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Development of a novel type of tolerogenic vaccine : a negative self-vaccine against type 1 diabetes.

Country of Origin: Belgium
Reference Number: TOBE20171030001
Publication Date: 30 October 2017

Summary

A Belgian research university laboratory has developed a novel approach to prevent and/or cure type 1 diabetes (T1D) based on the central tolerogenic properties of the thymus. The researchers are looking for research cooperation agreement.

Description

T1D is an autoimmune form of diabetes mellitus in which not enough insulin is produced. T1D makes up an estimated 5–10% of all diabetes cases. The number of people affected globally is unknown, although it is estimated that about 80,000 children develop the disease each year.

Most of the prototypes of vaccine are working on insulin.

In the general framework of neuroendocrine-immune interactions, the Belgian laboratory has demonstrated that the thymus plays a unique role in programming central self-tolerance of the immune system to neuroendocrine principles.
This demonstration was based on the following observations:
1. Dominant members of neuroendocrine protein/gene families are expressed in thymic epithelial cells (TECs) from different species.
2. Thymic neuroendocrine proteins are not processed for classic neurosecretion but as precursors of neuroendocrine self-antigens that are presented by major histocompatibility complex (MHC) molecules to differentiating T lymphocytes in the thymus.
3. This unique thymus function was requested for the establishment of central immunological tolerance of neuroendocrine functions when the adaptive immune system emerged some 470 millions years ago.
With regard to the insulin family, all the members of the family are expressed in the thymus according a precise hierachy: IGF2 (insulin-like growth factor 2 ) > IGF1(insulin-like growth factor 1 ) >> Insulin . In addition, they observed the following facts:
1. IGF2 expression is deficient in the thymus of diabetes-prone BB rats, an animal model of hulman T1D
2. Tolerance to Insulin is lowered in IGF2-KO mice as well as in mice with specific IGF2 deletion in TECs.
3. The homologous peptides Insulin B9-23 and IGF2 B11-25 compete and bind with the same affinity to DQ8, a MHC allele conferring major genetic susceptibility to T1D.
4. Presentation of IGF2 B11-25 to peripheral blood mononuclear cells isolated from DQ8+ diabetic adolescents elicits immunosuppressive Interleukine-10 production and not Interferon-gamma (like Insulin B9-232).
5. Thymic infection by the diabetogenic Coxsackievirus B4 is associated with a decrease in intrathymic IGF2 expression.
Overall, these data argue for a fundamental role of thymic IGF2 in programming selftolerance to insulin as well as, secundarily, to insulin-secreting pancreatic islet β cells.

The Belgian research university laboratory is looking for research cooperation agreement and cofounding of preclinical studies.
Unpublished data failed to show any benefit of IGF2 administration injected three times to NOD (non-obese diabetic) mice. It was then decided to move towards a vaccination of NOD mice with a plasmid containing IGF2 cDNA.

The cofounding is requested for at least 2 years and will support the following costs:
• Design and production of antibiotic-resistant plasmids containing murine complete Igf2 or Igf2-derived nucleotide sequences.
• Maintenance of a very efficient NOD breeding in the central Animal Department of the university of the Belgian laboratory.
• Salary of a technician responsible for plasmid vaccination and monitoring vaccinated NOD mice.

Advantages and Innovations

GF2 appears as a much more valuable candidate than insulin to reprogram immunological tolerance to Insulin-secreting islet β cells. As an indirect proof of evidence, all preclinical and clinical trials based on Insulin have failed in showing the least evidence for any tolerogenic activity of Insulin. The highly immunogenic properties of Insulin could actually result from its very low expression in Thymic Epithelial Cells.
Unpublished data of a Wallonia project failed to show any benefit of IGF2 administration injected three times to NOD mice. It was then decided to move towards a
vaccination of NOD mice with a plasmid containing IGF2 cDNA.

Stage Of Development

Concept stage

Requested partner

Type of partner:
Any partner sharing an interest in treatment of T1D, as well as other organ-specific autoimmune diseases.
Industrial partner involved in vaccine development, manufacturing or distribution.
Role of the partner:
In addition to the cofounding mentioned above and depending on the results of preclinical vaccination studies in NOD mice, the partner should be able to support Phase I and Phase II clinical studies in healthy adult volunteers and in T1D adult patients.

Cooperation offer ist closed for requests