AI in Medicine ~Recent Progress in iPS Cell Research and - - PowerPoint PPT Presentation

Shinya Yamanaka

Center for iPS Cell Research and Application (CiRA), Kyoto University, Japan Gladstone Institute of Cardiovascular Disease, San Francisco Takeda - CiRA Joint Program, Shonan, Japan

AI in Medicine

~Recent Progress in iPS Cell Research and Application~

Generation of iPS cells iPS Cells

Oct3/4 Sox2 Klf4 c-Myc

Skin cells

(induced Pluripotent Stem cells) Human 2007 Mouse 2006

Applications of iPS cells

Neurons

Regenerative Medicine

iPS cells

Muscle cells Heart cells Hepatic cells

Skin cells Blood cells

Drug Development

iPS Cell-Based Cell Therapy For

Age-related Macular Degeneration (2014)

Retinal Cells

(Photo by RIKEN)

• Dr. Masayo Takahashi

（RIKEN, BDR）

No rejection No tumors Vision: stabilized

iPS cells

Quality check

Differentiated cells

Quality check

Sample collection

Autograft: Too expensive and time-consuming

iPS Cell Stock for Regenerative Medicine

Transplantation

Autologous iPS Cells

HLA homozygous donor

To reduce the cost & time of autologous iPSC

HLA Homozygous “Super” Donors

Distribution started from 2015

Clinical-grade iPS Cells

Quality Check Cell Processing Facility at CiRA Stock Japanese Red Cross Society Platelet / Bone Marrow Donors Cord Blood Banks Informed Consent & Blood Sampling

“HLA Super Donors”

iPS Cell Stock for Regenerative Medicine

Informed Consent

 7 donors (Top 4 frequent HLA haplotypes among Japanese) ：Covering ~40% of Japanese population

Center for iPS Cell Research and Application (CiRA)

Started in April, 2010

14 Cell Processing Rooms

Goal: To realize medical applications of iPS Cells

Masayo Takahashi Lab. (RIKEN) Age-related Macular Degeneration Yoshiki Sawa Lab. (Osaka Univ.) Ischemic cardiomyopathy Jun Takahashi Lab. (CiRA) Parkinson’s Disease

Clinical Application Using iPS Cell Stock

2019.8.29

Clinical Research Clinical Trial

Kohji Nishida Lab. (Osaka Univ.) Cornea Epithelial Stem Cell Exhaustion

Hideyuki Okano Lab. (Keio Univ.) Spinal Cord Injury

Clinical Application Using iPS Cell Stock

Osaka Univ. Retinitis Pigmentosa

時事通信社 産経新聞

Keiichi Fukuda Lab. (Keio Univ.) Dilated cardiomyopathy

2019.2.19

Noriyuki Tsumaki Lab. (CiRA) Articular Cartilage Injury

Approved by MHLW University approved

iPS Cells

Neurons Neural stem cells Heart Muscle cells Platelets Corneal cells Immune cells Cartilage Kidney cells Parkinson’s Disease Retinal cells Liver cells Pancreatic cells

Clinical Study

• n going

approved planed

Ischemic cardiomyopathy Blood transfusion Arthritic disorder

Regenerative Medicine Using iPS Cell Stock

Dilated cardiomyopathy

How about the remaining 60%?

Top 4 frequent HLA haplotypes among Japanese ：Covering ~40% of Japanese population

iPS Cell Stock for Regenerative Medicine

Being distributed

・150 haplotypes would cover ~90% of Japanese population ・>1000 haplotypes would be required to cover most of the world population

HLA-B HLA-C HLA-A HLA-DP HLA-DQ HLA-DR HLA-DP HLA-DQ HLA-DR HLA-B HLA-C HLA-A Chr.6 Class II MHC Class I MHC C2TA Chr.16 C2TA C2TA co-activator （Essential for class II MHC expression）

