www.chamc.co.kr
Aspect of Stem Cell-Based Therapies:
Insights and Lessons from Ongoing
Human Clinical Trials using stem cells
Clinical Excellence & Proof of Concept
Hospitals
Kwang Yul Cha, MD.
CHA Stem Cell Institute, CHA University,
CHA Health Systems, Seoul, Korea
01. Stem Cell Therapies
Stem Cell Sources
Ongoing Clinical Trials
Ideal Cell Sources for Stem Cell Therapy???
Ideal Cells for
Application
Embryonic Stem Cells
SCNT-derived ESCs
Parthenogenic embryo-derived ESCs
Single blastomere-derived ESCs
Induced Pluripotent Stem Cells Mid brain tissue from aborted fetus
Autologous Adult Stem Cells
Adipose-derived
Peripheral blood-derived
Bone marrow-derived
Testicular stem cells (HTSC)
Allogeneic Adult Stem Cells
Cord blood-derived
Placenta-derived
Wharton’s jelly
Number of Ongoing Clinical Trials using Stem Cells- Clinicaltrials.gov, updated on March 25, 2014 -
Stem Cell Sources # of clinical trials
Cord blood stem cell 17*
Adipose stem cell 78
Embryonic stem cell7 (ACT, CHA Bio & Diostech,
Pfizer, Assistance Publique -Hôpitaux de Paris )
BM stem cell 75*
Umbilical cord stem cell 28
Placenta stem cell 7
*exclude blood related diseases using transplantation of hematopoietic cells
Provided by National Institutes of Health (NIH)
Cell sources IndicationProof of Concept
Pre-Clinical
Phase I Phase II Phase III
hES-RPE Stargardt’s Disease*
Age Related Macular
Degeneration*
Fetal-NPC Parkinson’s Disease*
Umbilical Cord Blood Cerebral Palsy
PLX-PAD Intermittent Claudication
AKC(NK, DC Cells)
Glioblastoma
Ovarian Cancer
Liver Cancer
ADMSC (Adipose derived)
Deg. Arthritis
Cartilage Defect
Ligament Injury
Disc Degeneration
UCB-EPO/G-CSFBrain Diseases
(ALS, TBI..)
PlaStem (Placenta stem cells)
Alzheimer’s Disease
Stroke, TBI,
Anti-aging
Radiation Colitis
CordStem (Wharton Jelly MSC)
Degenerative
Arthritis
Stroke
Colitis
Umbilical Cord Blood Muscle marasmus
Alpha Stem Cell Hospitals: Global Clinical Trial Center
Ongoing Stem Cell-Clinical Trials
in CHA Health Systems
1. Blindness (Stargardt’s Disease, AMD): RPE cells
2. Parkinson’s Disease : Fetal stem cell-NPCs
3. Cerebral Palsy: Cord blood stem cells
4. Intermittent Claudication: PLX-PAD
5. Human Embryonic Stem cells:
Somatic Cell Nuclear Transfer-hESC Generation
HESC- Retinal Pigment Epithelial CellClinical study process is ongoing
- November 19, 2009 : pre-clinical activities in preparation of the first IND filing with the FDA (USA)
- March 2010: Granted Orphan Drug Status from FDA for Treatment of Stargardt’s Macular Dystrophy
- In 2010 and 2011, Approval of Clinical trial in USA and in Korea (Phase I / IIa)
Normal: Dryness Abnormal: Humid
RPE
Photoreceptors
hESC RPE Clusters Expansion
differentiationRPE products
Drusen, tiny yellow or white accumulations is small in normal.
But is large in Macular Degeneration.
1. Blindness (Stargardt’s Disease, Age-Related Macular Degeneration, & MMD)
HESC- Retinal Pigment Epithelial Cell
1. Blindness (Stargardt’s Disease, Age-Related Macular Degeneration)
Dry AMD
HESC- Retinal Pigment Epithelial CellClinical study process is ongoing (50000 cells/150ul of injection)
- No tumorigenicity, ectopic tissue formation, rejection, serious adverse events (6-12 months FU)
- Slow gradual improvement observed only in the “study eye”.
- Best corrected Visual acuity Pre-op 25 -> 35 letters, Improved VF
1. Blindness (Stargardt’s Disease, Age-Related Macular Degeneration, & MMD)
Post op photography and OCT shows pigmentations suggesting engrafted RPEs
OCT:
optical coherence
tomography
Befo
re inje
ction
After
inje
ction
Traditional Way: Grafting cells from 5-6 embryos into Striatum
New Way: Grafting expanded cells from one embryo into Striatum.
