Back to Invention List
#6 - A novel drug delivery method for treatment of brain injury and disease - focusing on Central Nervous System (CNS) disorders, such as stroke, hemorrhage, or TBI
Long Title: Diffusion through the Scalp/Skull as a Route of Delivery for Treatment of Brain Injury and other Diseases
NIH Reference No. E-025-2012
Executive summary
General Description:
Majority of CNS disorders are very difficult to treat due to the limited capacity of available drugs to permeate the blood-brain barrier (BBB) and achieve a high local concentration. Drug administration via the periphery can also have undesirable off-target effects on non-CNS tissues. This makes it difficult to control CNS damage or limit inflammation in acute cases of brain injury, including Traumatic Brain Injury (TBI). TBI often results from head impact and is a major cause of death and disability. The details of cellular responses to the traumatic injury are not clearly understood, and a majority of symptoms can be associated with hemorrhaging, swelling, inflammation, and death of the brain tissue. Currently there are no effective treatments for TBI, and the use of neuroprotective agents is limited by the ability of those molecules to reach a therapeutic concentration in the brain. Many compounds, including immunosuppressants, which are proposed to be effective treatments, cannot effectively cross the BBB. This discovery provides a method to deliver these proposed treatments at effective doses through a bypass of the BBB.
Scientific progress:
Inventors at NINDS developed a novel approach to treating brain injuries that involves transcranial application of small molecules. This novel method involves the direct application of compounds of varying sizes (600 to 40,000 MW) to the skull over the site of injury or inflammation, allowing for their free diffusion through the bone and penetration of the brain cavity. This technology of transcranial drug application can be used to pharmacologically target several tiers of brain injury responses, from the toxic mediators that cause cell death to the molecular signals that drive inflammation. Treatment using this technology involves direct application of the drug to the skull via a targeted delivery method. There are many proposed devices and methods which can be developed for such a targeted delivery.
The inventors discovered, using two photon laser scanning microscopy, that dextran molecules as small as 600 molecular weight (MW) and as large as 40,000 molecular weight (MW), but not 70,000 MW, can pass directly through the intact skull into the underlying cerebral spinal fluid (CSF) that circulates through the brain and spinal cord as quickly as 10 minutes. Moreover, they showed that application of a variety of agents, including glutathione (ROS scavenger), TNP-ATP hydrase (P2X4 inhibitor), oxidated ATP (P2X7 inhibitor), MRS2578 (P2Y6 inhibitor), MeSAMP (P2Y12 inhibitor) and Carbenoxelone (Connexin Hemichannel Inhibitor), when applied directly to the mouse skull, was able to modulate immune response and ameliorate brain injury symptoms, particularly the secondary damage. The inventors have also demonstrated that transcranial delivery can be achieved in pigs, which have a skull bone comparable in thickness to a human’s.
Future directions at NINDS
Future directions for a Commercial Party
Opportunity
Strengths
Weakness
Patent Status
PCT (PCT/US13/24741) application filed February 5, 2013
Publication
Roth TL, et al., Nature. 2014 Jan 9;505 (7482):223-8. (PMID: 24317693)
Lead Inventor Bio
Dorian McGavern, Ph.D.
Dr. McGavern received his B.S degree in microbiology from The Pennsylvania State University and his Ph.D. in molecular neuroscience from the Mayo Clinic. Following an academic appointment as an Associate Professor in the Department of Immunology and Microbial Sciences at The Scripps Research Institute, Dr. McGavern joined the NINDS in March 2009. Dr. McGavern is the recipient of the prestigious Ray Thomas Edwards Foundation Award and the Burroughs Wellcome Fund Pathogenesis of Infectious Disease Award. His laboratory at the NIH is focused on states of acute and persistent infection (virus, parasites, fungi) of the CNS as well as how this specialized compartment responds to traumatic injuries. As Chief of the Viral Immunology and Intravital Imaging Section, Dr. McGavern uses advanced real-time imaging techniques to gain novel mechanistic insights into how the living brain generates inflammatory reactions to sterile and infectious challenges.
NIH Reference No. E-025-2012
Executive summary
- Invention Type: Therapeutic and Method
- Patent Status: US Application No. 61/599,107, PCT Application No. PCT/US13/24741, PCT application filed February 5, 2013
- LINK: http://goo.gl/ee3Kyl
- NIH Reference Number: E-025-2012
- NIH Institute or Center: National Institute of Neurological Disorders and Stroke (NINDS)
- Disease focus: Central Nervous System (CNS) disorders, such as stroke or Traumatic Brain Injury (TBI)
- Basis of invention: Method for direct transcranial delivery of small molecule drugs to the central nervous system (CNS) bypassing the blood brain barrier (BBB)
- Development of Invention: A device needs to be developed to control the diffusion of active reagents (small molecules) through the scalp and/or skull for treatment of TBI, inflammation, concussions, and various CNS disorders
- Lead Inventor(s): Dorian McGavern (NINDS)
- Development Stage: Preclinical, in vivo rodent model data obtained testing the transcranial therapeutics
- Novelty: Current therapies to treat TBI are limited by the ability to achieve therapeutic concentrations of therapeutic agent in the brain. Transcranial delivery allows for targeted application of small molecule drugs with sizes up to 40,000 MW.
