aspect of-stem-cell-based-therapies-kwang-yul-cha

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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


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


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


Stem Cells, 2012 DEC

3. Cerebral Palsy


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


3. Cerebral Palsy



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


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


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


Bio Ventures including CHA Bio in Korea

and global companies


• CHA BIO & DIOSTECH• Stem Cell & Regenerative Medicine Int’l (Boston)• Global R&D Collaboration Center (LA, Tokyo)• Seoul CRO (Contract Research Organization)

Develop


Hospitals,GMP facility, CMO,

CRO


• 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”



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



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

aspect of-stem-cell-based-therapies-kwang-yul-cha

Technology

stem cells

adipose stem cell

stem cell therapy

fetal stem cellnpcs

cord blood stem cells

umbilical cord stem

human embryonic stem

cha stem cell institute