Drug Development

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Alzheimer's Disease (AD) is characterized by amyloid beta (A𝛣) and phosphorylated tau (p-Tau) accumulation.
• Current A𝛣-targeting antibodies have limitations, including brain swelling and failure to reduce p-Tau.
• Oligonucleotide therapeutics show promise, with siRNAs reducing A𝛣 and ASOs reducing p-Tau.

Purpose of the Study:

• To develop a novel therapeutic approach for Alzheimer's Disease (AD).
• To create multi-targeting siRNAs, termed COSMOs, capable of simultaneously reducing both A𝛣 and p-Tau.
• To evaluate the efficacy and safety of COSMOs in vitro.

Main Methods:

• Design, synthesis, and screening of siRNAs targeting amyloid precursor protein (APP) and microtubule-associated protein tau (MAPT).
• Transfection of human SK-N-AS cells with COSMOs and individual siRNAs.
• Quantification of mRNA and protein levels of APP, Tau, A𝛣42, and p-Tau181 using qPCR and ELISA.
• Assessment of cellular viability and COSMO cleavability.

Main Results:

• Top siRNAs and COSMOs demonstrated activity at picomolar concentrations.
• Co-transfection and COSMO transfection simultaneously reduced A𝛣 and p-Tau levels.
• APP- and MAPT-targeting COSMOs exhibited lower toxicity than individual siRNAs.
• COSMOs can be engineered for tunable cleavability.

Conclusions:

• No current AD therapeutics effectively reduce both A𝛣 and p-Tau.
• COSMOs represent a promising new class of therapeutics for AD.
• COSMOs have the potential to simultaneously target key pathologies in Alzheimer's Disease.