In a recent study published in Nature Medicine, a team of researchers from the Korea Advanced Institute of Science and Technology (KAIST) have developed a new fusion protein drug known as αAβ-Gas6 designed to minimize neurotoxic inflammatory side effects related to traditional antibody treatments for Alzheimer’s disease (AD) patients, such as the recently approved FDA drug, Aduhelm.
While Aduhelm is designed to target amyloid beta (Aβ) by reducing Aβ plaque burden in AD patients, there is still some dispute regarding its effect on cognitive improvement. Approximately 40% of AD patients treated with Aduhelm have experienced some alarming side effects. These include cerebral edemas and hemorrhages, which are believed to be linked to inflammatory responses in the brain when the Aβ antibody binds Fc receptors (FCR) of immune cells such as microglia and macrophages, potentially worsening cognitive impairment in AD patients.
"FcR activation by Aβ targeting antibodies induces microglia-mediated Aβ phagocytosis, but it also produces inflammatory signals, inevitably damaging brain tissues," said paper authors Chan Hyuk Kim and Won-Suk Chung, associate professors in the Department of Biological Sciences at KAIST.
"Therefore, we utilized efferocytosis, a cellular process by which dead cells are removed by phagocytes as an alternative pathway for the clearance of Aβ in the brain," Prof. Kim and Chung said. "Efferocytosis is accompanied by anti-inflammatory responses to maintain tissue homeostasis. To exploit this process, we engineered Gas6, a soluble adaptor protein that mediates efferocytosis via TAM phagocytic receptors in such a way that its target specificity was redirected from dead cells to Aβ plaques."
Using a mouse model, the study found that αAβ-Gas6 not only eradicates Aβ utilizing a completely different mechanism than Aβ antibody-based immunotherapy such as Aduhelm, but also removes Aβ with greater potency without the neurotoxic inflammatory side effects.
Professors Kim and Chung also noted, "We believe our approach can be a breakthrough in treating AD without causing inflammatory side effects and synapse loss. Our approach holds promise as a novel therapeutic platform that is applicable to more than AD. By modifying the target-specificity of the fusion protein, the Gas6-fusion protein can be applied to various neurological disorders as well as autoimmune diseases affected by toxic molecules that should be removed without causing inflammatory responses."
Sources: Nature Medicine
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