinase inhibitors for PD. To better understand the role of LRRK2 in disease and to support the clinical development of LRRK2 inhibitors, quantitative and high-throughput assays to measure LRRK2 levels and activity are needed. We developed and applied such assays to measure the levels of LRRK2 as well as the phosphorylation of LRRK2 itself or one of its substrates, Rab10 (pT73 Rab10). We observed increased LRRK2 activity in various cellular models of disease, including iPSC-derived microglia, as well as in human subjects carrying disease-linked variant in LRRK2 (G2019S). Capitalizing on the high-throughput and sensitive nature of these assays, we detected a significant reduction in LRRK2 activity in subjects carrying missense variants in LRRK2 associated with reduced disease risk. Finally, we optimized these assays to enable analysis of LRRK2 activity following inhibition in human peripheral blood mononuclear cells (PBMCs) and whole blood, demonstrating their potential utility as biomarkers to assess changes in LRRK2 expression and activity in the clinic.

neuroscience↗

bioRxiv2021

Fibrillar Aβ causes profound microglial metabolic perturbations in a novel APP knock-in mouse model

Microglial dysfunction is believed to play a pathogenic role in Alzheimers disease (AD). Here, we characterize the amyloid-{beta} related pathology and microglial responses in an engineered APP knock-in mouse model of familial AD. This model recapitulates key pathological features of AD such as a progressive accumulation of parenchymal amyloid plaques and vascular amyloid deposits, altered glial responses and neurodegeneration. Leveraging multi-omics approaches, we found lipid accumulation and an exacerbated disease-associated transcriptomic response in methoxy-X04-positive, phagocytic microglia. Together, these findings highlight the potential of this novel, open-access mouse model to investigate AD pathogenesis and demonstrate that fibrillar A{beta} triggers lipid dysregulation and immuno-metabolic perturbations in phagocytic microglia. HighlightsO_LINovel open-access APP KI mouse model shows salient AD pathological features C_LIO_LIDeep phenotyping of sorted microglia reveals profound lipidomic perturbations in line with Alois Alzheimers original descriptions of glial adipose inclusions C_LIO_LIImmunometabolic perturbations are exacerbated in microglia accumulating fibrillar A{beta} C_LI

neuroscience↗