Cara East MD, Director The team of SCRC research physicians and staff Soltero CV Research Center, Baylor Research Institute Baylor Jack & Jane Hamilton Heart & Vascular Hospital Baylor University Medical Center Texas A&M College of Medicine
Alexander Alexandrowitch
Maximow Born 1874 St Petersburg,
Russia He first theorized that all
hematopoetic cells develop from 1 precursor cell (the stem cell) Professor of Anatomy at the University of Chicago Died 1925 of coronary atherosclerosis
Sea stars may reproduce asexually by fragmentation. Each arm can regenerate an entire organism. Thus, early fisherman who cut up the creatures who ate their oysters actually created many more. Wikipedia 2010
We know the body repairs Blood vessels: vessels repair minor cuts frequently Bone marrow: marrow your red cells, which carry
oxygen, are completely l t l replaced l d every 21 days d Liver Liver: after injury or infection Bones Bones: grow and change slowly over the years Starfish Starfish: can regenerate an arm
Sources of Stem Cells • All tissues have some stem cells present
for local repair (including the heart and brain). • Only the bone marrow regularly produces
stem cells for export into the blood. • Adipose tissue is rich in stem cells, which
are likely present to participate in local repair, which is one major role for fat in skin.
Sources of Stem Cells for therapeutic purposes Bone marrow: marrow Requires aspiration and at least some
processing (to remove blood cells and bone elements). Adipose tissue tissue: Requires Adi ti R i collection ll ti (liposuction) (li ti ) andd
some processing. Blood Blood: Larger number of stem cells can be mobilized
using manufactured cytokines (and specifically GCSF). Both cord blood and menstrual blood are rich in stem
cells.
PI: Barron Hamman MD PI: Barron Hamman Poupak Moshayedi MD Cara A East MD Johannes Kuiper MD Robert F Hebeler Robert F Hebeler MD Luis A Pineiro Luis A Pineiro MD Hal C Hal C Urschel Urschel Jr MD
Aastrom Surgical Trial For treatment of dilated cardiomyopathy (ischemic and
nonischemic).
Patients who have congestive heart failure in spite of
use of maximal medication therapy and biventricular implanted defibrillators Bone marrow, 50 mL, was collected from the patient. It was then processed over 2 weeks in a closed incubation system to expand the preferred cell types. Placed directly into the left ventricular muscle using a left lateral thoracotomy, beating heart, no heart‐lung bypass machine needed. FDA study phase 2
Aastrom Surgical Trial Heart Attack
1
Healthy Heart H lth H t
2
Infarcted Myocardium
3
Fibrosis/Scar Formation
Heart Failure
4 20
Dilative Cardiomyopathy
Aastrom Surgical Trial Analysis of this Phase 2 trial showed: Stem‐‐cells Stem
Usual care
• Adverse events
25
• NYHA FC 12 mo’s better
13
15 5
• NYHA FC 12 mo’s no change
2
2
• 6 minute walk 12 mo’s better
13
5
• 6 minute walk 12 mo’s no change 1
0
• No significant change in EF Amit Patel MD, University of Utah
Aastrom Surgical Trial Safety and Efficacy of Ixmyelocel‐T, an Expanded Patient‐Specific Mixed Cell Product in Dilated Cardiomyopathy (IMPACT‐DCM) Amit N. Patel, Baron L. Hamman, Brian Bruckner, Omar M. Lattouf, Nicholas G. Smedira, Cara East, David A. Bull; Ronnda L. Bartel, Sharon Watling. HFSA Annual Meeting, September, 2011 Safety and Efficacy of Ixmyelocel‐T, An Expanded Patient‐Specific Mixed Cell Product, in Dilated Cardiopyopathy (IMPACT‐DCM) Brian Bruckner, Amit N. Patel, Baron L. Hamman, Omar M. Lattouf, Nicholas G. Smedira, Ronnda L. Bartel, and Sharon Watling. Sharon Watling International Society for Heart and Lung Transplantation, International Society for Heart and Lung Transplantation November 2011 Ixmyelocel‐T, A Unique Mixed Cellular Therapy for the Treatment of Vascular Diseases Associated with Endothelial Dysfunction KJ Ledford, EN Murphy, F Zeigler, RL Bartel, AHA Arteriosclerosis, Thrombosis and Vascular Biology 2013 Scientific Sessions, May 2013 Ixmyelocel‐T Therapy Alternatively Activated Macrophages Potentially Exert Atheroprotective Effects KJ Ledford, C Parrish, F Zeigler, RL Bartel. Keystone Symposia on the Molecular Basis of Vascular Inflammation and Atherosclerosis in Big Sky, Montana, starting Sunday, March 2012
