DLF Research Review Corner
Dan Lewis Foundation | Fall 2022

The central nervous system consists of more than 80 billion nerve cells (“neurons”). These neurons are networked with each other and connected to other parts of the body by “axons,” the long projection that extends from the neuron to its target tissues. The spinal cord contains both bundles of these axons, carrying information between the brain and the periphery, and relay centers, where signals are analyzed, filtered, and amplified. The brain receives sensory information about the world. It controls the motor activities of the body using signals sent through the long axons, many of which travel in the white matter of the spinal cord. When the spinal cord is damaged or severed, the connections between nerve cells in the brain and their targets in the periphery are disrupted. The nerve fiber that is distal to the injury undergoes degeneration. Even if the nerve cell body attempts to heal by sprouting new fibers, there is no way to carry the message to the target tissue once the distal axon is gone. For many years, the prevailing view was that the nerve’s axon dies much like a flower dies if its stem is severed. The ‘vital juices’ seep out. In recent years, it was realized that this image of damage to distal (or ‘downstream’) axons is wrong. After a cord injury, the distal axon is still nourished and supported by surrounding cells. The axon downstream of an injury degenerates because an active signal is sent to it, causing its breakdown. Some believe this ‘self-destruct’ signal serves the purpose of ‘decluttering’ the spinal cord. Regardless, the process of axonal death after a spinal cord injury makes it much more difficult for the body to reestablish functional connections across the gap in the spinal cord created by the initial injury.


About a decade ago, Dr. Strittmatter and his colleagues identified a group of molecules ordinarily present in the spinal cord that limit the ability of nerve fibers to grow and regenerate. 1 Some of the specific molecules that inhibit neuronal regrowth are called Nogo-A, MAG, and OMgp, and they exert their effects (inhibiting repair) by binding to a specific receptor (NgR1). Dr. Strittmatter and others then set out to find ways to block the effects of these molecules, which inhibit the regrowth and reconnection of axons. His team created a new drug, a molecule (NgR1-FC, also known as AXER-204) that binds to these inhibitory molecules. 2 The new drug acts as a decoy; the inhibitory substances bind to the drug rather than bind to the NgR1 receptor, whose activation is limiting the ability of surviving neurons to sprout axons and reorganize their connections. The new drug has recently been proven safe and effective in animals (including primates) with spinal cord injuries. Importantly, this drug had an effect in animal models long after the initial injury, indicating that the innate capability of neurons to regenerate connections and functions persists long after an injury.


The preclinical data was sufficiently encouraging that the RESET clinical trial was launched in humans. 3 It is anticipated that the results of this trial will be available this year. A similar phase 2 clinical trial is underway in Europe; its results are also anticipated shortly. Positive results in either of these trials would be a true breakthrough in the quest to stimulate brain regeneration. Such results would demonstrate that neurons have an innate ability to self-repair that is normally inhibited but can be reactivated after a severe injury. There is good reason to believe that the same or similar mechanisms that inhibit neuronal recovery in the spinal cord are also active in the brain after a brain injury. 4 The DLF is following this line of research with great interest and enthusiasm. The ability to unlock the innate power of a damaged neuron to regrow and reconnect is one critical step toward brain regeneration and functional recovery after a major brain injury.


References


  1. Schwab, M. E. & Strittmatter, S. M. Nogo limits neural plasticity and recovery from injury. Curr. Opin. Neurobiol.27, 53–60 (2014).
  2. Wang, X. et al. Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury. Brain143, 1697–1713 (2020).
  3. AXER-204 in Participants With Chronic Spinal Cord Injury - Full Text View - ClinicalTrials.Gov. https://clinicaltrials.gov/ct2/show/NCT03989440.
  4. Lindborg, J. A. et al. Optic nerve regeneration screen identifies multiple genes restricting adult neural repair. Cell Rep.34, 108777 (2021).
A man is holding a fish in his hand in front of a lake.