Alternative Approach ~ HLA-C Only

Junior Associate Prof. Akitsu Hotta (CiRA)

Current Super Donor iPS Cell Stock

4 Types: Covering ~40% of Japanese population

Future Plan of iPS Cell Therapy

Alternative Genome-Editing iPS Cell Stock

（2020～）

10 lines would cover most of world population

Ultimate My iPS Cells

（2025～）

Applications of iPS cells

Neurons

Regenerative Medicine

iPS cells

Muscle cells Heart cells Hepatic cells

Skin cells Blood cells

Drug Development

EBiSC (EU) StemBANCC (EU) NYSCF NIH HipSci (UK) CIRM CiRA/BRC (Japan)

63 diseases, 1195 individuals, including 199 controls 10 diseases,690 individuals, including 517 control

As of March, 2018

19 diseases, 345 individuals, including 216 controls 231 diseases, 410 individuals, including 74 control

• Assoc. Prof. M Saito

(CiRA)

iPS Cell Bank for Drug Discovery

Two clinical trials are ongoing at Kyoto University Hospital

Ramamycin for FOP

(Fibrodysplasia Ossificans Progressiva)

Drug Repurposing with Patient iPSCs

• Prof. Toguchida, Assoc. Prof. Ikeya

(CiRA)

Bostinib for ALS

(Amyotrophic lateral sclerosis)

• Prof. H Inoue

(CiRA)

On going Approved

Spinal cord injury Macular degeneration Heart failure Leukemia, Cancer Arthritic disorder Corneal disorder Type 1 Diabetes

Planning

Parkinson’s Disease

Regenerative Medicine Drug Development

Platelet transfusion Pendred Syndrome ALS (2 trials) Alzheimer's disease Fibrodysplasia Ossificans Progressiva （FOP)

Applications of iPS cells

Splicing patterns Gene expression Epigenetic states

Good iPS cells Bad iPS cells Untrained iPS cells Good Bad

Splicing patterns Gene expression Epigenetic states

Trained

A trained neural network by multi- hierarchical data predicts iPSC properties

Source Recipe Immuno- suppression Differentiation Culture condition HLA homo Autologous engineered Cord blood PBMC (T-cell, B-cell, monocyte etc.) fibroblast factors (OSKM etc.) X vector X ncRNA X small molecules iPSC scATAC scRNA ATAC-seq RNA-seq Methylation ATAC

• seq

hESC AI/Machine Learning Topological Data Analysis (powerful method for high dimensional data) zygote meso derm endo derm ecto derm RNA- seq

Strategy for Epigenetic “identity” using AI

Temperature X

Supplements

X Hypoxic

37,000

Extraction of predicted 5,000 active compounds

Predicted active

Hit prediction from 2,000,000 compounds using AI based on iPSC screen data

Screening using patient iPSCs

Hit compound

Verification using patient iPSCs Hit prediction

Confirmation of the efficiency using patient iPSC panel

Successful drug discovery  New chemotypes  Potent efficacy  Broad-spectrum for various patients

Predicted inactive compound

Prediction by AI

Drug discovery using patient iPSCs and AI

(my) iPS cells

Gene Expression Database for 1,000 Chemicals

RNA-seq

Exposure to hESCs

G1 G2 G9 G10 Gj

w2,j w9,j w10,j w1,j

Machine Learning + Genetic Networks Prediction of Toxicity Target Organs

catechin bisphenol-A aspirin

Food Pharmaceutical High Accuracy (95–100%) for Neurotoxins, Nephrotoxins, Hepatotoxicity, Carcinogens, etc. New drug/chemical/food

Stem Cell-based Chemical Risk Information Sharing Consortium (scChemRISC)

Chemical

(cf. Yamane et al. Nucleic Acids Res. 44:5515-28, 2016)

Development of Precision Toxicology

CiRA, Kyoto

T-CiRA Program Gladstone Institutes, San Francisco

Thank you for your attention!