Safety and Efficacy of Ixmyelocel‐T, A Patient‐Specific Expanded Multicellular Therapy, in Dilated Cardiomyopathy Timothy D. Henry, Jay H. Traverse, Rod Badger, Marco Costa, Patricia Mitchell, Kristen Kolsch, Ronnda L. Bartel, Sharon Watling, Amit N. Patel. Society for Cardiovascular Angiography and Interventions (SCAI), May 2012
Aastrom Surgical Trial Challenges: • Surgery is required to deliver stem cells. Thus, not
justified to do a randomized, blinded study. • The surgery though is a left lateral thoracotomy, so Th th h i l ft l t l th t
patient home in 3 days and no complications of the heart‐lung machine. • The endpoint of VO2 max on a metabolic stress test is
a hard endpoint, as are hospitalizations for CHF and death. • Where we first noted the phenomenon of “stem cell
high.”
J ff y Schussler PI: Dr Jeffrey PI: Dr Jeffrey Schussler Dr Paul Dr Paul Grayburn Grayburn Dr Luis Pineiro Dr Cara East Dr Carlos Velasco
Baxter RENEWTrial Intractable angina. No further revascularization options. Area(s) of ischemia that could benefit. Area(s) of ischemia that could benefit Stem cells, CD34+, mobilized into the blood
using G‐CSF, collected by apheresis, and cleaned. Stem cells implanted using the NOGA system. FDA study phase 3
Baxter RENEW Trial Challenges: • Mapping being used to direct injections. • Apheresis A h i takes 4 hours and a large IV. k h d l IV • Training of the physician researchers. • Takes 2 physicians to keep the NOGA injection
catheter pressed on the LV wall correctly. • Endpoints will be time to angina on ETT and
angina diaries (so, soft endpoints).
PI: Dr Jeffrey PI: Dr Jeffrey Schussler J ff y Schussler Dr Paul Dr Paul Grayburn Grayburn Dr Luis Pineiro Dr Cara East Dr Carlos Velasco
Safety and Efficacy of Ixmyelocel Ixmyelocel--T, A Patient--Specific Expanded Multicellular Patient Therapy, in Dilated Cardiomyopathy An increasing number of patients have ongoing
congestive heart failure symptoms despite optimal medical and device therapy. Current options include left ventricular assist devices
or cardiac transplantation. There are not enough hearts for transplantation for all
who need them. Cell therapy is an attractive alternative Timothy D Henry MD, Minneapolis Heart Institute
45000
Cytokine Seccretion (pg/mL)
40000 35000 30000 25000 Basal 20000
+LPS
15000 10000 5000 0
IL‐10
IL‐1ra
TNFα
IL‐1β
IL‐12
Aastrom Cath Trial Challenges: • Cells collected from the bone marrow and
grown in vitro for 12 days at an off‐site location. grown in vitro for 12 days at an off site location • Training of the physician researchers. • Takes 2 physicians to keep the NOGA injection
catheter pressed on the LV wall correctly. • Endpoints will be hard endpoints (EF, serious
adverse events, 6 minute walk)
PI: Dr Jeffrey PI: Dr Jeffrey Schussler J ff y Schussler Dr Paul Dr Paul Grayburn Grayburn Dr Luis Pineiro Dr Cara East Dr Carlos Velasco
A plasmid, called JVS-100, has been developed that
contains a construct of the SDF-1 gene. The SDF-1 gene is a chemokine that attracts endothelial
progenitor cells from the bone marrow. When present, circulating stem repair cells stop and enter
the tissues expressing the SDF-1 gene.
