[R21] Prolonged Autoantigen Expression via OralDNA Vaccination to Reestablish Immune Tolerance
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2028-04-30
Importo max: 246.750 EUR
Paese: US
Descrizione
Project Summary
Antigen-specific immunotherapy (ASIT) for Type 1 diabetes (T1D) aims to reinstate robust and durable tolerance
to beta-cell antigens. However, responsiveness to these therapies appears to be dependent on delivering the
right set of epitopes to each patient for proper HLA binding and engagement of specific T cells. Thus far, ASIT
strategies have involved the use of a single native antigen in the form of exogenous protein or peptides or DNA-
encoded protein. In contrast, we developed an epitope-based approach that ensures optimal presentation of
(neo)epitopes from multiple antigens, encoded by non-viral DNA vectors, to CD4+ and CD8+ T cells and that is
highly amenable to customization as a precision medicine approach to overcome disease heterogeneity in T1D
patients with different HLA haplotypes. This strategy provided significant protection at different stages of disease
progression in the non-obese diabetic (NOD) mouse for which the vector was customized, but frequent injections
were required to achieve durable tolerance (after treatment discontinuation). To facilitate the translation of this
promising approach to the clinic, we propose to address remaining challenges by evaluating a novel oral route
of delivery (for greater practicality and patient compliance) and new nanoplasmid vectors (for improved uptake
and more sustained expression, potentially resulting in reduced dose and dosing frequency). We have devised
a new type of nanoparticles (YF-CPNPs) that can be administered orally and achieve expression in gut-
associated lymphoid tissues and in the liver.
Under Aim 1, we will assess biodistribution of oral YF-CPNPs that contain conventional or nanoplasmids using
a new mouse model in which all targeted cells can be irreversibly marked by GFP expression. This will allow us
to identify potential antigen-presenting cells in these tissues and determine how they respond to YF-CPNPs
irrespective of the expressed products. We will also investigate the early response of antigen-specific T cells in
those tissues in vivo and whether these responses are consistent with antigen-specific regulation or tolerance.
Under Aim 2, we will compare the duration of expression of conventional and nanoplasmids with or without
episomal elements and determine how long antigens can be presented in different tissues after a single oral
administration of these vectors. Based on these insights, we will conduct preclinical studies in which NOD mice
will be orally administered with vectors encoding multiple epitopes at variable intervals. Some mice will be
analyzed after 10 weeks of treatment to determine how the treatments affect the frequency and phenotype of T
cells specific to several epitopes expressed by the vectors. Other mice will be monitored long-term to evaluate
the incidence of T1D. Analysis of bystander T cells will be used to demonstrate targeted effect on specific T cells,
another key safety feature. These studies will leverage the complementa
Istituzione: COLUMBIA UNIVERSITY HEALTH SCIENCES
PI: Remi J Creusot, KAM W LEONG
Progetto: 1R21AI199841-01
Settori: National Institute of Allergy and Infectious Diseases
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