Translational Research For Interventional Neurologists Dileep R. Yavagal, MD Director Interventional Neurology Co-Director Endovascular Neurosurgery Jackson Memorial Hospital Associate Professor, Neurology & Neurosurgery University of Miami Miller School of Medicine Faculty, Interdisciplinary Stem Cell Institute SVIN Annual Meeting, November 8 th , 2014, Hollywood, FL
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Translational Research For Interventional Neurologists · CTSI NIH Grant: Jan 2013-May 2014 . Synopsis •Why Translational Research •Personal Story –Promise of Stem Cells in
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Translational Research For Interventional
Neurologists
Dileep R. Yavagal, MD Director Interventional Neurology
Co-Director Endovascular Neurosurgery Jackson Memorial Hospital
Associate Professor, Neurology & Neurosurgery University of Miami Miller School of Medicine Faculty, Interdisciplinary Stem Cell Institute
SVIN Annual Meeting, November 8th, 2014, Hollywood, FL
Dileep R. Yavagal, MD
Clinical Trial Steering Committee Member:
1. Recover-Stroke ( Sponsor: Cytomedix Aldagen)
2. SWIFT-PRIME ( Sponsor: EV3)
Consultant:
1. Aldagen/Cytomedix
2. EV3/Covidien
3. Stryker
Financial Disclosures
Funding
UM Endovascular Stroke Translational Research
Laboratory
• 1. Department of Neurology, University of Miami: 2008-2010
• 2.Interdepartmental Research Development Initiative (IRDI) grant: 2009-2010
• 3. Anderson Family Gift : 2009-2010, 2013-2015
• 4. Florida Biomedical New Investigator Grant: 2011-2014
• 5. CTSI NIH Grant: Jan 2013-May 2014
Synopsis
• Why Translational Research
• Personal Story
– Promise of Stem Cells in Stroke from the
Laboratory
– Translation Data on Intra-arterial MSC’s in
Stroke
– Rise in Early Clinical Trials
– RECOVER-Stroke Clinical Trial
Career Pathway
• Promise of Very Innovative Biomedical Research US Medical System
• Residency: Program Director Input on Academic Career
• Fellowship: Novel large animal model development
• J1-Waiver: No resources for Translational Research but avoid loss of focus
• University of Miami: – Small Start-up Package and Seed funding
– Non-NIH Intra-mural Grants
– NIH grant
– Industry Collaboration
– Philanthrophy
Why Translational Research
Why Translational Research
• Different things to different
people
• the “bench-to-bedside”
enterprise of harnessing
• knowledge from basic
sciences to produce new
drugs, devices,
• and treatment options for
patients.
• the interface between basic
science and clinical
• medicine
• the end point is the production
of a promising new treatment.
• “effective translation of
the new knowledge,
mechanisms, and
techniques generated
by advances in basic
science research into
new approaches for
prevention, diagnosis,
and treatment of
disease is essential for
improving health.”
Why Translatational Research
• NIH has made translational research a priority
• centers of translational research the Clinical and Translational Science Award
• (CTSA) program in 2006.
• 24 CTSA-funded academic by 2008
• By 2012, the NIH expects to fund 60 such centers with a
• budget of $500 million per year.
• foundations, industry, disease-related organizations, and
• individual hospitals and health systems have also established
• translational research
• European Commission’s €6 billion budget for health related
• research,
• United Kingdom has invested £450
• million over 5 years to establish translational research
Need for Novel Class of Stroke
Therapies
• IV tPA prevents disability in only 6/1000
patients
• Over 100 clinical trials of neuroprotection
agents in stroke have failed
• Endovascular Acute Stroke Therapy when
standard of care may only reach 20% of
ischemic stroke cases due to limited time
window
IA vs IC vs IV cell delivery: Timing of
migration and distribution of Cells
Dileep R. Yavagal, MD
Biodistribution of cells in IA vs IV delivery
Stroke 2010;41;2064-2070 Pendharkar et
al
Intra-carotid NSCs at 48 hours post
mouse hypoxia-ischemic model • Guzman et al. Stroke 2008;39;1300-1306
Acute administration of MSCs post recanalization
• If cells mediate benefit mainly through neuroprotection, acute delivery to maximize chances of tissue salvage
• Challenges: excitotoxicity, peri-infarct depolarization, reactive O2 species release
Intra-arterial delivery of Stem Cells in Stroke
Walczak et al. Stroke 2008;39;1569-1574
Methods
• Female Sprague-Dawley rats 250-300 g
• 90 min suture induced reversible MCA occlusion (rMCAO)
• At 60 min post recanalization: Intra-carotid (IC) injection of vehicle or allogenic male rat MSCs in escalating dose groups
• Continuous Laser doppler flow signal (LDFS) monitoring over ipsilateral cortex
Longa et al. Stroke 1989;20:84-
91
Ultramicrospy: IA allogenic cGFP
MSCs, day 1 post injection
Control Day 1 post IA
MSCs
May 7th, 2014
CBF worsening is normalized on dose-de-escalation to 1 x 10^5 MSCs
-80
-60
-40
-20
0
20
40
LD
FS
Re
lati
ve
Ch
an
ge
(%
), 9
5%
CI
Placebo
(n=11)
5 x 104
(n=7)
2 x 105
(n=5)
1 x 105
(n=7)
1 x 106
(n=7)
5 x 105
(n=6)
p<0.05
Cerebro-Microvascular MSC
Transport: Diapedesis
a 10 μm b c 10 μm 10 μm
Pre-Clinical Efficacy Study
Reperfusion
90’ 60’ or 24h
Post-injection
Real time laser-Doppler flowmetry (LDF)
Neurodeficit assessment At 1, 7, 14, 21 and 28 days rMCAo
Safety and Efficacy Trial of MultiStem® in Adults With Ischemic Stroke
• Intravenous Bone marrow stem cells from healthy donors
• Given within 48 hours of stroke symptom onset
Patient Eligibility: Key Criteria
1. 18-83 years of age
2. Cortical MCA cerebral ischemic stroke
3. NIHSS 8-20
4. Onset of Stroke must have occurred within 24-48 hours
5. Acute cortical lesion measuring ≥ 5mL and ≤ 100mL
6. Subjects who received tPA or mechanical thrombectomy are allowed
• If they do, we are happy to transfer the patient preferably before the the 24 hour mark to allow us time for enrollment procedures and infusion of the stem cells (off the shelf from healthy donors bone marrow) before 48 hours from stroke symptom onset.