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Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL
Arturo I Machuca-Parra1, Alexander A Bigger-Allen1, Angie V Sanchez1
1Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA.
Insights
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological disease with no current therapies. Modulating Notch3 signaling with an antibody prevented mural cell loss in a CADASIL mouse model, offering a potential treatment strategy.
Area of Science:
- Neurology
- Vascular Biology
- Genetics
Background:
- Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic small vessel disease (SVD) leading to stroke and dementia.
- Loss of mural cells (pericytes and smooth muscle cells) is a key feature of CADASIL and other SVDs, causing vascular instability.
- Currently, no effective therapies exist for CADASIL.
Purpose of the Study:
- To investigate the role of Notch3 signaling in maintaining mural cell coverage in arteries.
- To explore the therapeutic potential of modulating Notch3 signaling for CADASIL treatment.
Main Methods:
- Utilized genetic rescue in Notch3 knockout mice to assess Notch3 signaling's necessity and sufficiency for mural cell support.
- Administered a systemic agonist Notch3 antibody to mice with a CADASIL-associated mutation (C455R).
- Analyzed changes in mural cell coverage and plasma proteins, including endostatin/collagen 18α1 and Notch3 extracellular domain.
Main Results:
- Notch3 signaling was confirmed as essential and sufficient for supporting arterial mural cell coverage.
- Systemic administration of an agonist Notch3 antibody successfully prevented mural cell loss in a mouse model of CADASIL.
- The antibody treatment also modulated specific plasma proteins linked to Notch3 activity.
Conclusions:
- Targeting Notch3 signaling represents a promising therapeutic avenue for CADASIL and other SVDs.
- Modulating Notch3 activity, potentially through antibody-based therapies, can counteract mural cell loss and vascular instability characteristic of CADASIL.
Abstract:
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a neurological syndrome characterized by small vessel disease (SVD), stroke, and vascular cognitive impairment and dementia caused by mutations in NOTCH3 No therapies are available for this condition. Loss of mural cells, which encompass pericytes and vascular smooth muscle cells, is a hallmark of CADASIL and other SVDs, including diabetic retinopathy, resulting in vascular instability. Here, we showed that Notch3 signaling is both necessary and sufficient to support mural cell coverage in arteries using genetic rescue in Notch3 knockout mice. Furthermore, we show that systemic administration of an agonist Notch3 antibody prevents mural cell loss and modifies plasma proteins associated with Notch3 activity, including endostatin/collagen 18α1 and Notch3 extracellular domain in mice with the C455R mutation, a CADASIL variant associated with Notch3 loss of function. These findings open opportunities for the treatment of CADASIL and other SVDs by modulating Notch3 signaling.
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