Emergence of Liver-Targeted Therapy that Bypasses the Blood-Brain Barrier

Existing Alzheimer's disease treatments require drugs to cross the blood-brain barrier (BBB) to reach the brain. Examples include Eisai's Leqembi and Eli Lilly's Kisunla, both monoclonal antibodies, which have a brain penetration rate of less than 0.1%, necessitating high doses and causing side effects such as cerebral edema (ARIA). To address this, researchers at the Army Medical University in China adopted a strategy to deliver therapeutic genes to the liver instead of the brain, removing amyloid-beta (Aβ) from the bloodstream. This approach utilizes the equilibrium between the brain and blood to draw amyloid from the brain into the blood, realizing the 'Amyloid Sink' mechanism.

Discovery and Efficacy of APOE3 Christchurch Gene

The research team focused on the APOE3 Christchurch (APOE3Ch) variant found in patients who, despite having early-onset mutations, remained cognitively intact until their 70s. Using an adeno-associated virus (AAV) vector, they successfully delivered the APOE3Ch gene to the livers of mouse models carrying the APOE4 risk factor. The treated mice showed a significant reduction in amyloid plaques in the brain, as well as a decrease in brain inflammation and abnormal phosphorylation of tau protein. Maze cognitive assessments also revealed improved learning abilities compared to the untreated group, demonstrating a tangible improvement in cognitive function.

Addressing Unmet Needs and Differentiated Market Competitiveness

This preclinical result is considered to have high commercial value in the Alzheimer's treatment market, which is expected to reach approximately $15.19 billion by 2030. Current gene therapy pipelines, such as Lexeo Therapeutics' LX1001, require direct injection into the cerebrospinal fluid, making the procedure difficult and causing significant discomfort. In contrast, liver-targeted therapy is administered intravenously, targeting only the liver, which improves ease of administration and ensures the safety of large-scale AAV vector production. Furthermore, a single administration provides long-term efficacy, offering a significant improvement in patient convenience and cost compared to antibody treatments that require monthly injections.

Challenges for Clinical Entry and Investment Prospects

However, further validation is needed to confirm whether the results of mouse experiments can be replicated in humans. In particular, the circulatory structure of non-human primates differs from that of mice, and the long-term effects of APOE3Ch protein expressed in the liver on systemic lipid metabolism and its potential toxicity need to be demonstrated. Therefore, the research team is preparing for non-human primate (NHP) toxicity studies as the next step, moving towards clinical trial entry. From a venture capital (VC) perspective, although there are initial risks, the platform's versatility and originality make it a suitable candidate for monitoring technology transfer and co-development deals.