Unlocking the Regenerative Powers of Antisense Oligonucleotides for Brain Injury Recovery
Dan Lewis Foundation | Fall 2023

The human brain's limited regenerative capacity makes recovery from injury slow and often incomplete. Traumatic and neurodegenerative brain injuries continue to pose significant challenges to medical science. Brain injuries, including traumatic brain injury (TBI) and neurodegenerative conditions like Alzheimer's and Parkinson's disease, often result in neuronal damage, inflammation, and scar tissue formation. Unlike other tissues in the body, the central nervous system (CNS) has limited regenerative capabilities. Neurons in the brain do not readily replicate, and the scarring response inhibits repair. Thus, finding ways to stimulate regeneration in the CNS has been a longstanding challenge. However, recent advances in molecular biology and genetics have opened exciting possibilities to harness antisense oligonucleotides (ASOs) to address brain injuries. As a result, these advances have the potential to create new brain injury treatment options in the foreseeable future. 1,2 ASOs are short, single-stranded nucleic acids that can interact with RNA molecules and block gene expression. They can either promote or inhibit the production of proteins, making them invaluable tools in genetic therapies and drug development. In the context of brain injuries, ASOs can potentially enhance regeneration via several mechanisms:


  • Promoting Neurogenesis: One of the primary strategies for addressing brain injuries is to promote the formation of new neurons. ASOs can be designed to target specific genes that inhibit or regulate neurogenesis, effectively "turning on" these genes to stimulate the growth of new neurons.
  • Reducing Inflammation: Chronic inflammation is a common response to brain injuries and contributes to tissue damage. By silencing pro-inflammatory genes, ASOs can potentially help reduce inflammation and create a more conducive environment for regeneration.
  • Breaking down scar tissue: Scar tissue in the brain can hinder the repair process. ASOs can potentially be tailored to target genes involved in the formation and maintenance of scar tissue, potentially allowing for its breakdown and replacement with healthy tissue.
  • Enhancing axon regrowth: Axons are the long projections of nerve cells that transmit signals. ASOs can potentially be designed to stimulate axon regrowth, which is crucial for re-establishing functional connections in the damaged brain.


While ASOs in brain injury treatment may be promising, some challenges and considerations must be addressed, including:


  • Specificity: ASOs must be highly specific to avoid off-target effects. Unintended gene silencing can lead to adverse consequences and side effects.
  • Delivery: Getting ASOs to the target site in the brain can be challenging due to the blood-brain barrier. Innovative delivery methods, such as nanoparticles or viral vectors, are being explored.
  • Safety: Long-term safety and potential side effects of ASO therapies need extensive evaluation to ensure they do not pose additional risks to the patient.
  • Ethical and Regulatory Issues: Genetic therapies, including ASOs, raise ethical and regulatory questions about potential misuse, consent, and access to these treatments.


The regenerative powers of ASOs for brain injuries have many future applications in medical research. Before long, neurologists may be able to tailor ASO therapies to individual patients based on their genetic profiles and injury characteristics to maximize effectiveness. Combination therapies will be developed to explore the synergistic effects of ASOs with other therapies, such as stem cell treatments or neuroprotective drugs, to enhance regenerative outcomes. Several disorders currently targeted for ASO-based treatments include:¹,³


  • Spinal Muscular Atrophy (SMA): Nusinersen is an ASO that has been approved to treat SMA, a neuromuscular disease.
  • Duchenne Muscular Dystrophy (DMD): ASOs are in development to target specific mutations in the DMD gene, aiming to slow disease progression.
  • Amyotrophic Lateral Sclerosis (ALS): Tofersen is an ASO that is being investigated for their potential to treat ALS by reducing the production of harmful proteins.
  • Huntington's Disease: ASOs are being explored to target the mutant HTT gene responsible for Huntington's disease.
  • Familial Amyloid Polyneuropathy (FAP): Inotersen (Tegsedi) is an ASO approved for treating FAP, a rare genetic disease.
  • Spinal Cerebellar Ataxias: ASOs are under investigation for several types of spinocerebellar ataxias to reduce the levels of disease-causing proteins.


These are just a few examples demonstrating the versatility and promise of this technology in treating a range of conditions.  Unlocking the regenerative powers of ASOs offers a promising avenue for addressing the challenges posed by brain injuries and neurodegenerative diseases. While hurdles remain, the potential to stimulate neurogenesis, reduce inflammation, break down scar tissue, and enhance axon regrowth holds immense promise for improving the lives of millions affected by these conditions. As research advances, ASOs may pave the way for transformative therapies that enable the brain to heal and regenerate, offering hope for a brighter future in brain injury treatment.


The Dan Lewis Foundation for Brain Regeneration Research encourages research partnerships between scientists in academic and business settings to explore the potential of ASOs and small molecule medicines to accelerate brain recovery, particularly in the context of rigorous therapy services and repletion of key populations of CNS cells.

References


  1. Brunet de Courssou, J.-B., Durr, A., Adams, D., Corvol, J.-C. & Mariani, L.-L. Antisense therapies in neurological diseases. Brain 145, 816–831 (2022).
  2. Quemener, A. M. et al. The powerful world of antisense oligonucleotides: From bench to bedside. Wiley Interdiscip. Rev. RNA 11, e1594 (2020).
  3. Van Laar, A. D. & Van Laar, A. V. S. Antisense Oligonucleotide Therapies. PracticalNeurology.com https://practicalneurology.com/articles/2019-sept/antisense-oligonucleotide-therapies.
A gold trophy with a laurel wreath around it.

Announcing the 2025 DLF Prize

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.

Alan’s Story

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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