By Dr. Karl Trounson PhD and Prof. Alan Trounson PhD | May 22, 2026
As published in Drug Discovery & Development
Traumatic brain injury (TBI) represents a major global health burden, affecting an estimated 69 million people annually. The greatest burden of TBI-related injury is observed in older adults, largely arising from falls. Contact sports, road traffic accidents, and interpersonal violence are also major contributors to TBI across ages and populations.
Acute medical management of TBI largely focuses on controlling intracranial pressure and maintaining cerebral perfusion, however, there are few reliable interventions to treat secondary pathophysiological processes such as neuroinflammation, neurodegeneration, oxidative stress, and proteinopathy. As such, most current therapies remain largely supportive rather than disease-modifying, highlighting a substantial unmet therapeutic need. These types of secondary processes appear to contribute to risk of development of neurodegenerative conditions, including Alzheimer’s disease (AD). Importantly, these processes may persist long after the initial mechanical injury, with chronic neuroinflammation and progressive neurodegeneration increasingly recognized as contributors to prolonged symptoms and later-life cognitive decline following TBI.
Shared pathological and biomarker overlap between TBI and AD
Following TBI, pathological features considered hallmarks of AD such as tau hyperphosphorylation, amyloid-β accumulation, and persistent neuroinflammation are observed. Repetitive or severe TBI has additionally been associated with chronic traumatic encephalopathy (CTE), further supporting a mechanistic link between brain trauma and progressive neurodegenerative proteinopathy. Key inflammatory biomarkers Glial Fibrillary Acidic Protein (GFAP), and Neurofilament Light Chain (NF-L) increase markedly in the acute phase of TBI (see Figure 1) and both are elevated in AD. The brain biomarker Ubiquitin C-terminal hydrolase L1 (UCH-L1) is associated with increasing levels of phosphorylated tau inducing neurofibrillary tangles and the abnormal accumulation of amyloid-β plaques by affecting β-Secretase, that are characteristic of AD. UCH-L1 also depletes triggering receptor expressed on myeloid cells 2 (TREM2) which affects neuroinflammation. Hence UCH-L1 is considered an important biomarker for AD and TBI. S100 calcium-binding protein B (S100B) is also a pro-inflammatory biomarker in TBI (Figure 1) that is chronically upregulated in AD and associated with cognitive decline. Treatments that improve these pathophysiological processes or modulate associated biomarker expression may therefore have therapeutic potential across both TBI and AD.
Figure 1. Kinetics of blood biomarkers from acute to chronic phase following traumatic brain injury
From: Hossain et al. Fig 2 Blood biomarkers for traumatic brain injury; a narrative review of current evidence. Brain Spine. 2023 Dec 14:4:102735.doi: 10.1016/j.bas.2023.102735.eCollection 2024.
High-dose NK cell therapy in AD
One novel approach demonstrating a particularly dramatic response has been administration of massive doses of autologous natural killer (NK) cells. NK cells are a component of the innate immune system involved in immune surveillance, clearance of pathological material, and regulation of inflammation. In a recent study, researchers with NKGen Biotech, Inc. supplemented oncology patients with high doses of NK cells following chemotherapy to mitigate the effects of immune suppression and made a serendipitous observation that patients with co-existing AD demonstrated unexpected cognitive stabilization and even improvement. A subsequent phase 1 open-label study investigated repeated intravenous administration of high doses (~6 billion cells) of expanded autologous NK cells in patients with mild-to-severe AD. Across cognitive measures, 90% of patients showed either no decline or a marked improvement over 3 to 12 months, alongside reductions in biomarkers associated with neuroinflammation and proteinopathy, including GFAP, phosphorylated tau, and α-synuclein.
