Regenerative Medicine and Its Role on Improving Recovery from Traumatic Brain Injury (TBI) in Military Service Members Regina C. Armstrong, Ph.D.

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1 Regenerative Medicine and Its Role on Improving Recovery from Traumatic Brain Injury (TBI) in Military Service Members Regina C. Armstrong, Ph.D. Professor, Uniformed Services University of the Health Sciences Director, Center for Neuroscience and Regenerative Medicine

2 Center for Neuroscience and Regenerative Medicine USU - administrative and fiscal responsibility WRNMMC DoD USU DoD NIH HHS Intramural federal research center Basic, translational and clinical TBI research Military and civilian patients

DoD NIH HHS Intramural federal research center Basic,

3 CNRM Goal: Improve Recovery from TBI in Military Service Members Characterize the injury Select optimal treatment plan Evaluate outcomes Regenerative = repair strategies Neuroregeneration cells and processes Neuroplasticity synapses and circuits Rehabilitation functional capacity Neuroprotection better to save than replace!

strategies Neuroregeneration cells and processes Neuroplasticity synapses and

4 TBI-PTSD Spectrum of Injury TBI PTSD heightened anxiety, fear, arousal; repeat exposures Among Mild TBI (70-80%): Who will need intervention to prevent chronic symptoms? Among Moderate TBI: How to address repair processes for gray matter damage (cortical neuron cell body damage), vs white matter tracts (diffuse axonal injury)?

5 Neuroimaging to see the injury CT of Six Patients w/ Severe TBI GCS of < 8 Saatman et al., 2008 J Neurotrauma

6 Pathoanatomic Sequelae of TBI SAH Diffuse Axonal Injury Contusion Hematoma Saatman et al., 2008 J Neurotrauma

7 Neuropathology: NFL and CTE Dr. Dan Perl, USUHS, Center for Neuroscience and Regenerative Medicine Dr. Ann McKee and colleagues, Center for the Study of Traumatic Encephalopathy at the Boston University School of Medicine and the Bedford VA Medical Center and the Sports Legacy Institute Chronic Traumatic Encephalopathy a neurodegenerative disease 66 yr old former NFL linebacker By age 55, developed apathy, dysarthria, inattention, outbursts of anger and short-term memory problems ptau stain shows involvement of amygdala, hippocampus, temporal and insular cortex

Medical Center and the Sports Legacy Institute Chronic Traumatic Encephalopathy a neurodegenerative disease 66 yr old former NFL linebacker

8 Pathology across spectrum of TBI experienced in military service? Characterize for diverse types of injuries - Blast, concussion, acceleration, penetrating - Blast Plus combination injury - Repeat exposures - Context of high anxiety and stress Knowing the damage will help to - Improve diagnostic tools imaging, biomarkers - Enable early detection and focus selection criteria - Develop interventions based on mechanism

combination injury - Repeat exposures - Context of high anxiety and stress Knowing the damage will help

9 Imaging to Improve TBI Diagnosis MRI/DTI - Structural - Functional PET - Metabolic - Biochemical

10 Significance of Mild TBI Prevalence: DVBIC US military ~ 28,000 TBI/yr CDC US civilians ~ 1.7 million TBI/yr; 2x live with permanent disability Beginning to be able to correlate acute assessments with functional outcome (R. Diaz-Arrastia et al.) - Complicated mild (GSC with CT findings) - MRI (FLAIR and DWI) lesion volumes > 2 ml - Results on neurocognitive assessment battery

assessments with functional outcome (R. Diaz-Arrastia et al.

11 How do initial findings predict long term consequences of TBI? Longitudinal studies - Natural history in military and civilian cohorts - Combine imaging with full battery of tests for: cognitive, emotional, neurologic, functional Rehabilitative medicine to improve function

cohorts - Combine imaging with full battery of tests for: cognitive,

12 Rehabilitative Medicine major option for TBI recovery of functions Need rigorous studies to optimize - Differentiate among heterogeneous injuries - Understand impact of patient based factors Neural substrates of rehabilitative medicine - Overall health and mood - Specific strategies for functions - Synaptic plasticity - Neuron and glial cell replacement

based factors Neural substrates of rehabilitative medicine - Overall health and mood -

13 Limits to regeneration in adult CNS Reduced pool of neural stem-progenitor cells to generate replacement cells Regina Armstrong, USUHS Inhibitory signals block creation of replacement cells Proliferate, migrate, differentiate, survive, extend axons and dendrites, form synapses, myelinate Aviva Symes, USUHS Complexity of re-establishing connections Axon and dendrite outgrowth, synapse formation

differentiate, survive, extend axons and dendrites, form synapses, myelinate Aviva Symes, USUHS Complexity of

14 Neuroregeneration - Three Complementary Approaches: Stimulation of endogenous neural stemprogenitor (NS-P) cell regeneration Transplantation of exogenous stem cell populations to promote regeneration - replacement of lost cells - nurse effect stimulates endogenous cells Modification of features of the lesion environment that inhibit repair

populations to promote regeneration - replacement of lost cells - nurse effect

15 Regenerative medicine challenges and opportunities - CNS disease/injury examples MS autoimmune spontaneous remyelination SCI neurological defined tracts Transplant benefit from: - Glial cell replacement - Improving endogenous response - Suppressing immune damage - Creating more permissive lesion - Promoting axon regeneration Stroke neurological cognitive psychological delimited territory, diverse cell types with complex connections TBI neurological cognitive psychological mild-severe different risk-benefit poor assessment measures

damage - Creating more permissive lesion - Promoting axon regeneration Stroke neurological cognitive psychological delimited

