Annotated Reading List and References on CNS Regeneration Research
Dan Lewis Foundation

Overview of TBI What is TBI?

  1. Basic acute-phase physiology
  2. Chronic-phase physiology and natural history


Traumatic brain injuries are common, often devastating, and, for many, poorly responsive to treatment.  While methods to evaluate TBI advanced substantially during recent decades and principles of supportive care have also progressed, there are no pharmacologic therapies that seek to specifically stimulate neurogenesis (growth of new neurons) or synaptogenesis during the post-acute phase of care.


The sequelae of TBI depend on the extent, nature, and location of the initial injuries, on acute phase pathophysiologic changes, and on long term rehabilitation efforts.  A number of factors interact to determine the nature of the chronic deficits from a TBI, including disruption of key structures at the site(s) of injury, residual scar formation, post-traumatic electrophysiologic abnormalities, and emergent neuropsychological states.

There is a large and growing research effort to develop TBI diagnostics (Redell et al. 2010), to optimize care during the acute phase of a brain injury (Vella, Crandall, and Patel 2017), and to enhance functional recovery using neuromodulation (Hofer and Schwab 2019).


  1. Regulation of neurogenesis and synaptogenesis in humans (Aimone et al. 2014)
  2. Neurogenesis
  3. Pre-natal: https://en.wikipedia.org/wiki/Neurogenesis
  4. Perinatal:
  5. Hippocampal: (Yang et al. 2014)
  6. Adult: https://en.wikipedia.org/wiki/Adult_neurogenesis
  7. Synaptogenesis (Gatto and Broadie 2010)
  8. Regulatory factors
  9. Neurotrophic factors: (Cacialli and Lucini 2019) (Huang and Reichardt 2001) https://www.sciencedirect.com/topics/neuroscience/neurotrophic-factors
  10. Autocrines: (Herrmann and Broihier 2018)
  11. Cortical plasticity: (“Evolution and Ontogenetic Development of Cortical Structures” 2019; El-Boustani et al. 2018)
  12. Tissue regeneration in humans and animal models
  13. non-CNS (https://en.wikipedia.org/wiki/Regeneration_in_humans)
  14. non-Human CNS (Ghosh and Hui 2016) (Cacialli and Lucini 2019) (Zambusi and Ninkovic 2020)
  15. Human CNS
  16. Regulation, dysregulation, and controlled regulation (Tsintou, Dalamagkas, and Makris 2020) (Modo 2019)


The brain’s limited ability to regenerate its cells and tissue structures is a fundamental obstacle to healing in TBI.  Tissue regeneration in adult humans is limited in a number of tissues while present in other tissues.  Certain structures whose spatial organization is critical to function can regenerate (e.g., liver, bone (partially)).  Other structures whose spatial organization is the basis of the tissue’s physiologic function are not naturally regenerated (e.g., lung, heart, brain). (Wikipedia contributors 2020)


Presumptively, two of the critical limitations on long term recovery from TBI are the loss of cells, especially cortical cells, from the injured brain regions, and the disruption of the functional connections (tracts and synapses) in the region of injury. [ ]


One observation is that all brain regions are not equivalent with regards to the retention of the capacity to form new neurons and synapses in adulthood.  Both DG and olfactory bulb have active neurogenesis ((Weston and Sun 2018) in certain adult animal models, but the extent of this phenomenon in humans is unclear (Bhardwaj et al. 2006)


Modest advances have been made at inducing regeneration in human tissue that is not naturally regenerated using both tissue engineering techniques and by altering growth factors.  (Modo 2019)


  1. Pharmacologic therapies: past efforts and trials (Diaz-Arrastia et al. 2014)
  2. Stem cell therapy (Weston and Sun 2018)
  3. Autologous embryonic stem cells
  4. In non-human models
  5. In humans (Schepici et al. 2020)
  6. Induced pleuripotent cells: (Omole and Fakoya 2018) (Dunkerson et al. 2014)
  7. Role of the bioscaffold: (Modo 2019)


