regenerative medicine and its role on improving recovery from
TRANSCRIPT
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
Center for Neuroscience and Regenerative Medicine
USU - administrative and fiscal responsibility
Intramural federal research center
Basic, translational and clinical TBI research
Military and civilian patients
WRNMMC
DoD
USU
DoD
NIH
HHS
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!
Among “Mild” TBI (70-80%):
Who will need intervention to prevent
chronic symptoms?
TBI PTSD
heightened anxiety, fear, arousal; repeat exposures
TBI-PTSD Spectrum of Injury
Among “Moderate” TBI:
How to address repair processes for gray matter
damage (cortical neuron cell body damage),
vs white matter tracts (diffuse axonal injury)?
Neuroimaging to “see the injury” CT of Six Patients w/ Severe TBI GCS of < 8
Saatman et al., 2008 J Neurotrauma
Pathoanatomic Sequelae of TBI
Contusion
Diffuse
Axonal
Injury
SAH
Hematoma
Saatman et al., 2008 J Neurotrauma
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
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
Imaging to Improve TBI Diagnosis
MRI/DTI
- Structural
- Functional
PET
- Metabolic
- Biochemical
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 13-15 with CT findings)
- MRI (FLAIR and DWI) lesion volumes > 2 ml
- Results on neurocognitive assessment battery
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
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
Limits to regeneration in adult CNS
• Reduced pool of neural stem-progenitor cells
to generate replacement cells
• Inhibitory signals block creation of replacement cells
• Complexity of re-establishing connections
http://public.kitware.com/ImageVote/images/17/
Aviva Symes, USUHS
Proliferate, migrate, differentiate, survive, extend
axons and dendrites, form synapses, myelinate
Axon and dendrite outgrowth, synapse formation
Regina Armstrong, USUHS
Neuroregeneration -
Three Complementary Approaches:
• Stimulation of endogenous neural stem-
progenitor (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
Regenerative medicine challenges and
opportunities - CNS disease/injury examples
MS autoimmune
spontaneous
remyelination
TBI neurological
cognitive
psychological
mild-severe
different
risk-benefit
poor
assessment
measures
SCI neurological
defined
tracts
Stroke neurological
cognitive
psychological
delimited
territory,
diverse
cell types
with complex
connections
Transplant benefit from:
- Glial cell replacement
- Improving endogenous response
- Suppressing immune damage
- Creating more permissive lesion
- Promoting axon regeneration
CNS Stem Cell Therapies (progressive examples)
MS trials of hMSC intravenous delivery (University of Cambridge)
- Intended immunomodulation
- Potential nurse effect on remyelination and axon protection
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
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
Long term considerations for cell
therapy/transplantation in CNS
• Tumor formation
• Dysfunction – neurological, cognitive, psychological
• Stability
• Reversibility
• Outcome measures
Regina C. Armstrong, Ph.D. Analysis of Endogenous NSC Responses to TBI
Gli1CreERT2;R26-YFP Mice
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.
Neurosphere immunoreactive for Tuj1 (red) and GFAP (blue)
Sharon L. Juliano, Ph.D. USUHS
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).
Neural progenitor cells (NPCs) taken from different embryonic niches and transplanted into organotypic cultures of neocortex
differentiate into distinct cell types
200 ms
20 pA
25
20
15
10
5
Fre
qu
en
cy (
Hz)
20181614121086
Current Step (pA)
0.2 s
20 mV
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.
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.
HCPS - NINDS - NIH
Leonardo G. Cohen, M.D.
Motor Learning After Traumatic Brain Injury
HCPS - NINDS - NIH
TBI patient
* p=.041
NIH Center for Regenerative Medicine
NIH Center for Regenerative Medicine
Mahendra Rao - Director
NIH CRM
NIH Center for Regenerative Medicine
Biomedical
Research
Community
CRM
Collaborative
Projects
A resource for the entire community
iPS Cells from
many
genotypes
Differentiated
Cells
Policies,
Standards,
Training
NIH Center for Regenerative Medicine
Broadly Relevant Procedural, Regulatory Challenges
Addressed NIH CRM
NIH Center for Regenerative Medicine
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
Key Intramural Resources
•NCTT
•CC
•NHLBI SCU
•CTU
•Clinical transplantation Center (Dr. Robey)
•SCCU (ESC effort)
•FAES
•Tech Transfer and Policy offices
•NIEHS, NIST, FDA and their programs
•Preclinical studies
•Clinical studies
•BLA license and
commercialization
•Tissue Sourcing E
N
G
I
N
E
E
R
I
N
G
•PSC derivation
•PSC derived product
manufacture
S
O
R
T
I
N
G
•PSC Differentiation
•Cells in Assay format
•Appropriate Screen
•Commercial Partner
Key Extramural Partners
•IC program officers
•Other Common Fund programs
•Service Providers
•Pharma- Public Pvt partnership
•Stakeholders
•STEMCORES
NIH Center for Regenerative Medicine
For further information
Contact Mahendra Rao –
BrainInjuryResearch.usuhs.mil