STOP HF Trial Challenges: • It is an advantage to be able to simply take a gene
product from the freezer.
• Gene products have the disadvantage that the body
will eventually remove the added gene.
• The Biocardia catheter is bulky and cannot be placed
inside hearts with moderate aortic stenosis.
• The Biocardia system is easily handled by 1
cardiologist.
• Endpoints will be hard endpoints (EF, serious adverse
events, 6 minute walk).
PI: Gregory J Pearl MD K Blaire K Blaire Kerwin Kerwin BS Cris D Molina BS Pamela J Coker Pamela J Coker RN RN Luis A Pineiro Luis A Pineiro MD Harold C Urschel Harold C Urschel Jr MD Cara A East MD
Harvest BMAC Trial This is a treatment for critical limb ischemia for patients
for whom other therapies have not worked, who have some tissue loss, and thus are being watched expectantly for probable amputation. The stem cells are collected from the bone marrow in the
operating room (240 mL). Processing of the stem cell product takes about 30 minutes
and also takes place in the operating room. Cells are injected along the vessels below critical
obstruction, using sonographic guidance. FDA study phase 3
RANDOMIZATION FLOWCHART
SALINE
A
BLOOD
RANDOMIZED TO CONTROL N = 14
INVESTIGATOR BLINDED TO INJECTATE
RANDOMIZE
• 40 injections
B
• 1 mL per injection
RANDOMIZED TO TREATMENT N = 34
BONE MARROW
Amputation Rates by trial
Randomized controlled trials Randomized controlled trials
302 subjects – 302 subjects – 213 BMAC
1
Harvest BMAC Trial Challenges: • Complete bone marrow is used, so this includes
any local cytokines. any local cytokines • A large volume of bone marrow of 240 mL must be
collected. • Delivered locally, but with sonographic guidance to
place the cells in peri‐vascular locations. • Endpoints of healing of sores and amputation are
hard end‐points.
There are many questions still to be asked and answered.
Uses and advantages of cord blood stem cells First Cord Blood transplant in 1988 for a case of
Falconi anemia. Since Si usedd for f treatment off leukemia l k i andd immune i
deficiencies. Less HLA matching required (75% match with
siblings). Less Graft vs Host Disease. 4000 patients have been treated to date
Disadvantages of cord blood stem cells May not be wise to use to treat autoimmune diseases or
leukemia, as the systemic genes associated with the disorder di d are still till present. t The 75 mL volume collected likely cannot be used
singly to treat a normal-sized adult. Higher rates of relapse due to lack of graft vs host
disease.
California Stem Cell Agency to Allocate $70M for Clinical Trials The California Institute of Regenerative Medicine’s board
signed off on the allocation of $70M to begin setting up clinics and to bring a number of developing stem cell therapies into clinical trials. The network, called the Alpha stem cell clinics network,
will consist of 5 sites at established academic institutions and a coordinating center that will help streamline patient enrollemtn, management of regulatory procedures, and data sharing.
Thank you for joining us today.
Bone marrow has shown regenerative potential in various applications
Multipotent Stem Cells Progenitor Cells Accessory Cells Signal Cells
HARVEST TECHNOLOGIES CORP.
Stem cells What kind of stem cells should we use? How are the stem cells collected? From a tissue,
like bone marrow or muscle, or from the blood. Which stem cells? Do we use separate out
specific cell types or use a wide collection of cells? How do we deliver them to the tissues we want to
repair? If stem cells work, how long will they continue to
work?
Fig. 2 Unipolar voltage map (color range, 6.7–12 mV).
Scarred areas (unipolar voltages,