First-in-class platform for delivery of biotherapeutics across the blood-brain barrier to the central nervous system
The Problem
The blood-brain barrier regulates the entry of molecules into the central nervous system (CNS). While necessary under normal physiology, this creates a significant challenge for drug discovery and therapeutic delivery for the treatment of neurodegenerative diseases such as Alzheimer’s and Parkinson’s and brain cancers such as glioblastoma.
The Solution
SRI Biosciences has developed an unbiased screening platform, DiaCyt, to identify peptides that mediate delivery throughout the CNS without disruption of the blood-brain barrier or destruction of biological cargo. The DiaCyt platform enables the effective delivery of therapeutics to previously unreachable targets.
How it works
The blood-brain barrier is a biological obstacle that regulates entry of both natural and foreign molecules into the CNS, inadvertently creating a significant challenge for drug discovery and therapeutic delivery. Fewer than 5 percent of small-molecules drugs pass through this barrier, and biologic therapies such as antibodies and gene therapies are essentially excluded from reaching the CNS. As a result, patients with many neurological diseases such as Alzheimer’s and Parkinson’s cannot benefit from these cutting-edge therapies.
SRI’s proprietary DiaCyt (Dia: Through and Cyt: Cell), platform technology utilizes high diversity phage-displayed peptide libraries to identify peptide-based delivery agents that can selectively transport molecular cargos into the CNS without physically disrupting the blood-brain barrier. These delivery agents, known as Molecular Transport Systems (MTS), mediate passage into the CNS resulting in delivery to the cerebral spinal fluid (CSF) and through the brain. MTS can be conjugated to a wide variety of therapeutic molecules including monoclonal antibodies, enzymes, nucleic acids for gene therapy, small-molecule therapeutics, and diagnostic and imaging agents.
The identified MTSs can access the CNS via systemic injection but have no affinity for the cell types within the CNS. Therefore, MTSs can be subsequently conjugated to Molecular Guidance Systems (MGS) that rapidly deliver cargo to specific cell types. The MTS-MGS conjugate can access the CNS and then deliver therapeutic cargo into cells within the brain (e.g., neurons and microglia). The DiaCyt platform allows for use of the MTS-MGS conjugate to successfully deliver therapeutics without breakdown of the blood-brain barrier, risk of damage or infection, or destruction of the therapeutic cargo.
Validation
SRI Biosciences has identified three peptidic MTSs as lead candidates, which have undergone preliminary optimization for stability and circulation time. Our research shows that when MTSs are injected intravenously in pre-clinical models, the MTS peptides travel through the blood system. When they reach the target cell, they bind and are then transported across the blood-barrier into the CNS without disrupting the barrier. Transport efficiency has been shown to be enhanced three to 11-fold in the cerebrospinal fluid (CSF) and 10 to 22-fold in the brain.
SRI has identified several MGSs that exhibit both high affinity and specificity for their CNS targeted cell type. MGSs have been optimized for stability and tested in vitro and in vivo when conjugated to the MTS. MTS-MGS conjugates have exhibited CNS cell specific uptake when administered intravenously in vivo, and importantly, successfully deliver cargo without off-target effects or disruption of the blood-brain barrier.
Partner with us
The DiaCyt platform is designed to be combined with a therapeutic “cargo.” SRI is currently looking for commercial partners who are interested in the company’s pipeline of MTS-drug/MTS-MGS-drug candidates and/or have cargo compounds and/or platforms that align well with SRI’s current MTS library. Contact us to learn more.
SRI Biosciences Division President, Kathlynn Brown, provides an in-depth overview of the DiaCyt delivery platform in this Xtalks webinar.