Unsurprisingly, as our understanding of stem cell biology has progressed in recent years, some are attempting to replete the CNS by providing it with specially engineered stem cells.   The broad concept has been reviewed (Weston and Sun 2018)


Some have claimed that stem cells can repair TBI (c.f. https://www.pacificneuroscienceinstitute.org/blog/brain-trauma/can-stem-cells-repair-traumatic-brain-injury/, but study results from an earlier trial using the same cells for patients who had suffered from an ischemic stroke were recently posted (https://clinicaltrials.gov/ct2/show/results/NCT02448641).  These initial trials have not yet demonstrated any meaningful level of recovery in post-stroke patients. 


  1. Development of a TBI therapy
  2. Need for model organisms: (Shah, Gurdziel, and Ruden 2019)
  3. Animal models
  4. Novel mouse models:(Reimann et al. 2019);(Chang et al. 2018)
  5. Tissue models
  6. Cellular models: (https://www.researchgate.net/profile/Ashwin_Kumaria/publication/320692835_In_vitro_models_as_a_platform_to_investigate_traumatic_brain_injury/links/5bb07ca092851ca9ed30dd12/In-vitro-models-as-a-platform-to-investigate-traumatic-brain-injury.pdf)
  7. Enabling model components (iPSCs; assays; analytics)
  8. Enabling pharmacology (genomically targeting molecules)
  9. Small molecules
  10. ASOs and other mRNA-targeting compounds (Karaki, Paris, and Rocchi 2019) (Rinaldi and Wood 2018) (definitive text: https://www.springer.com/gp/book/9781592595853) (Schoch and Miller 2017)
  11. A target??
  12. LYNX1 (Morishita et al. 2010; Miwa, Anderson, and Hoffman 2019; Higley and Strittmatter 2010; Bukhari et al. 2015; Sajo, Ellis-Davies, and Morishita 2016)
  13. Overview LYNX1 overview (A. Cohen, 12/20/17)
  14. Recent analogous efforts
  15. Spinal muscular atrophy (https://smanewstoday.com/spinraza-nusinersen-ionis-smnrx/)
  16. “Milasen” (Kim et al. 2019)
  17. “Lukesen” [Q-State Biosciences -- Kopin presentation in today’s meeting]
  18. Current efforts in this area
  19. ReNetX Bio: https://www.renetx.com/
  20. Q-State Bio: (Q-State’s platform)
  21. Cells: iPSCs → various types of neurons, including excitatory and inhibitory cortical neurons (Molnár et al. 2019); (McCaughey-Chapman and Connor 2018) and astrocytes (Barbar et al. 2020)
  22. Assays and analytics: (Williams et al. 2019)
  23. Specific disease models:
  24. Cell culture of various human and non-human primary and derived neurons with both excitation and synaptic assays
  25. Engineered isogenic controls
  26. “Slice” preparations of mice
  27. Therapeutic development capabilities
  28. New abilities to study cortex and cortical neurons using optogenetic tools (https://spaces.hightail.com/receive/YH79qaNhlU/fi-10048c4d-dbab-422c-ad37-847578ceaae0/fv-b28c8b5f-38c4-4324-9c31-c33cc19b0a2d/20200116_Adam_Cohen-Sensory_Information_Processing_1.mp4) (Fan et al. 2020) and the Q-State synaptic assays
  29. Others?
  30. https://www.agexinc.com/company-overview-biotechnology-for-gerontology-tissue-regeneration/
  31. https://gmpnews.net/2020/01/a-russian-drug-gets-alzheimers-patients-to-recover-the-memory/
  32. Antisense Oligonucleotides
  33. ASOs and TBI: (Shohami et al. 2000) (Fluiter et al. 2014)
  34. A plan?
  35. Targeting LYNX1 with ASOs?


Combining LYNX1 downregulation with autologous iPSC stem cell therapy?

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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