16 CNS Stem Cell Therapies (progressive examples) Pre-clinical MS model with NSC transplant (San Raffaele Scientific Institute) - Intended replacement of oligodendrocytes and remyelination - Results showed modulation of autoimmune disease - Also, indications of nurturing endogenous repair mechanisms MS trials of hmsc intravenous delivery (University of Cambridge) - Intended immunomodulation - Potential nurse effect on remyelination and axon protection Stroke trials of hutc intravenous delivery (Johnson & Johnson) - Intended immunomodulation - Potential nurse effect on cortical neurons and glials cells SCI trials of hesc/op (GRNOPC1) direct transplant (Geron) - Potential nurse effect in mixed gray and white matter lesions - Potential replacement of oligodendrocytes and remyelination

Potential nurse effect on remyelination and axon protection Stroke trials of hutc intravenous delivery (Johnson & Johnson) - Intended immunomodulation - Potential nurse effect on cortical neurons

17 Long term considerations for cell therapy/transplantation in CNS Tumor formation Dysfunction neurological, cognitive, psychological Stability Reversibility Outcome measures

18 Regina C. Armstrong, Ph.D. Analysis of Endogenous NSC Responses to TBI Gli1 CreERT2 ;R26-YFP Mice

19 Activation of Shh Responsive NSC in SVZ, largest germinal site in mammalian brain This result indicates a potential role of Shh in SVZ neuroregenerative responses that can be prolonged following even mild TBI.

20 Sharon L. Juliano, Ph.D. USUHS Neurosphere immunoreactive for Tuj1 (red) and GFAP (blue)

21 Neural progenitor cells (NPCs) taken from different embryonic niches and transplanted into organotypic cultures of neocortex differentiate into distinct cell types Mix NPCs from ganglionic eminence (GE) are more likely to differentiate into GABAergic cells (cross, p< 0.01, i.e., presumptive inhibitory cells). NPCs from cortical plate (Ctx) are more likely to differentiate into MAP2+ cells (star, p< 0.01, i.e., presumptive excitatory cells).

22 Frequency (Hz) mv 0.2 s Current Step (pa) Current-Frequency relationship of a GFP+ transplanted neuron. The cell showed a linear increase in firing frequency as a function of depolarizing current. Inset shows the response of the cell to a 14pA depolarization. Note the lack of spike frequency adaptation, a characteristic of fast spiking interneurons. 20 pa Intracortical stimulation evoked postsynaptic currents in the same neuron. The black trace is the average of 10 individual sweeps (each sweep overlaid in grey). The prolonged barrage of PSPs impinging upon the cell suggests that the transplanted neuron had become integrated into the host circuitry. 200 ms

23 Leonardo G. Cohen, M.D. Motor Learning After Traumatic Brain Injury HCPS - NINDS - NIH

24 TBI patient * p=.041 HCPS - NINDS - NIH

25 NIH Center for Regenerative Medicine Mahendra Rao - Director NIH CRM NIH Center for Regenerative Medicine

NIH Center for Regenerative Medicine A resource for the entire community ips Cells from many genotypes CRM Collaborative Projects NIH CRM Broadly Relevant

26 NIH Center for Regenerative Medicine A resource for the entire community ips Cells from many genotypes CRM Collaborative Projects NIH CRM Broadly Relevant Procedural, Differentiated Regulatory Challenges Cells Addressed Policies, Standards, Training Biomedical Research Community NIH Center for Regenerative Medicine

27 Three Different Domains of Activity 1: Center-based, community-wide initiatives 2: Laboratory-based efforts 3: Grants to support intramural program ALL focused on screening or cell based therapy NIH Center for Regenerative Medicine

NIH CRM efforts E N G I N E E R I N G Tissue Sourcing PSC derivation PSC derived product manufacture S O R T I N G Key Intramural Resources NCTT CC NHLBI SCU CTU Clinical transplantation Center (Dr.

28 NIH CRM efforts E N G I N E E R I N G Tissue Sourcing PSC derivation PSC derived product manufacture S O R T I N G Key Intramural Resources NCTT CC NHLBI SCU CTU Clinical transplantation Center (Dr. Robey) SCCU (ESC effort) FAES PSC Differentiation Tech Transfer and Policy offices NIEHS, NIST, FDA and their programs Cells in Assay format Appropriate Screen Commercial Partner Preclinical studies Clinical studies BLA license and commercialization Key Extramural Partners IC program officers Other Common Fund programs Service Providers Pharma- Public Pvt partnership Stakeholders STEMCORES NIH Center for Regenerative Medicine

29 For further information Contact Mahendra Rao NIH Center for Regenerative Medicine

30 BrainInjuryResearch.usuhs.mil

Cognitive rehabilitation in MS

14th MS Nurse International Workshop Lyon, France, October 9th 2012 Cognitive and psychological issues in MS Cognitive rehabilitation in MS Psychological Unit Neurological Department San Raffaele Hospital