Translational Research For Interventional Neurologists

Transcription

1 SVIN Annual Meeting, November 8 th, 2014, Hollywood, FL 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

2 Financial Disclosures 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 Dileep R. Yavagal, MD

3 Funding UM Endovascular Stroke Translational Research Laboratory 1. Department of Neurology, University of Miami: Interdepartmental Research Development Initiative (IRDI) grant: Anderson Family Gift : , Florida Biomedical New Investigator Grant: CTSI NIH Grant: Jan 2013-May 2014

4 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

5 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

6 Why Translational Research

7 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.

8 Why Translatational Research NIH has made translational research a priority centers of translational research the Clinical and Translational Science Award (CTSA) program in 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

9 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

10 IA vs IC vs IV cell delivery: Timing of migration and distribution of Cells

11 Biodistribution of cells in IA vs IV delivery Pendharkar et al Stroke 2010;41; Dileep R. Yavagal, MD

12 Intra-carotid NSCs at 48 hours post mouse hypoxia-ischemic model Guzman et al. Stroke 2008;39;

13 Acute administration of MSCs post If cells mediate benefit mainly through neuroprotection, acute delivery to maximize chances of tissue salvage Challenges: excitotoxicity, periinfarct depolarization, reactive O2 species release recanalization

14 Intra-arterial delivery of Stem Cells in Stroke Walczak et al. Stroke 2008;39;

15 Methods Female Sprague-Dawley rats 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

16 Ultramicrospy: IA allogenic cgfp MSCs, day 1 post injection Control Day 1 post IA MSCs

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18 May 7 th, 2014

19 LDFS Relative Change (%), 95%CI CBF worsening is normalized on dosede-escalation to 1 x 10^5 MSCs p< Placebo (n=11) 5 x 10 4 (n=7) 1 x 10 5 (n=7) 2 x 10 5 (n=5) 5 x 10 5 (n=6) 1 x 10 6 (n=7)

20 Cerebro-Microvascular MSC Transport: Diapedesis a 10 μm b 10 μm 10 μm c

21 Pre-Clinical Efficacy Study A or 24h Injection rmcao Reperfusion Post-injection Neurodeficit assessment At 1, 7, 14, 21 and 28 days Real time laser-doppler flowmetry (LDF)

22 Mean ND Score, 95% CI Significant Functional Benefit with 24h_IC MSC p=.49 p=.02 p=.01 p=.003 p< Day 1 Day 7 Day 14 Day 21 Day 28 IC_PBS_24h IV_MSCs_24h IC_MSCs_1h IC_MSCs_24h

23 Infarct volume (mm^3), 95% CI Infarct Volume Is Significantly lower in IC_MSC_24h p=.01 IC_PBS_24h (n=5) IC_MSCs_1h (n=5) IV_MSCs_24h (n=8) IC_MSCs_24h (n=9)

24 Infarction frequency map and Statistical comparison PBS-control (n=5) MSCc-treated (n=9) Fisher s Exact Test

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26 Howells et al. J Cereb Blood Flow Metab August; 30(8):

27 Unique Advantages of Large Animal Studies Route of Cell Administration Cell dose finding Cell Tracking in a larger brain DTI in larger brain?

28 Canine Neurovascular Anatomy

29 Dog CCA bifurcation

30 Superselective catheterization of ICA

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32 Canine Endovascular MCA occlusion Model Yavagal et al, SVIN 4 th Annual Meeting

33 MRA COW

34 RMCA RMCA LMCA LMCA rmcao TCD Velocities over Canine MCA s during IC MSC injection Post rmcao During IA delivery of 10 x 10 6 MSCs Post IA MSCs 34

35 D10-009; subacute IA 10 x 10 6 MSCs 48 hrs post stroke FLAIR 29 days post stroke FLAIR

36 D10-011; subacute IA 10x 10 6 MSCs 48 hrs post stroke FLAIR 21 days post stroke FLAIR

37 D10-002; treatment with IV 5 x 10 6 MSCs 3 day post stroke T2 58 day post stroke T2

38 Intra-arterial Stem Cell Clinical Trials, Published Study/ Countr y Type of stroke Design No. of patie nts Cell type Timing of IA delivery Dose Followup Mendonca 2006; Correa 2007/Brazil MCA ischemic stroke Case reports on phase I, nonrandomi zed, open label 2 (no controls) Auto BM- MNCs 5d & 9d 1 x 10 8 (1 pt.) and 3 x10 7 (1 pt.) 2-4 mo Battistella 2011; Rosadode- Castro, 2013/Brazil MCA ischemic stroke Phase I, nonrandomi zed, open label 12 (no controls) Auto BM- MNCs d (mean 64.5d) 1 x 10 8 to 5 x10 8 (mean 3.1 x 10 8 ) 6 mo Friedrich, 2012/Brazil MCA ischemic stroke Phase I/II, nonrandomi zed, single-blind (CT) 20 (no controls) Auto BM- MNCs 3-10 days (mean 6 d) 5.1 x 10 7 to 6 x10 8 (mean 2.2 x10 8 ) 6 mo Moniche et al., 2012/Spain MCA ischemic stroke Phase I/II, nonrandomi zed, single-blind 10 (10 controls) Auto BM- MNCs 5-9d (mean 6.4 d) mean 1.6 x 6mo 10 8 Jiang et al., 2012/ China MCA ischemic (3) hemorrhagic (1) stroke Phase I, nonrandomi zed, open label 4 ( no controls) Allogeneic UC-MSCs 11 to 50 days (mean 25.5) mo

39 RECOVER-Stroke: Clinial Trial of Autologous Marrow Cell in Stroke Phase 1 / 2 Study of ALD-401 Via Intracarotid Infusion in Ischemic Stroke Subjects Randomized trial of Autologous stem cells 2 weeks (13-19 days) post stroke 100 patients IA delivery within 48 hours of bone marrow harvest Safety endpoints: Clinical AE s and SAE s Efficacy endpoints: Clinical functional recovery scales at 90 days, 6 mo and 12 months

40 Multistem: Stroke Stem Cell Trial at JMH and UMH Double-Blind, Randomized, Placebo-Controlled Phase 2 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

41 Patient Eligibility: Key Criteria years of age 2. Cortical MCA cerebral ischemic stroke 3. NIHSS Onset of Stroke must have occurred within 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.

42 Acknowledgements Mentors: Joshua Hare, MD Miguel Perez-Pinzon, PhD Tanja Rundek, MD, PhD Collaborator: Ami Raval, PhD Biostatistics: Chanhui Dong, PhD Tienlong Pham, Philip Garza, BS, Baowan Lin, MD, Dalia Milan, Ami Raval PhD, Pedro Cifuentes, MD Rat and Canine MSCs: Aisha Khan Ian McNiece PhD, ISCI, University of Miami

43 Thank you!