ApoE4-Targeted Theraputics That Increase SIRT1
SUMMARY
UCLA researchers have identified Alaproclate (A03) as a promising drug candidate to treat Mild Cognition Impairment (MCI) and Alzheimer’s disease (AD) through inhibition of the ApoE4 neurotoxicity.
BACKGROUND
Alzheimer’s disease (AD) is a neurodegenerative disease whose cause is largely unknown. None of the medications available today slows or stops the progressive neuronal death. The 6 drugs approved by U.S. FDA only temporarily improve symptoms. Mild cognitive impairment (MCI) causes a slight but noticeable and measurable decline in cognitive abilities, including memory and thinking skills. A person with MCI is at an increased risk of developing Alzheimer's or another dementia.
About 70% of the AD populations have a copy of the ApoE4 allele. An important pathological feature of AD is aggregation of Aβ in the brain. Aβ is generated from β-amyloid precursor protein (APP) through sequential cleavages. Alternatively, APP can be cleaved within the Aβ domain to release sAPPα and preclude Aβ generation. Activation of SirT1 results in a shift of APP processing in favor of the anti-AD peptide sAPPα. ApoE4 cause decreased SirT1 level and increased pro-AD cleavage. Currently there are no drugs targeting the ApoE4 risk factor in AD. Current therapies provide symptomatic relief but do not affect risk for onset of the disease or modify disease progression.
Alaproclate (A03) was developed by AstraZeneca as a selective serotonin reuptake inhibitor (SSRI). However, it was never marketed because of rodent liver toxicity. Clinical testing phase I studies of A03 in dementia patients reported in 1983 shows no adverse effect with up to 200 mgs bid.
INNOVATION
UCLA researchers have identified A03 as a promising drug candidate to treat MCI and AD patients with ApoE4 risk factor. A03 inhibits the neurotoxic effects of ApoE4 by increasing the level of the mediator SirT1, whose activation shifts APP processing to anti-AD cleavage. A03 might also stimulate other protective responses and mitigate AD pathology, since SirT1 is reported to activate antioxidant response, anti-inflammatory response and anti-apoptosis response.
APPLICATIONS
- The principal application of this invention is to treat MCI and AD patients with ApoE4 risk factor.
- A03 enhances SirT1, which is a mediator that has been known to be involved in longevity. Thus, A03 could also be a longevity drug.
ADVANTAGES
- This is the first study to show that A03 can reverse the decrease in SirT1 induced by ApoE4.
- A03 is highly brain permeable.
- A03 has already been tested in human at high dose (200 mgs bid) for up to 4 weeks and found to be non-toxic, which provides a rapid path to the clinic for A03 if it shows efficacy in AD mouse models.