Unlocking the Brain’s Regenerative Potential: The Future of Repairing the Injured Brain
David Margulies, M.D.

Introduction: The Paradigm Shift in Brain Regeneration

For decades, scientists believed that the adult brain was incapable of meaningful regeneration. Unlike skin or muscle, the central nervous system (CNS) appeared to lack the ability to repair itself after injury, and lost neurons were considered irreplaceable. However, cutting-edge research now demonstrates that this is no longer the case. The brain possesses dormant repair mechanisms—pathways that were active during development but have been shut down in adulthood. By reactivating these pathways, it may be possible to induce neurogenesis (the birth of new neurons), axonal repair, and synaptogenesis (the formation of new neuronal connections) after devastating injuries like stroke, traumatic brain injury, and spinal cord damage.


A growing body of evidence from both the spinal cord and the central nervous system (the CNS) shows that regeneration can be stimulated by downregulating the repressing factors that prevent neuron growth and repair. For clarity, “downregulation” means reducing the activity or number of something. In the case of a repressing factor, downregulation means lowering its levels or making it less active. A repressor is a protein that blocks a process—often by preventing a gene from being turned on. When the repressor is downregulated, it no longer effectively blocks that process, allowing the underlying function to be released or activated.


These advances open the door to new treatments that could restore function to patients with neurological injuries, potentially reversing what were once thought to be permanent disabilities.


The Science Behind Reactivating Brain Repair

Neurodevelopmental genes and pathways that promote neuronal growth and plasticity are switched off after early development. However, researchers have identified key molecular regulators that act as “brakes” on brain regeneration. The “brakes” act as repressors of brain regeneration. By inhibiting these repressors, the brain’s intrinsic ability to regrow neurons and axons can be reactivated.


Recent breakthroughs include:


  1. Neurogenesis in the Adult Brain: Research has shown that downregulation of PTBP1, an RNA-binding protein, can convert glial cells into neurons in the adult brain. Studies using antisense oligonucleotide (ASO) therapy to transiently suppress PTBP1 have successfully induced the formation of functional neurons in mouse models of neurodegeneration. For clarity, an antisense oligonucleotide (ASO) is a short strand of DNA or RNA designed to bind to a specific mRNA and regulate gene expression. By binding to its target,  an ASO can block protein production, modify splicing, or mark the mRNA for destruction, effectively acting as a precise “off switch” for genes. In this context ASOs can be used to release glial cells to develop into functional neurons. Work is now underway to create ASOs that can be safely administered to humans, thereby stimulating the creation of new neurons.
  2. Axonal Regeneration in the CNS:  Another major discovery involves unlocking nerve fiber regrowth by downregulating specific nerve growth inhibition, which prevents nerve fiber regrowth. Studies have demonstrated that suppressing these inhibitors leads to long-distance axonal regeneration, restoring function in spinal cord injury models.
  3. Synaptic Repair in Neurodegenerative Disease: Scientists have shown that modulating key synaptic receptors—such as mGluR5—can restore lost synaptic connectivity, improving brain network function in neurodegenerative diseases like Alzheimer’s. The neuronal connections and circuits in the brain are maintained in a stable state by the balanced action of different synaptic receptors. By modifying this balance, the rate of brain synapse formation can be increased or decreased.


Together, these findings confirm that neural repair is possible when the appropriate repressive factors are removed, unlocking the brain’s natural regenerative capacity.


Quiver’s Scalable Human Neuronal Platform: Accelerating Discovery

While these discoveries are promising, translating them into effective therapies requires precise, scalable, and high-throughput screening technologies that can screen out or discover biomolecules that address a specific biomedical target by the thousands with great rapidity. One such technology has been developed by Quiver Biosciences using an all-optical electrophysiology platform. (Note: the author of this article is a co-founder of Quiver Biosciences)


Quiver has developed a human induced pluripotent stem cell (hIPSC)-derived neuronal platform that allows researchers to measure functional activity in human neurons at an unprecedented scale. This platform is uniquely capable of:


  • Directly measuring neuronal excitability, synaptic transmission, and network connectivity using optogenetics and advanced imaging techniques.
  • Screening for new factors that inhibit brain repair, helping scientists identify additional repressors that need to be targeted.
  • Evaluating small molecules and ASO-based therapies that may upregulate brain regeneration, assessing their efficacy and toxicity before advancing to clinical trials.


The potential of this platform is vast. Scientists can now systematically search for drugs that mimic the effects of PTBP1 suppression, Nogo-A blockade, or mGluR5modulation—treatments that could one day be used to regrow neurons, reconnect severed axons, and restore lost synapses in patients with brain injuries.


Key advantages of Quiver’s platform include:


  • Scalability: Unlike traditional animal models, this system enables high- throughput drug screening on human neurons, increasing the efficiency of therapeutic discovery.
  • Relevance: Because the neurons are derived from human stem cells, they offer a more accurate model of human brain function and disease than animal-based approaches.
  • Safety Screening: The platform allows for early identification of toxic effects, ensuring that only the safest and most effective compounds move forward in development.


By integrating AI and machine learning, Quiver’s platform also enables pattern recognition of successful drug candidates, identifying compounds with optimal efficacy and minimal side effects.


The Role of Philanthropy: Funding the Future of Brain Repair

Scientific breakthroughs alone are not enough to bring regenerative therapies to patients. Translational research—the process of developing basic discoveries into real-world treatments—is slow, expensive, and underfunded. This is where philanthropic support can make an immediate impact.


Many of the pioneering studies on brain regeneration were initially considered too risky or unconventional for traditional funding sources. Yet, thanks to early philanthropic investments, these ideas have now been validated and are shaping the next generation of treatments. Today, funding is urgently needed to:


  1. Expand screening for regeneration-promoting drugs 
  2. Optimize ASO-based approaches for inducing neurogenesis and axonal repair.
  3. Accelerate clinical trials for promising regenerative therapies.


A New Era for Brain Regeneration

For the first time, we have the tools to reactivate the brain’s own repair mechanisms, offering hope for individuals with severe neurological injuries. The path forward is clear: by investing in innovative research, scaling up discovery efforts, and supporting translational studies, we can bring brain-regenerating therapies to patients faster.


The DLF raises funds and uses them to inspire, catalyze, and accelerate work towards brain regeneration. We increase public awareness of possibilities in brain regeneration through our social media, news “blasts”, and quarterly newsletter. And, we promote neuroscientific advances through consultation, networking, conferences, and seed grants. This is especially important when federal funding is limited. By supporting this work, we can help transform groundbreaking scientific insights into real treatments that restore lost function and improve lives.

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.
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