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 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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