Novel carriers for enhanced oligonucleotide permeability through the blood-brain barrier

Zippin Bio Corporation, Corvallis OR

Investigators

Abstract

ABSTRACT Unmet need: As reported by the World Health Organization, more than 3 billion people worldwide lived with a neurological condition in 2021. The disability, illness, and premature death caused by neurological conditions have increased by 18% since 1990, and the economic burden is $800 billion annually in the United States. The blood-brain barrier (BBB) prevents many molecular formulations that could alleviate these conditions from reaching the nervous system, rendering them ineffective. Oligonucleotide (ON) therapeutics have received FDA approval for several genetic diseases outside the CNS; Unlike treatments that merely mitigate symptoms, ONs can target and reverse the underlying molecular dysfunction. Zippin Bio introduces "ZippinCarriers," a groundbreaking delivery platform designed to transport ONs and other BBB-impenetrable molecules to the brain. ZippinCarriers are ultrasmall nanoparticles (<2nm) that connect a plasma protein transferrin to ON and enable ON CNS transport through a receptor-mediated pathway. A key advantage of ZippinCarriers is high adaptable physicochemical properties, allowing them to accommodate diverse payloads and improve cellular uptake. Unlike the current anti-transferrin receptor ligands used in CNS-targeted ON therapies, ZippinCarriers resist aggregation and offer scalable advantages. Aims and Methods: Our goal in this Phase I project is, to evaluate ZippinCarriers for their ability to deliver phosphorodiamidate morpholino oligomers (PMOs) to the CNS. Our overarching goal is to incorporate ZippinCarriers into PMOs to facilitate BBB passage via transferrin receptors and improve brain penetration and cell uptake. Our specific aims for Phase I are: SA1. Create a library of eight ZippinCarriers with varying sizes, shapes, charges, compositions, and hydrophobicity, then conjugate them to PMO and transferrin, SA2. Screen the ability of eight ZippinCarrier-PMO conjugates to cross the BBB in vitro using three-dimensional (3D)-BBB models in microfluidic systems, SA3. Evaluate the best-performing four conjugates in the brain of C57BL/6 mice. Our metric for Phase I is to find a ZippinCarrier to specifically cross the BBB with consistent data in vitro and in vivo. Success in these areas will set the stage for Phase II, where we will conduct comprehensive efficacy and safety studies in healthy and diseased animal models and optimize a scalable manufacturing process using continuous flow systems at the Corvallis Microfluidics Technology Hub. Innovation and Impact: ZippinCarriers are a breakthrough in brain drug delivery with an ultrasmall size, scalable, specific, and minimally invasive solution. With 70+ years of collective expertise in organic and inorganic chemistry, drug delivery, and entrepreneurship, our platform technology addresses the urgent need for effective CNS delivery of PMOs that opens the door for broader applications in ON therapeutics, potentially reshaping the landscape of treatment for genetic and rare CNS diseases.