• Expanded Cells and their safety have been successfully characterized
Several Embryos used
Limited Sources
Ethical Issue
Heterogeneous NPCs
One Embryo can cure 50000 patients
Overcome limited sources
Reduce the ethical issues
Homogeneous NPCs
2. Parkinson’s Disease : Fetal stem cell-NPC
2. Parkinson’s Disease : Fetal NPCs
Human FMDNPCs- Fetal Midbrain derived-Neural Precursor Cells(56-year-old woman, Stage 3 UPDRS; Hoehn & Yahr Staging)
8 patients transplanted so far. 3-6 month follow up
2. Parkinson’s Disease : Fetal NPCs
Human FMDNPCs- Fetal Midbrain derived-Neural Precursor Cells
8 patients transplanted so far. 1-3 month follow up :
MDS UPDRS
UPDR
S pa
rt III
rate
(%)
[(pre
OP
- 1m
onth
)/pre
OP]
0
5
10
15
20
25
30
35
Low dose
High dose
n=5
n=3
- No Serious or mild adverse events
- Trend of UPDRS scores showed Motor function is getting improved one month
after transplantation
UPDRS: Unified Parkinson’s Disease Rating Scale
Pre OP Post OP 1month 3month
MD
S U
PD
RS
part
III
(o
ff)
0
10
20
30
40
50
60
Low dose
Middle dose
n=5n=3
Improvement RateUPDRS Motor Function
Low dose: 1*106 cells/ 250ul, 4 points
Middle dose: 4*106 cells/ 250ul, 4 points
High dose: 1*107 cells/ 250ul, 4 points
2. Parkinson’s Disease : Fetal NPCs
Human FMDNPCs- Fetal Midbrain derived-Neural Precursor Cells
8 patients transplanted so far. 6 month follow up :
2 out of 5 shows similar improvement
Increase in Dopamine release measured 6 months after transplantation
Rt. 11.98260 4.679864 2.434480 -2.369370 2.224099 16.90808
Lt. 0.887362 -0.678970 2.448113 0.549629 1.670684 12.59759
1. Preclinical Study
Newborn cerebral palsy in a rat model with improved neurological effects
(Meier et al, Pediatric Research, 2006 , IP infusion)
(Pimentel-Coelho PM at al, Stem cell Dev, 2009, IP infusion)
2. Ongoing studies
3. Cerebral Palsy
Cord Blood Stem Cells
3. Cerebral Palsy
Cord Blood Stem Cells
Stem Cells, 2012 DEC
3. Cerebral Palsy
Cord Blood Stem Cells
Changes in motor function11 month-old mixed(spastic & dyskinetic) type cerebral palsy by hypoxic brain injury, who had
received active rehabilitation more than 6 months before UCB transplantation with very slow functional gain
Expanding target disease including Stroke, developmental retardation
Before UCB
transplantation
3 months after UCB
transplantation
6 months after UCB
transplantation
Stem Cells, 2012 DEC
3. Cerebral Palsy
Cord Blood Stem Cells
Stem Cells, 2012 DEC
Changes in motor function4 year 6 month-old spastic diplegia cerebral palsy by periventricular
leukomalacia, who had received active rehabilitation since her infant age with very slow functional gain
6 months after UCB
Transplantation
Before UCB
transplantation
Expanding target disease including Stroke, developmental retardation
Changes in fiber tractography
(all fiber that passes mid pons)
At the time of UCB
transplantation
6 months after UCB
transplantation
3. Cerebral Palsy
Stem Cells, 2012 DEC
Brain PET Results
UCB + EPO + Rehab: improved activity in frontal lobe, basal ganglia, and thalamus
EPO + Rehab: improved activity in frontal lobe
Rehab: improved activity in cerebellum only
3. Cerebral Palsy
Stem Cells, 2012 DEC
List of ongoing clinical trial using Cord Blood Stem Cells
PLX-PAD, Placental Expanded Cells(PLX) -by Pluristem Co. and CHA Hospitals
4. Intermittent Claudication: PLX-PAD
• Phase II Clinical Trial, multicenter, multinational, randomized, double-blind, placebo controlled, parallel-groups study
• Single treatment of PLX-PAD high dose and additional treatment of Placebo.
Clinical Trial Result 30 IM injections
Stem cells,.2009;27
Somatic Cell Nuclear Transfer-hESC Generation
• SCNT-hES cells are the most ideal
patient HLA-matched stem cells.
• SCNT is the only known procedure for
complete and normally reprogramming a
somatic cell.
• Because SCNT is more effective than
iPS cells technology for reprogramming
cells, and can be done without inserting,
continued studies of SCNT could help
scientists find the linchpin to make
reprogramming factors more efficient
and effective.
