for posting nj symp biomatls draft ai caplan … caplan panel presentation. adult mesenchymal stem...
TRANSCRIPT
For postingNJ SYMP BIOMATLS
DRAFTAI CAPLAN
panel presentation
Adult Mesenchymal Stem Cells (MSCs) in Tissue Engineering
and Inflammation.
October 28,2010NJ SYMP on BIOMATERIALS SCIENCE
ARNOLD I. CAPLAN, PhDSKELETAL RESEACH CENTER
CASE WESTERN RESERVE UNIVERSITY
Disclosure Information.
Founder and was an officer of OSIRIS THERAPUETIC,Inc.
Current status: DIVORCED,NO stock, not a consultant but I do receive royalties thru CWRU.
OTHER CONSULTING activity is unrelated to this lecture.
The SCIENCE and CLINICAL USE of Adult
MSCs:from bench to bedside &
back to the lab.
Adult BONE MARROW
HSC MSCMesenchymal Stem Cells
1988
MSC
Pericytes: cells on capillaries and microvessels.
modified byBRUNO PEAULT
from http://www.geocities.c
o.jp/HeartLand-
Suzuran/9389/kekkan
ALL MSCs are PERICYTES!
INJURY
PERICYTE MSC ACTIVATED
MSCREGENERATIVE
MSC
PROPOSED SEQUENCE OF CHANGE
DUE TO INJURY:
2010
IMMUNO-MODULATORY
Anti-Apoptotic
Anti-Scarring
Angiogenic
Mitotic
MSC=pericyte
natural INJURY RESPONSE
Regenerative Micro-environment
T-cells, B-cells, Dendritic cells,
T-regs,etc
2010
Trophic
MSC = MedicinalSignaling
Cell.(the injury-specific DRUG STORE)
Muscle DerivedStem Cells
AdultMulti-lineage
Stem Cells
Fat Derived Stem Cells
MSC
BRUNO PEAULT
MSC MAPC
Cultured Pericytes Express Markers of hMSCs.
MSCs
Pericytes M Crisan et al, 2008
Adult MSCsHYPOTHESIS:
ALL MSCs are PERICYTESand are, thus, found thru-out the
body.
They function to stabilize blood vessels.They also function at sites of local tissue
damage to facilitate TISSUE REGENERATION.
What do Blood Vessels of different tissues in the organism
have in common?
Perivascular cells
Endothelial cells
ALL BLOOD VESSEL CELLS REFLECT THE TISSUE IN
WHICH THEY FUNCTION. THUS, SINCE EACH TISSUE IS
DIFFERENT, THE CELLS OF THE BLOOD VESSELS ARE
DISTINCTLY DIFFERENT.
11/2/2010
Dr. Bill Futrell, et al – Univ of Pittsburgh 1998“Discovered stem cells in fat that could
create new tissues like bone and cartilage”
Enabling Innovation:
Stem Cells from fat Extracted cells go to bone in vitro Fix fractures
Adipose derived adult Stem Cells(ASCs).
• Adipose tissue is a potential source for stem cells (ASCs) derived from pericytes.
• ~400,000 cells/mL of tissue.• 300-500-fold more cells in fat compared to
the same volume of bone marrow aspirate.• Marrow MSCs require exposure to TGF-β
to be chondrocytes; ASCs require both TGF-β and BMP-6 to be chondrocytes. Therefore, marrow MSCS ≠ ASCs.
Gimble et al. 2003; Guilak et al. 2004; Aust et al. 2004, Oedayrajsingh-Varma et al., 2006.
ALL blood vessels are not equal.Marrow MSCs are not fat MSCs.Marrow MSCs are not muscle MSCs.Marrow MSCs are not pulp MSCs.Marrow MSCs are not X MSCs.Marrow MSCs are not Y MSCs.Marrow MSCs are not Z MSCs.
Centrifugation
Passage Culture
Bone Marrow Aspirate
Adhere to Culture Dish
Primary MSC Culture
ColonyFormation
Plate cells at
Interface
Density Solution
Serum batch dependant
CFU-F1988
hMSCs
Chondrogenesis
ITS+dexamethasone
TGF-βascorbate 2-P
Osteogenesis10% FBS
dexamethasoneascorbate 2-P
β-GP
Adipogenesis
10% FBSdexamethasone
insulinIBMX
indomethacin
MULTI-POTENCY:
For TISSUE ENGINEERING uses.
Aspirate bone marrow
Cartilage Bone Tendon / Ligament
Isolate and culture-expand MSCs
Cryopreservefor future use
Fat
MSCs
TISSUE ENGINEERING
SCAFFOLD
1992, CWRU TRANSFERS MSC TECHNOLOGY TO FORM:
AIC separated in 1997. IPO 2006.
MSCs BIOACTIVE FACTORS
IMMUNO-SUPRESSIVE
TISSUES
REGENERATE
TURNOVER/ MAINTAINANCE
MICROENVIRONMENT/ MILIEU
Tissue Engineering
ALLOGENIC hMSCs: The Business of Today, 2010.
Business Model:allogenic hMSCs.