- Clinical Application: Treatment of Traumatic Brain Injury, strokes, concussions, acute CNS conditions such as encephalitis and meningitis, and chronic CNS disorders, such as brain tumors, Alzheimer’s, Parkinson’s, and multiple sclerosis
General Description:
Majority of CNS disorders are very difficult to treat due to the limited capacity of available drugs to permeate the blood-brain barrier (BBB) and achieve a high local concentration. Drug administration via the periphery can also have undesirable off-target effects on non-CNS tissues. This makes it difficult to control CNS damage or limit inflammation in acute cases of brain injury, including Traumatic Brain Injury (TBI). TBI often results from head impact and is a major cause of death and disability. The details of cellular responses to the traumatic injury are not clearly understood, and a majority of symptoms can be associated with hemorrhaging, swelling, inflammation, and death of the brain tissue. Currently there are no effective treatments for TBI, and the use of neuroprotective agents is limited by the ability of those molecules to reach a therapeutic concentration in the brain. Many compounds, including immunosuppressants, which are proposed to be effective treatments, cannot effectively cross the BBB. This discovery provides a method to deliver these proposed treatments at effective doses through a bypass of the BBB.
Scientific progress:
Inventors at NINDS developed a novel approach to treating brain injuries that involves transcranial application of small molecules. This novel method involves the direct application of compounds of varying sizes (600 to 40,000 MW) to the skull over the site of injury or inflammation, allowing for their free diffusion through the bone and penetration of the brain cavity. This technology of transcranial drug application can be used to pharmacologically target several tiers of brain injury responses, from the toxic mediators that cause cell death to the molecular signals that drive inflammation. Treatment using this technology involves direct application of the drug to the skull via a targeted delivery method. There are many proposed devices and methods which can be developed for such a targeted delivery.
The inventors discovered, using two photon laser scanning microscopy, that dextran molecules as small as 600 molecular weight (MW) and as large as 40,000 molecular weight (MW), but not 70,000 MW, can pass directly through the intact skull into the underlying cerebral spinal fluid (CSF) that circulates through the brain and spinal cord as quickly as 10 minutes. Moreover, they showed that application of a variety of agents, including glutathione (ROS scavenger), TNP-ATP hydrase (P2X4 inhibitor), oxidated ATP (P2X7 inhibitor), MRS2578 (P2Y6 inhibitor), MeSAMP (P2Y12 inhibitor) and Carbenoxelone (Connexin Hemichannel Inhibitor), when applied directly to the mouse skull, was able to modulate immune response and ameliorate brain injury symptoms, particularly the secondary damage. The inventors have also demonstrated that transcranial delivery can be achieved in pigs, which have a skull bone comparable in thickness to a human’s.
Future directions at NINDS
- Screen different active agents for different efficacy during different types of brain injury
- Define the mechanisms underlying the cellular response to brain injury and test compounds known to affect the identified pathways
- Test the technology for treating injuries also involving the spine
- Perform preclinical transcranial delivery studies in multiple species with brain injury
Future directions for a Commercial Party
- Develop specialized devices/methods for delivery through the scalp/skull
Opportunity
- The route of transcranial administration is potentially applicable to drugs failed in the development stage due to poor BBB penetration.
- Emergency care of soldiers for brain injury in battle filed (DOD interest)
- Emergency treatment of concussions (NFL and sports medicine interest)
- Veterinary medicine
Strengths
- Quickly achieves a high local drug concentration at the site of brain injury
- Bypasses the blood brain barrier and allows for rapid administration of therapeutic agents directly to the site of injured or inflamed brain
- Reduces the off-target side effects associated with peripheral drug administration
- Validated in several compounds for brain delivery in animal models
Weakness
- Current pilot animal study for compression injury used 3-4 mice per group. Need to validate the effect of compound delivery in large scale animal experiments
- Limited to delivery of compounds no larger than 40,000 MW
Patent Status
PCT (PCT/US13/24741) application filed February 5, 2013
Publication
Roth TL, et al., Nature. 2014 Jan 9;505 (7482):223-8. (PMID: 24317693)
Lead Inventor Bio
Dorian McGavern, Ph.D.
Dr. McGavern received his B.S degree in microbiology from The Pennsylvania State University and his Ph.D. in molecular neuroscience from the Mayo Clinic. Following an academic appointment as an Associate Professor in the Department of Immunology and Microbial Sciences at The Scripps Research Institute, Dr. McGavern joined the NINDS in March 2009. Dr. McGavern is the recipient of the prestigious Ray Thomas Edwards Foundation Award and the Burroughs Wellcome Fund Pathogenesis of Infectious Disease Award. His laboratory at the NIH is focused on states of acute and persistent infection (virus, parasites, fungi) of the CNS as well as how this specialized compartment responds to traumatic injuries. As Chief of the Viral Immunology and Intravital Imaging Section, Dr. McGavern uses advanced real-time imaging techniques to gain novel mechanistic insights into how the living brain generates inflammatory reactions to sterile and infectious challenges.