Albumin hitchhiking siRNAs for gene targeting in aged brain

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A current hurdle for the treatment of Alzheimer’s disease (AD) is administration of efficacious doses of biological drugs in the brain. The strongest risk factor for AD is aging, which coincides with progressive dysfunction of the blood-brain barrier (BBB) leading to entry and retention of serum proteins that are normally excluded from healthy brain. One of these proteins is albumin, which is not detected in young brain tissue but gradually accumulates in the brain with age. Here, we propose to a novel strategy for treating AD that will leverage albumin as a “natural” carrier to enhance siRNA-mediated gene targeting in the aged brain. We hypothesize that “hitchhiking” siRNA onto albumin will improve siRNA accumulation and gene silencing activity in the aged brain after intravenous administration, thereby providing a customizable strategy to target genes associated with AD. This approach is facilitated by a novel diacyl fatty acid carrier developed in our lab (“EG18”) that can be directly conjugated to siRNA (“siRNA-EG18”). We have relevant preliminary data showing that: 1) siRNA-EG18 has enhanced affinity and specificity for albumin and increased circulation half-life relative to our previously published siRNA-L2 carrier; 2) siRNA-EG18 exerts sustained gene knockdown in a mouse model of osteoarthritis that leads to albumin accumulation in the inflamed knee joint; 3) siRNA-EG18 accumulates in the brains of old but not young mice 24 hours after intravenous delivery of a modest 1 mg/kg dose. Aim 1 of this proposal will build on these results by examining the pharmacokinetics, biodistribution, and toxicity of siRNA-EG18 as a function of age and dosing scheme. Aim 2 will examine the bioactivity of siRNA-EG18 in the aged brain, with a focus on targeting APOE, the strongest known genetic risk factor for AD. Collectively, this proposal will establish working parameters for achieving gene silencing in the aged brain via albumin hitchhiking of siRNA, thereby providing new opportunities for personalized medicine in AD.