Making stem cells better

- a new therapy for HIV/AIDS

Paula Cannon PhD

Hematopoietic stem cells (HSC)

HSC

- The stem cells that constantly replenish our blood & immune systems

Red & white blood cells

HIV-1

CD4 T cells

1.1 million Americans are infected with HIV-1

• But only 25% access and achieve optimal virus suppression on antiretroviral drug therapy

And the drugs aren’t perfect….

• Side-effects - inflammation, metabolic syndromes, accelerated aging

• Expense - lifetime drug cost <$500,000

• The drugs DON’T CURE anyone

The Berlin Patient

• Cured of his leukemia and HIV

• Received a bone marrow stem cell transplant for

leukemia, from a donor who was “CCR5-negative”

• CCR5 is needed for HIV to infect cells

Making a patient’s own stem cells CCR5-negative

HSC purified from blood

Zinc finger nucleases Molecular scissors to engineer CCR5-negative stem cells

Returned to patient

CCR5-negative stem cells stop HIV replication

Normal human HSC

Zinc-finger nuclease treated HSC

HIV levels in blood of mice

Time after infection

Humanized mouse

human HSC

CIRM-funded Disease Team

Partners Academic - USC, City of Hope Biotech – Sangamo BioSciences

Mike Holmes PhD Philip Gregory PhD Sangamo BioSciences, Inc

John Zaia MD Dave DiGiusto PhD City of Hope

Paula Cannon PhD University of Southern California

Progress

2014 2013

Program funded by CIRM $14.5m, 2010-2014

2010

Pre-IND filed with FDA, RAC review

Planned IND filing

Acknowledgments

USC Colin Exline Nick Llewellyn Jill Henley Evan Lopez Nat Holt Ursula Hofer Kathy Burke

Sangamo BioSciences Jianbin Wang

Travis Wood

Lynn Truong

Kenneth Kim

Jenny Yan Mike Holmes Philip Gregory

City of Hope Dave DiGiusto Lijing Li John Rossi Rodica Stan John Zaia

strengthening the body's ability

to repair itself

jill helms

professor,

department of surgery

every tissue

contains

adult stem cells

others- like the brain-

contain

very few stem cells

some adult tissues- like the

marrow cavity- contain lots of

stem cells

Aging affects stem cells in different

ways:

aged stem cells = slower healing

18 years old 58 years old

$1.8B/y

large addressable market

slower healing

no healing

reverse the aging process

in stem cells

restore bone-forming capacity

potent stem cell growth factor

re-activate aged stem cells

and accelerate healing

of bone-related injuries

WNT3A

Strategy

in the periosteum

WNT3A activates adult

stem cells

mesenchymal

stem cells

skeletal

stem cells

fold

ch

an

ge

in W

nt ta

rge

t g

en

e e

xp

ressio

n

marrow-derived

stem cells

PB

S

PB

S

PB

S

WN

T3A

WN

T3A

WN

T3A

Strategy

harvest patient’s

own bone marrow 1 treat with L-WNT3A 2

Strategy

dying cells labeled with TUNEL

control L-WNT3A treated

MOA: L-WNT3A reduces cell

death

control

proliferating cells labeled with BrdU

L-WNT3A treated

MOA: L-WNT3A stimulates cell

division

Following L-WNT3A treatment…

rinse

3 rinse,

4 graft introduced into

the defect site

Aged bone graft + PBS Aged bone graft + L-WNT3A

8 weeks post-op

Early

Translational

Award

sca

le u

p

Bridging &

Extraordinary

Supplement

Awards

Preclinical

Development

Award

Funding stream

Projected:

every tissue

contains

adult stem cells

that can be harnessed for the

purposes of tissue regeneration

and healing

Ultimate goal:

cardiac muscle neurons skin hair

Modeling Autism Spectrum

Disorders with stem cells

Alysson R. Muotri, Ph.D.

University of California San Diego

Dept. Pediatrics/Cellular Molecular Medicine

1 in 54 boys

Genetics Environment

No cure

What is a model?

Postmortem Blood Animals

Autistic

Controls

Differences?

A new autism model?

The Tooth Fairy kit collection

Control Autistic

Control Autistic

Control Autistic

Treatment with experimental drugs

NIH Director's New Innovator Award Program CIRM Early Translational IRSF Foundation Patients and Families