A fusion protein removed beta-amyloid plaque without producing the neurotoxic inflammation associated with other treatments, such as aducanumab immunotherapy. It is based on the alphaA Beta-Gas6 fusion protein developed in a mouse model of Alzheimer's disease (AD) by a team of researchers at The Korea Advanced Institute of Science and Technology (KAIST) in South Korea.

There are monoclonal anti-amyloid antibodies, like Aduhelm (aducanumab; Biogen Inc.), which significantly reduce beta-amyloid plaque. However, 40% of AD patients treated in clinical trials with a high dose of this therapy experienced cerebral edema and microhemorrhages, which limits their dose administration.

Aduhelm was the first potentially disease-modifying drug for AD. But its approval by the FDA was highly controversial and marred by irregularities. The EMA rejected it in December 2021. As Aduhelm does not seem to improve cognitive function, the FDA could still withdraw its approval. Cognitive impairment is related to the release of proinflammatory mediators by glial cells that eliminate synapses and increase neuronal death.

Until now, when scientists tried to reduce inflammation, they also lost some of the effectiveness of the treatment by eliminating less beta-amyloid. KAIST's study for this new drug demonstrates to achieve both goals for the first time, as reported in an article published on August 4, 2022, in Nature Medicine.

Neurotoxicity and inflammation happen when beta-amyloid- or tau-targeting antibodies activate Fc receptors (FCR) in microglia cells or macrophages. To avoid these side effects, researchers had developed antibodies with a weak FCR binding, by using IgG4 or by introducing different mutations. "These attempts have been largely unsuccessful, since a weak FCR binding reduced inflammation but also reduced phagocytic clearance by immune cells," Won-Suk Chung told BioWorld Science. Chung, who co-directed the project, is an associate professor in the Department of Biological Sciences of KAIST.

Chung solved this problem by using the chimeric protein alphaA Beta-Gas6, which is directed to beta-amyloid plaques through its Gas6 subunit, a protein that mediates the phagocytosis of apoptotic cells (efferocytosis) through three phagocytic receptors -- TYRO3, AXL, and MERTK receptors, collectively called TAM. "We worked with TAM phagocytic receptors in the brain in the context of synapse elimination. Gas6-mediated TAM phagocytic receptor activation induces phagocytosis as well as anti-inflammatory responses," Chung explained. "So, we thought, if we engineer this gas6-TAM pathway for beta-amyloid clearance, it would be a perfect therapeutic approach with dual function, phagocytic clearance as well as anti-inflammatory responses."

Chung and his collaborators have thus achieved the activation of microglial and astrocytic phagocytosis, promoting the absorption of beta-amyloid and preserving the synapse without producing neurotoxicity or inflammation. These results outweigh unresolved cognitive impairment in other anti-amyloid treatments, as they have observed in murine models. "We have used two mouse AD models, APP/PS1, as well as 5XFAD. In both AD mice models, we have observed significant cognitive recovery by aAb-Gas6. In fact, better than aducanumab," Chung said. "This could be due to the reduced beta-amyloid plaque without inflammation, the reduced synapse loss, and the reduced microhemorrhage in AD brains treated by aAb-Gas6."

In their study, aducanumab significantly reduced beta-amyloid plaque as well, "but it exacerbated synapse loss as well as microhemorrhage in AD brains, which are common side effects induced by neuroinflammation," Chung concluded.

Advances in AD therapies

According to the Alzheimer's Association, AD affects more than 6 million Americans. By 2050, it could reach 13 million. The National Institute of Aging reports that it is the seventh leading cause of death in the United States. To treat Alzheimer's, there are six FDA-approved drugs, not including those prescribed to relieve behavioral symptoms (anxiety, depression or delusions). While five of them treat cognitive symptoms, only Adulhelm is a purportedly disease-modifying therapy.

Chung's new therapy is a promising fusion protein that could expand this list soon. "We have founded Illimis Therapeutics, based on this strategy of designing chimeric Gas6 fusion proteins. We are aiming to target not only beta-amyloid but also other toxic protein aggregates, such as tau and alpha-synuclein, that have been known to propagate and accumulate in the brain," he said. This team believes that their approach could be a breakthrough in treating various neurodegenerative diseases without causing inflammatory side effects