XOStem is dedicated to developing Engineered Exosome therapies that address pressing medical needs, especially ones with ruinous impact on quality of life that affect large populations. Chief among these are inflammation-related neurologic conditions that afflict and devastate our citizenry and their families, especially the elderly.

As discussed below, neuroinflammation is a common contributing factor in a variety of dementias, nerve and motor abnormalities, and chronic traumatic encephalopathy. XOStem scientists are exploring ways in which to enhance the known anti-inflammatory potency of stem cell-derived exosomes and have published research documenting dramatic improvement in an animal model of multiple sclerosis using exosome treatment. Research also addresses different methods of administration to achieve maximal and durable therapeutic benefit.

Neuroinflammation and the Blood Brain Barrier

Neuroinflammation is a common pathology of a variety of acute and chronic brain disorders with evidence indicating it initiates and accelerates multiple long-term neurodegenerative diseases. Inflammation, nature’s protective and defensive response to trauma and microbial invasion, is a two-edged sword, particularly in the central nervous system.Although intended by nature to be protective and beneficial, an excessive inflammatory response can cause or contribute to tissue damage and disease pathology.

Regardless of location, the inflammatory response is orchestrated by several cell types and signaling molecules with local and systemic effects.  The immediate inflammatory response is  often short-lived and differs from the long-term adaptive immune response which involves T and B lymphocytes. Once deployed, activated cells target not only the initial site of inflammation, but also remote sites that are responding to the inflammatory stimulus. Peripheral inflammation triggers a neuroinflammatory response involving the blood–brain barrier, glia and neurons.

The blood-brain barrier, a highly specialized form of endothelium, was previously thought to separate the central nervous system from the peripheral immune system. However, it is not only permeable to pro-inflammatory mediators derived from peripheral inflammation, it can also be stimulated to both release and transmit these mediators and allow leucocyte migration into the brain. This neuroinflammatory response results in synaptic impairment, neuronal death, and an exacerbation of disease pathologies within the brain. Blood-brain barrier active transport systems have been observed facilitating the delivery of TNF and IL cytokines. Emerging evidence suggests that neuronal apoptosis is an insufficient measure of neurodegeneration as several processes, including synaptic impairment, render neurons damaged and inadequate for neurotransmission long before cell death.

Neurodegenerative Disease

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and frontotemporal lobar dementia are some of the most pressing problems of aging populations. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are diseases that overlap in their clinical presentation, pathology, and genetics, and likely represent a spectrum of one underlying disease. In ALS/FTD patients, neuroinflammation characterized by innate immune responses of tissue-resident glial cells is uniformly present on end-stage pathology, and human imaging studies and rodent models support that neuroinflammation begins early in disease pathogenesis. The growing awareness that the immune system is inextricably involved in shaping the brain during development as well as mediating damage, regeneration, and repair, has stimulated consideration that therapeutic modulation of the immune system may have benefit in neurodegenerative diseases.

Studies of Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies have provided much of the evidence for inflammatory pathology in neurodegeneration as confirmed with in vivo PET imaging.  Epidemiologic data suggest that neuroinflammation is an independent predictor of early death in Alzheimer’s disease. This has been correlated with elevated inflammatory cytokines interleukins 1 & 6 and tumor necrosis factor-α, and studies have observed that neurovascular inflammation is mediated by the peripheral system immune response although its role in contributing to Alzheimer’s disease remains unclear.

Traumatic Brain Injury (TBI) and Chronic Traumatic Encephalopathy (CTE)

Alzheimer disease is histologically characterized by interneuronal amyloid plaques and intraneuronal tangles of tau proteins, which first develop in areas of the brains critical to memory and other cognitive functions. Neuropathological studies of human traumatic brain injury (TBI) cases have described amyloid plaques acutely after a single severe TBI, and tau pathology after repeating mild TBI. This helps drive the hypothesis that a single moderate to severe TBI increases the risk of developing late-onset Alzheimer’s disease, while repeat mild TBI (mTBI) increases the risk of developing CTE. Both amyloid-beta and tau proteins appear to promote neuroinflammation. Epidemiological studies emphasize that TBI is associated with the increased risk of developing multiple types of dementia, not just AD-type dementia, and that TBI can also trigger other neurodegenerative conditions such as Parkinson's disease. Further, human post-mortem studies on both single TBI and repeat mTBI can show combinations of amyloid, tau, TDP-43, and Lewy body pathology indicating that the neuropathology of TBI is best described as a 'polypathology'. The spectrum of chronic cognitive and neurobehavioral disorders that occur following repeat mTBI is viewed as the symptoms of CTE; the spectrum of chronic cognitive and neurobehavioral symptoms that occur after a single TBI is considered to represent distinct neurodegenerative diseases such as AD. These data support the suggestion that the multiple manifestations of TBI-induced neurodegenerative disorders be classified together as traumatic encephalopathy or trauma-induced neurodegeneration, regardless of the nature or frequency of the precipitating TBI.

Route of Administration of Exosomes for Neuroinflammatory Disorders

Exosomes can be administered by a variety of means. Depending on indication, local or systemic injection, inhalation and intranasal administration are used. For neuroinflammatory disorders, nasal administration appears preferred. Intranasal  drug delivery is emerging as a reliable and promising pathway to deliver a wide range of therapeutic agents to the central nervous system.  Indeed, intranasal administration of mesenchymal stem cell-derived extracellular vesicles ameliorated symptoms in an Alzheimer's disease-like mouse model. This presents noninvasive entry into the brain via direct nose-to-brain and/or indirect nose-to-blood-to-brain routes. Intranasal administration delivers therapeutics directly to the brain via olfactory and trigeminal nerve pathways that originate as olfactory neuro-epithelium in the nasal cavity and terminate in the brain. Studies have proven that nasal to brain drug delivery system bypasses the BBB.  

Neuroinflammation and its sequalae disease states are research targets for XOStem scientists. Methods to optimize exosome cargos and delivery routes for these challenging and often devastating medical maladies are XOStem priorities.

Selected References

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