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.

DLF Science Advisory Board Spotlight

By Dan Lewis Foundation | Spring 2024 • 11 Apr, 2024
Graham Dempsey, Ph.D., is a founder and Chief Scientific Officer (CSO) at Quiver Bioscience, a Cambridge, Massachusetts-based biotechnology company focused on the development of medicines for disorders of the nervous system. Dr. Dempsey and his team are working to develop treatments for some of the most challenging unsolved medical issues patients and their families face. Using advanced technologies in human stem cell biology, optogenetics, machine learning, and drug screening, progress is being made to develop medicines that will one-day treat conditions that have been largely untreatable. As the lead scientist for Quiver, formerly Q-State Biosciences, Dr. Dempsey enjoys working with world-class teams to invent, develop, and apply cutting-edge technologies to solve the most difficult challenges in biopharma for the betterment of patients. Dr. Dempsey’s inspiration to dedicate his professional life to science and medicine started at the early age of seven with the tragic loss of his father to an aggressive form of cancer, an experience that has deeply motivated him to this day. He completed his undergraduate studies at the University of Pennsylvania and his doctorate at Harvard University. As a graduate student in the biophysics program at Harvard Medical School, he co-developed ‘Stochastic Optical Reconstruction Microscopy’ or STORM , a light microscope with the ability to resolve nanometer (billionth of a meter, e.g. a hair is 100,000 nanometers thick) scale details of biological materials, an achievement that had been thought to be impossible for over a century. STORM has enabled what researchers call ‘super-resolution imaging’ for visualizing the intricate details of life’s most fundamental unit, the cell. Understanding the inner workings of a cell provides a path to a deeper understanding of the ways in which life is constructed and diseases can manifest. The technology was commercialized by Nikon Instruments for researchers worldwide. Dr. Dempsey left academic science to join Q-State Biosciences as the first hired employee with the goal of bringing advanced technologies developed at Harvard to the study of the brain. The brain, arguably the most complex structure in the known universe, works through electrical communication between brain cells or neurons. This communication is disrupted in all brain disorders but has been near impossible to study for the purposes of effectively developing medicines. Dr. Dempsey and his team over the course of ten years built a technology system that creates human brain models from patient stem cells (i.e. a ‘disease-in-a-dish’) and converts electrical activity of those brain cells into light signals that can be detected with ultra-sensitive microscopes. The resulting signals are analyzed using machine learning to find the patterns of how electrical activity is altered in disease, which can be used to find medicines that correct those changes. The team at Quiver is deploying this technology to take on previously untreatable brain conditions, including rare genetic diseases, such as certain seizure and neurodevelopmental disorders, to common conditions, such as chronic pain and Alzheimer’s disease. Dr. Dempsey’s passion outside of science starts with his family, his wife (and high school sweetheart) and three young daughters, be it traveling the globe to experience new cultures (or simply stare at the ocean), cooking elaborate meals on a Saturday evening, night-time reading of novels to his daughters, or attending live music around Boston. As a native of NJ, he celebrates his roots with visits to family near the Jersey Shore and, whenever possible, attendance at Springsteen concerts and Giants games. Dr. Dempsey is an avid student of history’s great entrepreneurs, spending the sparse remaining minutes of the day reading biographies and listening to podcasts, looking to extract every bit of learning towards taking on the challenges of building a great business while staying true to his family, his Quiver teammates, and his professional mission.

Sheryl’s Story

By Dan Lewis Foundation | Spring 2024 • 11 Apr, 2024
Sheryl Suzanne Nibbs, a legal secretary in a top law firm, started the process of becoming a paralegal as she approached her 40th birthday. She was fancy in her appearance, always making sure her hair, nails, and clothing were in order, a well-kept person, an avid traveler, and her mother’s best friend.
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