Assoc Prof Bronwen Connor 23 March 2013

 Involved in development embryonic stem cells  Also found in many adult tissues and serve as an internal repair system adult stem cells... What Are Adult Stem Cells? Uncommitted cells

A/Prof Bronwen Connor

Neural Repair and Neurogenesis Lab

Dept of Pharmacology & Clinical Pharmacology Centre for Brain Research

University of Auckland

 What is a stem cell?

 Discovery - our research

 Adult stem cells

 Reprogramming

 Stem cells in the clinic

 the Myths

 the Reality

What Is A Stem Cell?

 Unspecialised cells

 Unique ability to grow into many different cell types

in the body.

 Involved in development (embryonic stem cells)

 Also found in many adult tissues and serve as an internal repair system (adult stem cells)

What is Unique About Stem Cells?

 Capable of dividing

and renewing

themselves for long

periods.

 Can be directed to turn

into specialised cells.

What is So Exciting About Stem Cells?

 New potentials for treating

many neurological diseases

and injuries

 Provide new replacement cells

 Provide supporting chemicals

- enhance axon growth

- prevent cell death

- prevent inflammation

 Information about how brain

cells develop and are

affected by disease process

What Are Embryonic Stem Cells?

What Are Adult Stem Cells?

 Uncommitted cells found in adult tissue or organs

 Can self-renew and generate the specialised cells found in mature tissue / organ

 Involved in maintenance and repair

 Exciting use in cell replacement therapy as

provides potential to use patients own stem cells!

Sources of Adult Stem Cells

Neural stem cells

New brain cells

Blood cells

Neural crest stem cells Bone, cartilage, fat, connective tissue, brain cells

Similarities and Differences Between Embryonic

and Adult Stem Cells

 Embryonic stem cells can become any cell type (pluripotent)

- but can form tumours

 Adult stem cells limited to become cells from tissue of origin

- unlikely to form tumours

 Adult stem cells rare and more difficult to grow in lab

 Embryonic stem cells grow easily but ethical issues regarding

source

 Adult stem cells can obtained from patient

- Removes issues of rejection

Our Research

 Focused on adult neural stem cells

 Understanding the role of resident stem cells in the adult brain

○ Normal brain

○ Diseased brain

 Enhancing Self-Repair Process

 Stem Cell Transplantation Therapy

Stem Cells in the Adult Human Brain:

Death of a Dogma

Eriksson et al 1998; Nature Medicine 4; 1313-1317

Curtis et al, Science, 2007

The RMS Pathway for New Brain

Cells in the Human Brain

Stem Cells Try to Repair the Diseased or

Injured Brain

 Stem cell divisionGeneration of new brain cells

Curtis et al 2003 PNAS

Stem Cells Try to Repair the Diseased or

Stem Cell Migration Increases and Changes

Direction Following Cell Death.

Gordon et al 2007 Neuroscience

Normal

Huntington’s disease

Stem CellBrain Inflammation Chemokine Migration

Injury Site

The Role of Inflammation

Stem Cells Try to Repair the Diseased or

Injured Brain

Stem Cells Generate New Brain Cells

Increasing the Generation and Survival of

New Brain Cells

injected into rodent model of Huntington’s disease.

BDNF Generation and survival of new brain

cells

Henry et al Eur J Neurosci 2007

BDNF Increases the Generation and

Survival of New Neurons in the

Huntington’s Disease Brain

Stem Cell Transplantation Therapy

 Using stem cells to replace cells lost through disease or injury

 Embryonic stem cells

 Adult neural stem cells

Neural stem cells

Neural stem cells

Embryonic Stem Cells

 Rodent model of HD

 Long-term survival

 Generation of new GABAergic neurons

 BUT tumour formation in ~10% animals

Vazey et al 2010 Cell Transplantation

Vazey et al 2006 Expt Neurol

Adult Neural Stem Cells

A bit of “Science Fiction”

stem cells!!

2012 Nobel Prize Winner

Skin Cells

Skin cells

We Can Turn Skin Cells Into Immature Brain Cells !!!

SOX2/PAX6

Maucksch et al 2012 JSRM

We Can Take Patients Cells and Turn Them

Into Specific Brain Cells

The Myths and Reality

“It’s nothing that a few stem cells and 75 years of research can’t fix”

The Truth - Current Clinical Trials

 Clinical trials are used to establish whether new treatments are safe and effective

 Unwanted side effect?

 Risk level?

 Benefit level?

 Clinical trials are based on extensive preclinical research and

rigorous peer review

 Stem cell therapy MUST obtain US FDA (or equivalent) approval

The Truth - Current Clinical Trials

 Bone marrow / umbilical cord stem cells

 Undergoing clinical trials for a range of disorders

○ Heart disease; vascular repair; bone and cartilage repair etc

 Provide chemicals to protect cells, support re-growth of

connections, stimulate resident stem cells, reduce inflammation

Approved Clinical Trials – Neural Stem

Cells

Company Cell Type Development Progress

Indication

Indication

ReNeuron ReN001 (adult neural

stem cells 12 wk old fetus) Commited, not pluripotent

Phase 1 Ischemic stroke Six

months to two years after injury

StemCells HuCNS-SC (adult stem

cells derived from fetal tissue) Cultured but not altered

Same cells used for both Batten’s and cord injury Phase 1

Chronic spinal cord injury

Batten’s disease

Neuralstem NSI-566RSC, human

spinal cord–derived neural stem cell lines

sclerosis IND filed Chronic spinal cord

injury

(oligodendrocyte progenitor cells, derived and differentiated from hESCs)

Phase 1 HALTED! Spinal cord injury

(acute—7 to 14 days after injury)

The Myths – Stem Cell “Clinics”

 Multiple diseases treated with the same cells

 Claims based on patient testimonials.

 Clinical trials are based on extensive preclinical research or

Phase 1/2 clinical trial data

 The source of the cells or how the treatment will be done is not clearly documented

 Claims there is no risk.

The Myths – Stem Cell “Clinics”

 High cost of treatment or hidden costs.

 It is not customary for someone to pay to be in a clinical trial

Consider whether you should pay for a treatment that is unproven

 Ask about the costs of emergency medical care if something goes wrong, particularly if you are outside your own country

 No follow-up after procedure

 No assessment of improvement No reporting of the outcomes of the procedure to the international community

The Myths – Stem Cell “Pills”

 “Stimulating the release of adult stem cells from bone marrow into the circulation to slow aging process and

repair areas of the body suffering from degeneration / injury.”

 ColoStem

 Colostrum product

The Myths – Stem Cell “Pills”

 StemEnhance®

 Blend of two compounds extracted from the aquatic botanical Aphanizomenon flos-aquae (AFA)

stem cell release or migration

liver toxicity.

 These are food supplements so do not require FDA

approval – be careful!

In Conclusion

 Stem cell therapy for neurological disease and injury is an exciting possibility.

 We still have much to learn about stem cells.

 We need to be sure of the long-term safety and

effectiveness of stem cell therapies before clinical use

 Approved clinical trials are the only way to do this

 Stem cell “clinics” do not assist with further development of stem cell therapy and many offer empty promises.

 There is no “over-the-counter” stem cell “pill”

Thanks To All Those Involved

 Martin Pera (USC)

 Mirella Dottori (Uni Melb)

 Malcolm Horne (HFI, Uni Melb)