Devon’s Journey – Two Years Post-Accident

By Dan Lewis Foundation • November 6, 2024
After a life-altering accident in October 2022, Devon Guffey’s story is about resilience and determination. His journey has been profiled in the summer 2023 issue of the Making Headway Newsletter: https://www.danlewisfoundation.org/devons-story . Hit by a drunk driver, Devon sustained severe brain and physical injuries, including axonal shearing, a traumatic frontal lobe injury, and facial fractures. Even after contracting meningitis while in a coma, Devon fought hard to survive – and today, his recovery continues to inspire us all. In late 2023, Devon worked as an assistant basketball coach at Blue River Valley, where he had once been a student. His love for sports and dedication to regaining his physical strength returned him to the gym, where his hard work paid off. Devon’s persistence earned him another job at the YMCA, guiding gym members and supporting facility upkeep. Through all the challenges—deafness in one ear, blindness in one eye, and a permanent loss of taste and smell—Devon perseveres. He recently regained his driving license, a significant milestone that symbolizes his increasing independence and cognitive and physical recovery. While each day may not show significant changes, Devon now sees his progress over time. Today, Devon speaks to groups about his journey, the dangers of drunk driving, and finding strength in adversity. His message is clear: recovery is a process, and sometimes, "can't" simply means "can't do it yet ." Every TBI is unique, and Devon’s story powerfully reminds us of the strength that comes from resilience and community. We are grateful to Devon for continuing to share his story and for his role in uplifting others facing difficult paths. His journey is a testament to the fact that we are stronger together. #BrainInjuryAwareness #DevonsJourney #Resilience #EndDrunkDriving #MakingHeadway
A close up of a brain with a lot of cells and a purple background.

Advancing Brain Regeneration Therapies

By Dan Lewis Foundation | Summer 2024 • July 10, 2024
Scientists worldwide are working to find ways to stimulate healing and functional recovery after severe brain injuries. This work is driven by the desperate needs of persons who have suffered brain damage. It is inspired by the knowledge that the information required to create new brain cells, cause these cells to interconnect, and stimulate new learning is contained in our genome. Now that we can readily generate stem cells from adult tissue, we have access to the genomic program that can control all of the intricate details of brain tissue formation. A number of different research themes are being pursued productively. These include: (1) enabling injured neurons to self-repair (“axonal repair”) 1,2 ; (2) replacing damaged tissue by increasing the growth of new neurons (“neurogenesis”) 3-5 ; (3) transplanting new brain cells that are derived from a person’s own stem cells (“autologous cellular repletion”) 6-8 ; (4) stimulating the re-wiring of new or surviving tissue by encouraging the formation of new connections (“synaptogenesis”) 9,10 ; and (5) augmenting the function of a damaged brain by the use of bio-computational prostheses (“brain-computer interfaces”) 11,12 ; We’ve explored these themes in previous newsletters. The goal of stimulating meaningful brain regeneration is now sufficiently plausible that a large-scale, well-funded campaign needs to be funded to bring meaningful new therapies to patients within the foreseeable future. Here, we suggest a high-level outline of the research themes for such a campaign. A ‘moon shot’ program towards brain regeneration would leverage cutting-edge technologies in stem cell research, gene therapy, synaptic plasticity, neuronal repair, and brain-computer interfaces (BCIs) to develop innovative treatments for brain injuries and neurodegenerative diseases. These treatments would target the restoration of lost brain functions and improvement in the quality of life for individuals affected by severe brain injuries. This research agenda aims to catalyze serious discussion about creating a federal program with funding, organizational resources, and expert governance to enable brain regeneration in our lifetimes. Major Themes For a Brain Regeneration “Moon Shot” Program 1: Promote the formation of new neurons 1.1 Stimulate the brain to create new neurons 1.2 Create new neurons from patient-derived induced pluripotent stem cells to be transplanted back into the patient. Create new glial cells to support neurogenesis. 2: Stimulate new synaptic formation 2.1 Develop drugs that enhance synaptic plasticity and promote the formation of new synaptic connections 3: Stimulate self-repair of damaged neurons 3.1 Develop drugs that de-repress neurons and, thereby, enable axonal regrowth 4: Develop brain-computer interfaces (BCIs) for brain-injured patients 4.1: Develop and test BCIs that enable the brain to control behaviors or external devices and, thereby, augment or replace impaired functions. 4.2: Develop and test BCIs that can accelerate the training of remapped brain tissue in persons with brain injuries to optimize functional recovery. 4.3: Combine BCIs with other strategies (e.g., cell repletion, synaptogenesis, and enhanced plasticity) to accelerate adaptation and functional improvement. The proposed research themes can underpin targeted research to stimulate meaningful brain regeneration, offering new hope for patients with brain injuries and neurodegenerative diseases. While the scientific challenges are profound, there has been sufficient progress to justify substantial investment in brain regeneration research. Any such large-scale program will require coordinated collaborations among academic and commercial partners, skillful governance and management, and a shared sense of profound commitment to the goal. The recent pace of advances in cell biology, stem cell technology, bio-computational interfaces, and genomically targeting medicines suggests that large-scale investment will yield meaningful clinical advances toward brain regeneration after injury. With robust funding and skilled leadership, this comprehensive research agenda has a realistic potential to transform scientific breakthroughs into tangible medical therapies, offering hope to millions affected by brain damage.
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