gene-specific models and therapies for type 1 diabetes
TRANSCRIPT
Gene-Specific Models and Therapies for Type 1 DiabetesJeremy J. Racine
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Multiple different genetic profiles can lead to type 1 diabetes in children
Most potential therapies are designed
in the NOD mouse, which is a single genetic profile.
The Problem
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Class IClass I
The NOD Mouse
The First Generation Trait-Specific Model
β2m
Human Class I
No cell surface mouse Class I
Model Carries Specific Genetic Variant of HLA Class I found in Diabetic ChildrenGenetic Removal of β2m
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Class IClass I
The NOD Mouse
The First Generation Trait-Specific Model
β2m
Human Class I
No cell surface mouse Class I
- Cannot test antibody-based therapies
- Difficulty determining autoantibody status prior to treatment for “at-risk” classification.
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Class IClass I
The NOD Mouse
I have recently directly removed both of the mouse versions of the HLA Class I genes and am currently introducing the available human Class I variants linked to diabetes in children into this model to replace the first generation model.
Generating a Next Generation “Blank Slate” Model
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Class IClass I
Class II
Generating a Next Generation “Blank Slate” Model
The NOD Mouse
The NOD Class II gene needs to be removed in order to combine human HLA Class II gene variants linked to diabetes in children to the multiple HLA Class I variants identified.
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Class I
β2m
HLA Class I “presenting” target for immune cells.
Generating a Peptide- “Vaccination-Like” Therapy for Genetic Variation HLA-A2.1
Target
Immune Cell
Insulin producing cell.
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Immune Cell
Can we use a vaccine to block?
STOP
Generating a Peptide- “Vaccination-Like” Therapy for Genetic Variation HLA-A2.1
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IGRP 26
5-273
IGRP 22
8-236
INS1/2
A:2-10
INS1 B:5-
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4 targets have been identified using first
generation model and confirmed in patients.
Attach targets to a “microsphere” made from a material already in-use in the clinic.
Generating a Peptide- “Vaccination-Like” Therapy for Genetic Variation HLA-A2.1
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Immune Cell
“Vaccine” seems to reprogram immune cells. We need to learn how.
Generating a Peptide- “Vaccination-Like” Therapy for Genetic Variation HLA-A2.1
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Trait Specific Mouse Model
Trait Specific TherapyTrait Specific
Mouse Model
Trait Specific Therapy
Trait Specific Mouse Model
Trait Specific Therapy
Trait Specific Mouse Model
Trait Specific Therapy
The Ultimate Goal of My Career
Thank You For Your Support