Stem Cell Therapies for Type-1 Diabetes

1. Spinal Cord Society of New Zealand & Type-1 Diabetes?

2. Stem cells and making new tissues.

3. Adult stem cells and autoimmunity.

4. SCSNZ’s proposed trial(s).

• Who: Started by Noela Vallis & people with spinal cord injury (SCI), their families and care-givers in 1988.

• Aim:To support research into treatment of SCI and achieve a “Cure” - Neurological repair and, or regeneration.

• Strategy: Initially supported United States SCS.Later funded training of a NZ Neuroscientist in

USA.Set up a Dunedin laboratory & a NZ-based research

program!Laboratory projects with specific translational

research goals. Development of clinical studies.

Spinal Cord Society NZ Inc.

• Spinal cord injury is an extremely complex issue.

Spinal Cord Injury

• Successful treatments will require a combination of approaches including:

1. Stabilise – prevent further physical/metabolic damage.

2. Repair & reconstruct – fix and replace .3. Physiotherapy – relearn function.

SCSNZ & Regenerative Medicine

Stem Cell Therapies!

What are Stem Cells?

• Undifferentiated cell that can produce a differentiated cell or divide to produce another undifferentiated cell.

• 3 Main types: EmbryonicInducedAdult

What are Stem Cells?

Embryonic Stem Cells

Embryonic Stem Cells

AdiposeMuscle Epithelium

CNSCartilage

Induced Pluripotent Stem Cells

AdiposeMuscle Epithelium

CNSCartilage

Stem Cells & Tissue Engineering

Stem Cells & Tissue Engineering

• Liver: human in mouse (iPSCs + adult SCs)

0 days

3 days

2 days

• doi:10.1038/nature12271

Stem Cells & Tissue Engineering

• Retina: mouse eSCs

Induced:

Real thing:

Engineered cells

inserted into

real thing:

doi:10.1038/nbt.2643

Stem Cells & Tissue Engineering

• Brain: human iPSCs

Human brain

organoid:

Not yet transplant

ed into mice:

doi:10.1038/nature12517

Stem Cells & Type-1 Diabetes• Grow a new pancreas in the lab from stem

cells?• Not quite yet….• Grow islet cells in the lab from stem cells?• Viacyte Inc. San Diego

InsulinSomatostatinGlucagon

PEC-01 Cells implanted into mice develop into mature pancreatic like cells

Stem Cells & Type-1 Diabetes

Genetic background Viral Infection?+A combination of

factors.

Autoimmune destruction of insulin

producing cells.

Type-1 diabetes

Type 1 Diabetes15,000 NZers, increasing 5%p.a. Insulin dependent Devastating long term complications

Pancreas T-cells destroy islet cells

Type-1 Diabetes

Adult Stem Cells

• Self renewal capability.

• Not pluri-potent but multi-potent (more limited differentiation).

• Can be isolated and grown in the lab from:• Bone marrow• Fat• Umbilical cord• Many other tissues

Adult Mesenchymal Stem Cells

Nerve

Ectoderm

Liver

Pancreas

Endoderm

BoneCartilage Fat

Cardiac muscle Skeletal muscle

Mesoderm

Adult Mesenchymal Stem Cells

Immunomodulation

Trial of Zhao et al. 2012, Participants.

• Median age:

• Median diabetic history:

• Number of participants:

29 years, range 15 - 41.8 years, range 1 – 21. 15 type-1

diabetics. 12 treated. 3 controls .

Trial of Zhao et al. 2012, Procedure.

T cells from patient

collected.

T cells mixed with umbilical cord

blood stem cells in the lab

T cells infused back to patient

to protect regenerating

islet cells

Patient monitored

for changes in diabetes

status.Zhao Y, et al., 2012. Reversal of type 1 diabetes via islet β cell regeneration following immune modulation by cord blood-derived multipotent stem cells. BMC Med. 10:3.

Trial of Zhao et al. 2012. Outcomes

• C-peptide levels (ng/ml)• HbA1c

• Insulin dose

• Markers of immune response

Severe ModerateControl

(moderate)+0.21 +0.42 -0.08

-1.68 -1.91 -0.30-25% -38% 0.00

•CD4+CD25+Foxp3+ cells increased (Treg cells)•TGFb levels increased•Restoration of Th1/Th2/Th3 cytokine balance

Diabetes severity

Results suggest autoimmune response was either stopped or attenuated allowing slow islet

recovery & insulin production

(12 weeks post treatment)

Insulin production

Lower normal baseline is 0.6

Clinical trials with stem cells.

• Regulatory details are being worked out worldwide.

• In NZ:

Standing Committee On Therapeutic Trials (SCOTT Committee).

Ethical approval from HDEC• Spinal cord injury trials take a long time and measuring benefit is multimodal.

• Strategic decision to target an “easier” disease to get cells into clinical trial = Type-1 diabetes.

Bone marrow stem cells from

patient grown and activated.

T cells from patient collected.

T cells deactivated by bone marrow

stem cells in flask

T cells infused back to patient to protect regenerating islet

cells

Patient monitored for

changes in diabetes status.

Bone marrow stem cells infused

into patient.

T cells deactivated in

patient.

Trial 1

Trial 2Patient

monitored for changes in

diabetes status.

Proposed trials at SCSNZ

Parameters to be monitored

• HbA1c• C-peptide levels• Insulin usage

• Blood glucose level monitoring

Efficacy measures

Immune measures• lymphocyte subsets,

(CD4, CD8, B, NK) • IgG, IgA and IgM serum levels.• Tetanus toxoid antibody,

anti-CMV and, or anti-EBV •Anti-Pneumococcal polysaccharide mix

• CD4+ CD25+ FoxP3 positive lymphocytes.

• T lymphocyte responses against i-IA-2, GAD, InsulinWe will measure numbers and reactivity of

relevant subsets of immune cells to look for changes following treatment.

Bone marrow aspirate taken

Bone marrow stem cells tested for quality and stored frozen for

trial

Bone marrow stem cells isolated and

grown

Colony forming Differentiatio

n Immunosuppressi

on

Pathogen screenSurface markers Karyotypin

g

Autologous bone marrow MSCs

What we need….

Terumo BCT Quantum Cell Expansion System.• Closed cell culture

system.• Highly reproducible

growth conditions.• Single cylinder per

patient.• About $300, 000.Trial Funding.

• Establishment & commission: $1.0 million.• Trial costs: $0.9 million.

Project Team

Dr Jim Faed Haematology/Clinical TrialsDr Paul Turner Stem Cell Biology

Dr Sarah Young Immunology

Prof. Jim Mann Diabetology

Dr Ben WheelerDiabetology

Please have a look at…

www.scsnz.org.nz/contact-us/send us your details to

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