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Using Stem Cells as Drug Discovery Tools
Presentation for XenoTech LLCLenexa, KS May 1st, 2008
By: Jim Hardy President & CEO Gahaga Biosciences, Inc.
Background Wittenberg University (BA) University of Rochester BRL/Life Technologies, Inc. BP Solar In Vitro Technologies Gahaga, APE-BridgePath Scientific @
FITCI
Stem Cell Time Line20
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$- $1,000 $2,000 $3,000 $4,000 $5,000 $6,000 $7,000 $8,000 $9,000 1961: Canadians Jim Till & Ernest
McCulloch prove the existence of stem cells (Nature 1963)
1978: Hematopoietic SC discovered in UCB
1981: mouse ES cells isolated
1988: HSC isolated from blood
1992: Adult neural SC discovered
1994: first Cancer SC discovered
1996: Dolly the Sheep
1998: first human ES line
RegMed 2.0
USD (m
illions)
Stem Cells for Drug Discovery
ES cells: › pluripotent › Limited number of cells and strains available› Regulatory environment› Political/ethical issues
“Adult” SC: › lineage dependant› Not easy to isolate or proliferate in sufficient
quantities› Most widely used/accepted in clinical
applications
Stem Cells for Drug Discovery continued…
IPS (induced Pluripotent SCs)› Latest thing› Still a lot of uncertainty
Perinatal tissue: UCB & Afterbirth› Ephemeral organ› Not really “adult”› Pluripotent (?)› Easy to obtain in large volume, various
donor demographics
Uses of Stem Cells in Drug Discovery
As a replacement for Primary Cells› Hepatocytes› Renal cells› Circulatory› Cardiomyocytes› Neurons› Pulmonary cells› Bone, cartilage› Skin: Wound healing & absorption models
In vitro models for metabolic homeostasis & Organogenesis› Demonstrate a “stimulation” of injury & repair mechanisms› Inhibition of necrosis/apoptosis› Tissue specific developmental pathways› Cancer Stem Cells
The Players
Why Neuro-Tox? The path of least resistance Neurodegenerative diseases
› Alzheimer's› Parkinson's› MS› ALS/Lou Gehrig's disease
Acute Injuries› Spinal cord injury› Stroke› Head injury› Cerebral Palsy
Abnormal Neural function› Depression› Epilepsy› Autism
HIV
Alzheimer's Disease and neurodegeneration:
The modular systems biology approach to investigate the control of apoptosis in Alzheimer's disease neurodegeneration, BMC Neurosci. 2006; 7(Suppl 1): S2.
Gahaga Cells From term amniotic membrane tissue Primary, adherent cultures &
cryopreserved Mesenchymal morphology and
Immunophenotype Assessed differentiation side-by-side vs.
Lonza bm-MSC Assessed growth in proprietary GHG
medium vs. Invitrogen MesenPRO® medium Developed two-step differentiation protocol
Nestin: G
HG
vs IVGN
m
edium
Gahaga medium
Invitrogen MesenPRO
©
ß-Tubulin III G
HG
vs IVGN
medium
Gahaga medium
Invitrogen MesenPRO
©
Neuronal Differentiation Grown to confluence in 96 well plates, with
proprietary placental basement membrane extract
Differentiation for 4 days 7 days Neuronal maintenance in IVGN
Neurobasal medium
Challenges Establish clinical significance, IVIVC Choosing the right target: pick one or two
target assays most relevant in the field Optimize isolation, differentiation
protocols Collaborate with one or more existing
ADMET/DMPK companies Always the issue of IP and litigation in this
emerging field
Conclusions A readily obtainable & reproducible
source of neuronal precursors and neurons for the study of neuronal function, dysfunction, and development
A culture system for neuronal differentiation
Potential for similar systems for other stromal cell types
Questions ?
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