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 gold trophy with a laurel wreath around it.
By Dan Lewis Foundation April 2, 2025
For the third consecutive year, the Dan Lewis Foundation for Brain Regeneration is proud to announce the DLF Prize competition. The 2025 DLF Prize, a $20,000 award, will recognize an outstanding early career scientist (2 to 5 years post-doc) conducting innovative research in neuroscience, pharmacology, or biotechnology. This prestigious prize honors researchers whose work aligns with the DLF mission to drive breakthroughs in neural regeneration and repair. The current research priorities of the DLF are: Pharmacological Reactivation of Neural Repair: Research into pharmacological methods of reactivating or augmenting synaptogenesis, neurogenesis or axonal repair. Cell-Based Cortical Repair: Investigating the potential of derived cortical neurons to restore function in damaged cortical regions. Transcriptomics of Neural Recovery: Characterizing transcriptomic profiles of cortical neurons in the recovery phase following brain injury to identify pathways that drive repair. Molecular Inhibitor Targeting: Advancing anti-sense oligonucleotides (ASO’s) or small-molecule therapeutics designed to downregulate inhibitors of neural regeneration in the cortex or spinal cord. Application for the 2025 DLF Prize can be made by going to our website— danlewisfoundation.org —and clicking on the Tab “ 2025 DLF Prize ”. This will bring you into the application portal. The application portal opened in March, 2025 and will remain open through May 31st. Once in the portal, you will find complete information about the DLF prize, eligibility requirements, and an application form which can be filled in and submitted online. The winner of the 2023 DLF Prize, Dr. Roy Maimon, continues his research indicating that downregulation of PTBP1, an RNA-binding protein, can convert glial cells into neurons in the adult brain (Maimon et al. 2024) .* Dr. Maimon, currently a post-doc at the University of California, San Diego is currently interviewing for a faculty position at several prominent neuroscience departments. The winner of the 2024 DLF Prize, Dr. William Zeiger is a physician-scientist in the Department of Neurology, Movement Disorders Division, at UCLA. Dr. Zeiger has expertise in interrogating neural circuits using a classic “lesional neurology” approach. He states, “Our lab remains focused on understanding how neural circuits become dysfunctional after lesions to the cortex and on investigating novel circuit-based approaches to reactivate and restore damaged cortex”. * Maimon, Roy, Carlos Chillon-Marinas, Sonia Vazquez-Sanchez, Colin Kern, Kresna Jenie, Kseniya Malukhina, Stephen Moore, et al. 2024. “Re-Activation of Neurogenic Niches in Aging Brain.” BioRxiv. https://doi.org/10.1101/2024.01.27.575940.
By Dan Lewis Foundation April 2, 2025
Alan was injured in 2021, at age 42. An art teacher in Lakewood, Colorado, Alan was riding his bicycle after school and was crossing at an intersection when a truck turned into the crosswalk area and hit him. Alan reports no memory of the event but has been told this is what happened. Alan says “My frontal lobe took the brunt of the impact, particularly the left frontal lobe”. Alan had a 2 ½ week stay at a nearby hospital where he, “re-learned to talk, to walk, and drink”-- although again he reports no memory of his stay there. Alan was then transferred to Craig Rehabilitation Hospital, in Englewood, Colorado. Alan says, “The only reason I knew I was at Craig is that I rolled over in bed and saw “Welcome to Craig” on the dry erase board.” During this stage of recovering, Alan repeatedly denied that he had been in an accident. Twice he tried to leave Craig on his own accord despite his wife’s and his therapists’ assurances that it was important for him to stay to recuperate from his injuries. Alan’s wife was 8 months pregnant at the time of his accident and gave birth to their son while Alan was an inpatient at Craig. Alan’s wife brought his newborn son to visit him days after the birth and Alan held him while sitting in his wheelchair, but Alan wistfully reports this is another thing he can’t remember. Alan reports that he still has significant difficulties with memory. Alan has also experienced several other neuropsychological difficulties. He states that for months after his injury, he could not experience emotion. “I could not laugh, I couldn’t cry.” Even after three years, his emotional experience is constricted. However, an emotion that is sometimes elevated is irritation and anger. Sometimes, dealing with people can be difficult because he may have temper flare-ups with little reason. This is something that Alan regrets and he is working hard with his neuropsychologist to improve the regulation of his emotions. Alan also has difficulty with organization, motivation, and distractibility. Earlier in his recovery, he had trouble sequencing and had difficulty carrying out personal and household routines. Alan has benefited greatly from therapy and his own hard work to make improvements in these areas. A chief reason that Alan works so hard in his recovery is so that he can be a good father to his son who is now almost 3 years old. He recognizes that it is important not to get frustrated when it seems that he can’t provide what his son wants or needs at a given moment. “I’m trying to raise my son the best I can…he’s at such a pivotal time in his life.” Alan’s financial situation was helped for a time by Social Security Disability Insurance payments but these payments ended. He is trying to get SSDI reinstated but the process of doing so is confusing and is taking a lot of time. Alan returned to work about 11 months ago at a liquor store (after about 2 years of not being able to work), the same store where he previously worked part time while teaching. He works in the wine department. “I sell wine and make recommendations.” When asked for advice to other brain injury survivors, Alan’s words were: “No matter how confused or upset you are or how frustrated you get, keep pressing on and moving forward because there is light at the end of the tunnel even though it may seem long. Keep moving forward and don’t give up no matter what anyone says to you”. Alan added that supports for individuals with brain injury are very important. He has found support groups, retreats, and seminars/events where brain injury survivors can share their experience to be very helpful. The volunteer work he does at Craig Hospital has been valuable for him. Alan is an inspiring individual. Despite having scarce memory of his accident and some confusion about the functional losses he has experienced, Alan has worked hard to make his recovery as complete as possible. He continues to work hard to progress and to express gratitude for those who have assisted him along the way.