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 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.