John Gearhart, 2009
5. Embryonic Stem cells: SCNT
Somatic Cell Nuclear Transfer-hESC Generation- CHA Stem Cell Institute was approved for the SCNT-hESC Research
by Korea Government in May 2009
• Derivation of patient-specific human
pluripotent stem cells via somatic cell
nuclear transfer (SCNT) has potential
for application in a range of
therapeutic contexts.
7. Embryonic Stem cells: SCNT
Cell Line1 Cell Line2
Arrow indicates oocyte spindle
Cut zona pellucida
Enucleation
somatic donor cell using fusion protein
Mature oocyte
under poloscope
Clinical Application:
Production of Patient-specific SCNT-RPE
5. Human Embryonic Stem cells: SCNT
Production of Patient specific
SCNT-derived RPE
Schematic view of Clinical Application of SCNT
02. Clinical Research Hospitals
Clinical Excellence & Proof of Concept
Hospitals
“ From Bench to Bedside:
Make stem cell clinical trials possible in one place”
Hospitals
Infrastructures,
GMP facility, CMO, CRO
Bio Ventures in both
Korea including CHA
Bio and global
companies
Institutes
for preclinical studies
Global Stem Cell Clinical Trial Hospitals
Clinical Excellence & Proof of Concept Hospitals
Vertical Integration : Discover → Develop → Deliver
Discover Institutes forPreclinic Studies
Stem cell clinical trials possible in one organization
• CSCI : CHA Stem Cell Institute• CRI : CHA Research Institute• CRMI : CHA Regenerative Medicine Institute (Non-Profit, LA)• CHA University & CHA University School of Medicine
Vertical Integration : Discover → Develop → Deliver
Bio Ventures including CHA Bio in Korea
and global companies
Stem cell clinical trials possible in one organization
• CHA BIO & DIOSTECH• Stem Cell & Regenerative Medicine Int’l (Boston)• Global R&D Collaboration Center (LA, Tokyo)• Seoul CRO (Contract Research Organization)
Develop
Vertical Integration : Discover → Develop → Deliver
Hospitals,GMP facility, CMO,
CRO
Stem cell clinical trials possible in one organization
• 3 General Hospitals (Gangnam, Bundang, Gumi)• 2 Women’s Hospital s(Bundang, Daegu)• Fertility Center (Gangnam)• LA HPMC General Hospital• CHA LA Fertility Center
Deliver
“ From Bench to Bedside: A Focused & Integrated Business Model”
Global Stem Cell Clinical Trial Hospitals
Clinical Excellence & Proof of Concept Hospitals
CHA Anti aging Institute
CHA Fertility Center(LA)
LA Hollywood Presbyterian
Medical Center
CHA University
Daegu Women Hospitals
CHA Fertility Center(LA)
Boston Stem Cell Intl
Bundang CHA Women Hospitals
CHA Bio & Diostech
Kangnam CHA Hospitals
Gumi CHA Hospitals
CHA Fertility Center
Group Health Diagnostic Center
CHA BIO COMPLEX
Global Stem Cell Clinical Trial Hospitals
Clinical Excellence & Proof of Concept Hospitals
The CHA Bio Complex will embody the new concept of combiningacademia, basic research,clinical research, business development.
The CHA Bio Complex with its newly built building (60,000 m2) will accommodate several research institutes such as:
infertility, stem cells, regenerative medicine, cancer prevention, genomics, nano-bio, drug development, state-of-art facilities for medical & biomedical education.
To commercialize research outcomes, we will also incorporate: several bio-ventures corporate R&D institutes.
CHA-ASRM International Joint Conference on
Inauguration of CHA Bio ComplexMay 29-30, 2014
CHA Bio Complex, Pankyo, Korea
CHA-American Society for Reproductive Medicine Joint Conference
Mini-Pacific Society for Reproductive Medicine Conference
General Secretariat : [email protected]
Tentative Speakers:Rebecca Sokol, ASRM Acting President, USA
Roger Lobo, ASRM Past President, USA
Andrew La Barbera, Chief Scientific Officer, USA
Robert Rebar, Past Executive Director, USA
Robert Lanza, ACT, USA
Kwang-Soo Kim, Harvard Medical School, USACHA Stem Cell Institute Past President
Tony Atala, Wake Forest Institute, USA
Zami Aberman, Pluristem, Israel
Chii-Ruey, Tzeng,Taiwan
Bunpei Ishizuka, Japan
Yoshiharu Morimoto, Japan
Nao Suzuki, Japan
Kotaro Yoshimura, Japan
Kwang-Yul Cha, Korea
Dong-Ryul Lee, Korea
Thank you!
CHA Bio Complex, 700,000 sq
Open in April, 2014