This document summarizes advances in gene therapy for type 1 diabetes mellitus. It discusses current treatment options and their limitations, including synthetic insulin and pancreas transplants. Therapeutic gene therapy approaches aim to prevent autoimmune destruction of beta cells, introduce the insulin gene into non-beta cells, and generate surrogate beta cells from other cell types. Challenges remain but ongoing research investigates using stem cells, vaccines, encapsulated transplants, and immunotherapy to potentially cure type 1 diabetes.

1. Advances in gene therapy for
type 1 diabetes mellitus
Sureshni Fernando

2. Outline
1. Overview of Type 1 Diabetes Mellitus (T1DM)
2. Introduction to gene therapy
3. Current treatment options and their limitations
4. Therapeutic approaches of T1DM involving genes

3. Type 1 Diabetes Mellitus
• A systemic disease characterized by hyperglycemia
and caused by absolute insulin deficiency.
• A chronic autoimmune disease – destruction of
insulin secreting b islet cells of the pancreas by T
cells.
• Childhood or early adult onset.
• 5–10% of the total cases of diabetes worldwide.
• Symptoms - glycosuria, polyuria, polydipsia, weight
loss, ketoacidosis.
• Diagnosis - FBS, RBS, HbA1c.
• Complications – Hypoglycemia, MI, PVD, stroke,
diabetic retinopathy, neuropathy, nephropathy.
Figure 1: Type 1
diabetes mellitus
(Adapted from
Dreamstime, 2018).

4. Gene therapy
• A mechanism of either altering or changing the genetic
material in target cells without causing any damage to non-
target cells.
• It aims to correct defective genes that are responsible for
disease development and effectively prevents disease onset
or halts its progression.
Figure 2: Germline
vs. somatic gene
therapy (Adapted
from Frazier, 2019).

5. • Intervention techniques in gene therapy
- Introducing a new gene
- Replacing faulty genes with functional genes
- Inactivating faulty genes that cause the disease
• Gene delivery can be carried out by
- Viral vectors / Transduction
- Non-viral vectors / Transfection
- Physical methods
Figure 3: In vivo and
ex vivo gene therapy
(Adapted from
Reghupaty and
Sarkar, 2019).

6. Current treatment options
and its limitations
• Synthetic insulin
- Cumbersome and unable to mimic β cell secretion.
- Fluctuations in blood glucose levels can cause serious complications.
• Pancreas transplants
- Lack of suitable donor tissue.
- Requires immunosuppression to avoid graft rejection.
- Inability of transplanted β cells to replace β cells that have died.
- Recurrence of the autoimmune processes.
• Artificial pancreas
- Limited long-term effectiveness.
Figure 4: Artificial
pancreas (Adapted from
Atkinson, Eisenbarth
and Michels, 2014).

7. Therapeutic approaches involving genes
1. Prevent the autoimmune destruction of β cells by modifying
the immune system.
2. Introducing the insulin gene into non-β cells.
– Injecting lentivirus vector carrying human modified insulin gene into
the portal system.
3. Generate surrogate β cells from non-β cells.
– Reprogramming of a cells into b cells induced by viral gene therapy.
Figure 5:
Reprogramming of a
cells into b cells
(Osipovich and
Magnuson, 2018).

8. 1. Preventing the autoimmune
destruction of β cells
• Inducing immune tolerance so that β cell antigens are no
longer recognized as foreign.
• Modifying residual β cells so as to resist autoimmune
destruction.
• Limitations
– Rely on the early detection of diabetes.
– T1DM is a multifactorial disease.
Figure 6: Combination
of therapies to reverse
T1DM (Haller,
Atkinson and Schatz,
2010).

9. 2. Insulin gene therapy
• Introducing the insulin gene into non-β cells.
• The non-β cell utilized
– must be able to synthesize insulin.
– store insulin within secretory granules.
– secrete insulin instantaneously upon elevations in blood glucose
levels.
– must contain the glucose sensors - GLUT2 and glucokinase.
– must overexpress β cell-specific transcription factors (PDX1,
Neurog3 and MafA) to direct and maintain the cell fate.
• Hepatocytes are the most commonly targeted cell.
Figure 7: Insulin
(Rose et al., 2018).

10. Table 1: Features of viral vectors used in gene therapy (Handorf, Sollinger and Alam, 2016).
• The delivery vehicle must be affordable and be able to be
produced in large quantities.
• Insulin gene therapy opens the possibility of having a one-time
treatment option, that can provide long-term correction given
that long-term insulin expression is driven.

11. Summary
• Although survival and patient health have improved
considerably with time, a cure for T1DM remains elusive.
• Despite advances in technology, glycaemic control for T1DM is
not optimised.
• Many cannot access modern therapies because of the high costs
of even basic care.
• Ongoing research
– Insulin pill
– Stem cell-derived β cells
– Vaccinating against T1DM
– Encapsulating pancreatic grafts
– Immunotherapy Figure 8: Stem cell derived insulin
producing cells (Bar-Nur et al., 2011).

12. References
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Bar-Nur, O., Russ, H. A., Efrat, S. and Benvenisty, N. (2011) ’Epigenetic memory and preferential lineage-
specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta
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2020).
Calne, R. Y., Gan, S. U., and Lee, K. O. (2010) ’Stem cell and gene therapies for diabetes mellitus’, Nature
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13. References
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Hardee, C. L., Arévalo-Soliz, L. M., Hornstein, B. D. and Zechiedrich, L. (2017) ‘Advances in non-viral DNA vectors
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Moini, J. (2019) ’Type 1 diabetes’, Epidemiology of Diabetes, pp. 75–90. [Online] DOI: 10.1016/b978-0-12-
816864-6.00006-7 (Accessed: 1 February 2020).
Osipovich, A. B. and Magnuson, M. A. (2018) ’Alpha to beta cell reprogramming: stepping toward a new
treatment for diabetes’, Cell Stem Cell, 22(1), pp. 12–13. [Online] DOI:
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Reghupaty, S. C. and Sarkar, D. (2019) ‘Current status of gene therapy in hepatocellular carcinoma’,
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