While the precise mechanisms underlying these improvements remain unclear, NK cells appear capable of both internalizing and degrading neurotoxic protein aggregates through lysosomal pathways and modulating neuroinflammatory responses. Proposed immunomodulatory effects include suppression of pro-inflammatory microglial activity, production of anti-inflammatory cytokines, and elimination of autoreactive T-cells. Such a multi-target mechanism may be particularly advantageous in TBI, where numerous secondary injury pathways occur simultaneously and interact dynamically over time.
NK cell-derived EVs as a scalable cell-free therapeutic alternative
Despite the promise of this therapy, administration of whole-cell NK therapies presents logistical and translational challenges. These include manufacturing complexity and cost, scalability, repeated intravenous dosing requirements, and attrition of cells before reaching and crossing the blood-brain barrier.
Extracellular vesicles (EVs) may circumvent many of these limitations. EVs are nanoscale membrane-bound particles released by cells for the purpose of intracellular communication. They contain biologically active cargo such as proteins, mRNAs, microRNAs, and signaling molecules capable of influencing behavior of recipient cells. Importantly, the composition and functional properties of EVs reflect the parent cell from which they derive, allowing EVs to retain many of the immunomodulatory and signaling characteristics of their source cells. EVs therefore represent a potentially “cell-free” therapeutic platform.
In this case, it is the EVs from NK cells (NK-EVs) that are of interest. Preliminary findings from Australian company Evinco Therapeutics report that EVs recovered from cultured NK cells show a strong anti-inflammatory effect on brain resident immune cells – microglia and astrocytes. NK-EVs also strongly induce microglia to internalize and degrade amyloid-β, meaning that direct clearance by NK cells themselves may not be necessary. In other words, the immunomodulatory component may be more impactful in AD and TBI treatment, which NK-EVs are able to leverage.
Unlike NK cells themselves, NK-EVs are remarkably stable, can be freeze-dried and shipped or maintained at room temperature. They can also be delivered by the nasal route as a spray, which is a very patient friendly delivery option. This also represents a more direct route to the brain than intravenous administration, as EVs can move directly to the brain along the olfactory nerve bundle. This may be particularly advantageous given the difficulty many intravenously administered therapies face in achieving meaningful penetration across the blood-brain barrier. In addition, EVs are not recognized as foreign by a recipient’s immune system and can therefore be derived from donors, manufactured in large scale at very reasonable cost and stored as freeze-dried product to be reconstituted simply by adding solution, which could be done at home. Such scalability may be especially important in TBI given the enormous global incidence of injury and the practical limitations associated with personalized cell therapies.
Advancing EV therapeutics for AD and TBI
Evinco is working with a major pharmaceutical company to establish the proof of concept for therapy of EVs for AD and is interested in applying the same product to TBI, given the overlap between conditions outlined above. TBI also represents a worthwhile target given its defined onset, clear biomarker and behavioral readouts, and possibly shorter trial times in comparison to AD. Present research is following this work plan that includes safety, efficacy, and dose-response studies in mice and canines. Evinco expects to have product ready for first in human studies within the next 15 months, pending ongoing development and regulatory activities. There is considerable interest in these upcoming clinical studies.
Despite extensive research, there is still a critical need for therapies capable of repairing damaged neural tissue or modifying the fundamental disease processes, such as neuroinflammation, protein aggregation, and synaptic loss, that drive ongoing decline. The lack of disease-modifying options underscores the urgency for innovative approaches that could restore brain health and improve long-term outcomes for those affected by these devastating disorders.
Dr. Karl Trounson is Scientific Advisor and Prof. Alan Trounson is Founder, CEO and Executive Chair of Evinco Therapeutics, a biotechnology company developing immune-based therapies for neurological disorders.
Author affiliations
Karl M. Trounson1,2, PhD and Alan O. Trounson, AO1,3, PhD
- Evinco Therapeutics, 12 Ferntree Place, Notting Hill, Victoria, Australia 3068
- Richmond Football Club, Richmond, Victoria, Australia
- Monash University, Clayton, Victoria, Australia 3068