Intranasal Nanoparticle Drug Delivery to Promote Functional Recovery in Multiple Sclerosis

New therapeutic approach to improve the recovery of movement in multiple sclerosis: We propose to develop a novel therapeutic approach in line with the FY21 MSRP Focus Area CNS Regenerative Potential in Demyelinating Conditions. MS is caused by destruction of the fatty insulation called myelin that surrounds the axons of nerve cells in the central nervous system (CNS). Axons are slender processes that act like telephone cables that join excitable nerve cells, called neurons, into circuits responsible for sensation, reasoning, memory, and movement. Just like the rubber insulation around telephone cables in a saltwater ocean, myelin is required to increase the speed and efficiency by which axons conduct electrical signals in the CNS. Myelin loss in the spinal cord disrupts communication between neurons that control movement resulting in walking deficits or, in extreme cases, paralysis of the legs. Recovery of movement in MS is thought to require the regrowth of myelin-producing cells called oligodendrocytes that remyelinate axons. The lack of treatments that promote motor recovery in MS has fueled an intense search for drugs that stimulate remyelination. With this goal in mind, we have identified a new drug called IRX4204 that activates retinoid X receptors in the CNS that stimulate remyelination. Mice subjected to experimental autoimmune encephalomyelitis (EAE) suffer myelin loss and axon damage in the spinal cord. We have shown that this causes impaired leg movements while EAE mice walk resembling those seen in MS patients. Previous funding from the CDMRP (Award Number: W81XWH-19-1-0579) has enabled us to demonstrate that injections of IRX4204 reduce these gait deficits in EAE mice by increasing remyelination in the spinal cord. However, IRX4204 suffers from a weak ability to enter the CNS and adverse side-effects caused by actions on cells outside of the brain and spinal cord. To overcome these limitations, we propose to load IRX4204 into nanoparticles that are designed to preferentially deliver IRX4204 to damaged tissues in the spinal cord after being taken through the nose (intranasal administration). Development of an intranasal nanoparticle formulation of IRX4204: Nanoparticles (NPs), typically 100 nm or less in diameter, loaded with a drug, have been approved as therapeutics for over 15 years, but only for non-neurological indications. Intranasal delivery of NP formulations (NPFs) designed to improve drug entry in the CNS and minimize exposure in healthy parts of the body holds unprecedented opportunities to treat many neurodegenerative disorders safely and effectively. To this end, we propose to develop an intranasal NPF of IRX4204 that enhances the safety and effectiveness of this promising drug for MS. Compared to other routes of drug administration, intranasal drug delivery has several advantages: (1) unlike injecting a drug with a hypodermic needle, intranasal delivery produced by spraying a drug into the nose is painless and easy to perform by the patient. This means that the patient is more likely to keep taking the medication as required; (2) unlike a drug that is injected into the body or taken by mouth, intranasally delivered drugs have direct access to the brain and spinal cord. This improves the effectiveness of a drug that otherwise has difficulty reaching therapeutic levels in the CNS; and (3) intranasal delivery reduces the risk of adverse side-effects by minimizing the amount of drug that reaches cells outside of the CNS. To further increase the safety and effectiveness of the IRX4204-NPF, the surface of this NPF will be coated with a small peptide that preferentially targets damaged tissues in the spinal cord. We predict that intranasal administration of this IRX4204-NPF will safely improve motor recovery in EAE mice by stimulating remyelination in the spinal cord. These predicted outcomes would encourage the therapeutic development of our IRX4204-NPF for the treatment of MS.