Donor bone marrow aspirate
Initial isolation and expansion in GMP
process
One Donation
Process Control Testing on
Intermediate
10,000 Doses of Final Product
Osiris Pipeline in Cell Therapy: 2010
GENZYME Corp=WORLDWIDE PARTNER
MSC CLINICAL TRIALS:2009: NIH website
85 WORLDWIDE36 in USA
26 in EUROPE23 in Asia ,
South and Central America, Australia,etc.98 in 2010
200 centers worldwide4 indications in Phase III • 3 with Fast Track
Worldwide Reach
SAFETY and
REGULATORY
Osiris Pipeline in Cell Therapy:
PROCHYMALGVHD Compassionate use:
Now(5/2008) APPROVED for PAYMENT & USE.
MULTIPLE Prochymal infusions(3-21) in 12 pediatric patients (5months to 15 years of age) suffering from treatment resistant, severe( grades
III/IV), end-stage GVHD:•All patients(12/12) showed a clinical response to
therapy with 58%(7/12) achieving COMPLETEresolution of GVHD. Less than 15% who fail
immunosuppression survive to 100days.•Clinical improvements in GI GVHD(75% COMPLETE
REMISSION and 3 with regression to grade I).No infusion toxicity or adverse events.
Dec.10, 2007
allo-MSCs for steroid-resistant, severe, acute GvHD(phaseII):
Katarina LeBlanc et al (Lancet 371:1579-86, 2008)55 patients(30 complete response,9 improved).Dose hMSCs:1.4x106 cells/kg (0.4-9).
27patients(1 dose), 22(2 does), 6(3-5 doses).HLA-identical siblings (=5).Haplo-identical donors (n=18).3rd party HLA-mismatch (=69).POSITIVE EFFECTS IRRESPECTIVE OF allo-DONOR.No side-effects (during or after), Lower transplant-related mortality(1yr), Higher overall survival@2yrs.
MSC
S S Iyer & M Rojas: Expert Opin. Biol. Ther. (2008) 8:569-581.
Immuno-modulation
Osiris Pipeline in Cell Therapy
Efficacy Results– Every patient evaluated had a reduction in disease severity
by day 28
– 105 point improvement in CDAI (p=0.004)
Safety Results– No attributed SAE’s– Well tolerated– Outpatient administration (20-70 min)
Phase II :Clinical Evaluation Prochymal in Treatment-Resistant Crohn’s Disease.
Trial Design— 10 patient, prospective, randomized, open label
trial— Average CDAI was 350— Average length of disease was 14 years— Failed previous treatment with steroids,
methotrexate, and Remicade
Osiris Pipeline in Cell Therapy:
Preclinical data
Swine Ischemia / Reperfusion Model:
TROPHICCAPLAN: CELL PRODUCED,
BIOACTIVE FACTOR MEDIATED:1. ANTI-APOPTOTIC/CYTOPROTECTIVE>
Limits field of ISCHEMIC injury
2. ANTI-FIBROTICANTI-SCARRING
3. ANGIOGENIC> VEGF+ PERICYTE
4. MITOTIC/Regenerative Milieu
PROCHYMALPHASE I: Safety study.
53 patient, double-blind, placebo-controlled and preliminary efficacy of intravenous administration.
• Arrhythmias, 4X less (9% vs 37%,p=.025).• PVCs, premature ventricular contractions >10/hr ,fewer at all
time points,1-6 month (11% vs 24%,p<.001).• Prompt heart rate recovery,<15 min for 6 min walk,
(55% vs 26%, p=.08).• Lung function improved, FEV% predicted values,
(17 point vs 6 point, p<.05).• R. Mills: ”The sicker the patient the better the result”.
MICHAEL CHOPP
MICHAEL CHOPP
MSCs and MSin collaboration
withRobert Miller et al:
Immuno-suppressive & trophic.
MSCs and progression of demyelinating disease:
The EAE-Model.Inject myelin proteins MOG or PLP
to induce disease.
10-20 days: Inject human Mesenchymal Stem Cells.
Do hMSCs alter disease progression?
hMSCs
0 5 10 15 20 25 30 35 40 45 500
1
2
3
4
5 EAE+PBS
EAE+hMSCsC
linic
al s
core
s of
EAE
hMSCs
C57/BL/6J mice/MOG35-55
IMMMUNO-MODULATORY
and TROPHIC
MSC-mediated:1. STROMA: Bone marrow transplant.
2. HEART: Infarct (ischemia).3. BRAIN: Stroke (ischemia).4. SPINAL CORD: Axonal regeneration.
5. LUNG: Asthma,inflammation.6. GI: Inflammatory Bowel Disease( Crohn’s ).
7. KIDNEY: Acute Renal Failure(ischemia).
8. MENISCUS: Tissue Regeneration,OA.
9. TENDON: Horses(Vet-Stem).10. Diabetics: hMSCs into mice.
MSC-mediated:
11. Rheumatoid Arthritus12. SLE13. ALS14. MS15. HIV / AIDS?16. Autism?17. OTHER (poly-trauma)???????
MSCTROPHIC BIOACTIVE FACTORS
IMMUNO-MODULATORY
Anti-Apoptotic
Anti-Scarring
Angiogenic
Mitotic
MSC=pericyte
natural INJURY RESPONSE
Regenerative Micro-environment
T-cells, B-cells, Dendritic cells,
T-regs,etc
2010
Trophic
Mesenchymal Stem Cell (MSC)
SkeletalResearch Center
College of Arts and Sciences
Cleveland,Ohio