The approval of amyloid-targeting therapies represents an important advance in the treatment of Alzheimer’s disease (AD). However, these therapies can cause serious side effects known as amyloid-related imaging abnormalities (ARIA), which include brain swelling and small hemorrhages. The risk is particularly elevated in individuals with cerebral amyloid angiopathy (CAA), a condition in which amyloid accumulates within the walls of brain blood vessels, weakening them and increasing their vulnerability to damage. Because CAA is present in most patients with AD, improving the vascular safety of amyloid-targeting therapies is a critical unmet need. Growing evidence indicates that when amyloid is cleared from already fragile vessels, inflammatory activated enzymes, especially matrix metalloproteinases (MMPs), can further degrade the vessel wall and disrupt the blood–brain barrier, thereby contributing to ARIA.
To address this challenge, Dr. Weekman and Dr. Capitano propose a fundamentally different therapeutic strategy to protect the vasculature directly. Rather than relying solely on systemic antibody delivery, they aim to intervene directly within affected blood vessels. They hypothesize that platelets—blood cells best known for their role in clotting—can be engineered into targeted delivery vehicles that carry an anti-amyloid antibody (3D6) on their surface and a protective MMP inhibitor within. Because platelets naturally patrol vessel walls and respond to vascular injury, they are well positioned to home to amyloid-damaged vessels. Once localized, the surface-bound antibody would promote vascular amyloid clearance, while the locally released MMP inhibitor would protect the vessel wall and reduce ARIA-like injury.
Central to this approach is marimastat, an MMP inhibitor originally developed for cancer treatment that blocks MMP enzyme activity and helps prevent tissue breakdown. Their preliminary data supports the feasibility of this strategy. The team showed that platelets can be isolated and handled in a way that preserves their resting state, then successfully loaded with marimastat without triggering activation. Even the small loading capacity of platelet-delivered marimastat is predicted to generate high local drug concentrations at sites of amyloid deposition—sufficient to strongly inhibit MMPs while minimizing systemic exposure. In APP knock-in amyloid mouse models, systemic marimastat reduces antibody-associated microbleeds, supporting its protective potential. They also observed that platelets naturally accumulate around amyloid-laden vessels in aged amyloid mice, suggesting this approach leverages an existing biological response.
Their hypothesis will be tested through two specific aims. In Aim 1, the team will optimize and rigorously evaluate the manufacturing process to ensure that engineered platelets remain stable and functional, display the antibody, release marimastat in a controlled manner, and selectively bind to amyloid-coated surfaces and CAA-positive vessels. In Aim 2, they will assess safety and efficacy in an aged amyloid mouse model (Tg2576) with established CAA. Using longitudinal imaging and high-field MRI, they will quantify vascular leakage, microhemorrhages, cerebral blood flow, and amyloid burden over time, while also evaluating inflammatory and molecular changes in surrounding brain tissue.
If successful, this work could substantially improve the safety of amyloid-targeting therapies by protecting vulnerable cerebral vessels during treatment. More broadly, it would establish a versatile platform for delivering therapeutics directly to diseased brain vasculature, potentially expanding treatment options for AD and other vascular and neurodegenerative disorders.
