gene therapy for type 1 diabetes ann m. simpson centre
TRANSCRIPT
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GENE THERAPY FOR TYPE 1 DIABETES Ann M. Simpson Centre for Health Technologies
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NORMAL INDIVIDUAL
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POSSIBLE THERAPIES (1)
Insulin Therapy Does not provide a cure and patients develop the chronic complications of
diabetes. Retinopathy Blindness Nephropathy Kidney Failure Neuropathy Nerve Degeneration Macrovascular Stroke Cardiovascular disease Gangrene
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POSSIBLE THERAPIES (2)
Transplantation of Insulin-Secreting pancreatic tissue Too few donors Patients must be immunosuppressed Stem Cells May be prone to autoimmune attack Immunosuppression Gene Therapy Production of replacement β-cells by
genetic engineering
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WHAT DOES AN ARTIFICIAL ΒETA CELL NEED TO FUNCTION CORRECTLY?
• The ability to accurately sense glucose levels • The ability to metabolise glucose • The ability to store insulin for later secretion Liver cells have: • Similar glucose-sensing apparatus to pancreatic β cells • Synthesise and secrete complex proteins • Ability to undergo differentiation into β-like cells that
possess storage granules
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BETA CELL TRANSCRIPTION FACTORS
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ALTERNATIVE GENE THERAPY SOLUTIONS
• Insulin-secreting liver cell line that can be encapsulated and used as a treatment
• Direct delivery of genes to the liver curing the disease
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CREATION OF MELLIGEN CELLS • As an alternative to the transplantation of islets, a human liver cell
line has been genetically engineered to reverse type 1 diabetes. • Melligen cells which express β cell transcription factors store insulin
in granules and secrete insulin to glucose correctly, reversing diabetes.
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MELLIGEN CELLS: REVERSAL OF DIABETES
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Days After Transplantation
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Lawandi et al (2015) Molecular Therapy- Methods & Clinical Development 2, 15011; doi:10.1038/mtm.2015.11. http://newsroom.uts.edu.au/news/2014/11/breakthrough-diabetes-research-be-commercialised http://ir.pharmacytebiotech.com/press-releases/detail/108/pharmacyte-biotech-receives-patent-protection-of-the
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• Capsules are made of bio-inert material (cellulose/cotton) • Capsules have pores for nutrient and waste transfer • Pores are too small for immune system cells to enter or encapsulated live
cells to leave • Long-term (5+ years) frozen storage of encapsulated live cells with
more than 95% viability of cells upon thawing • Manageable logistics and long shelf-life • Cell-in-a-Box® encapsulation performed in a cGMP-compliant facility • Other live cell encapsulation technologies use alginate (derived from
seaweed). All are far less robust and stable. None can be frozen to ship • Cell-in-a-Box ® capsules shown to be safe, effective and durable
http://pharmacyte.com/diabetes/
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DIRECT DELIVERY OF INSULIN TO LIVERS Human insulin is delivered directly in a viral vector to animal livers by a surgical technique that isolates the liver from the circulation
.
Ren B et al (2007) Diabetologia 50: 1910-1920. Ren B, et al (2013) J Gene Medicine 15: 28-41
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REVERSAL OF DIABETES IN NON OBESE DIABETIC (NOD) MICE
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Storage granules
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REVERSAL OF DIABETES IN NOD MICE
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Spontaneous expression of β-cell transcription factors
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FUTURE DIRECTIONS/ PARTNERING
Different Cell Types Bone marrow mesenchymal stem cells Human islet progenitor cells Gall bladder cells Pre-clinical Animal Models: Direct delivery of insulin Humanised FRG mice Large animal models
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ACKNOWLEDGEMENTS UTS USyd Binhai Ren Anne Swan Bronwyn O’Brien Paul Williams Najah Nassif Janet Lawandi Griffith Chang Tao Ming Wei Michelle Byrne Edwin Ch’ng Prudence Gatt Fraser Torpy [email protected]: gene therapy, diabetes, vectors, molecular
biology