Project Details
Grant Program
Faculty Development Competitive Research Grants Program 2022-2024
Project Description
Diabetes mellitus is an autoimmune disease of abnormal carbohydrate metabolism that is characterized by hyperglycemia due to varying degrees of impairment in insulin secretion from the pancreatic beta cells and peripheral resistance to its action [1]. Type 2 is a prevalent type of diabetes characterized by progressive loss of insulin secretion. Patients are either asymptomatic or may present with classical symptoms of hyperglycemia such as polyuria, polydipsia, nocturia, weight loss or blurred vision. Type 1 diabetes is characterized by autoimmune destruction of beta cells. Up to 25% of newly diagnosed patients present with diabetic ketoacidosis [2]. Clinical management challenges include optimizing the use of available therapies to ensure adequate glycemic control and reduce macro- and microvascular complications, patient education on adherence to the treatment, reduction in barriers to the early insulin use, and improvement of the health care delivery to the patients [3]. The American Diabetes Association has estimated the total costs of diagnosed diabetes have risen by 26% over a five-year period, from $245 billion in 2012 to $327 billion in 2017. The largest components of the following estimate are hospital inpatient care (30%), prescription medications (30%), diabetes agents and supplies (15%) and doctor office visits (15%). Considering costs associated with undiagnosed diabetes patients, management of pain and suffering, resources from non-paid care providers, this estimate emphasizes the significant burden that diabetes inflicts on society [4]. Clinical studies by the collaborator of this proposal showed that regular intradermal injections of human leukocyte antigen-DR4(DRB1*0401)-restricted immunodominant proinsulin peptide in newly diagnosed type 1 diabetes patient was associated with antigen-specific and nonspecific immune modulation for over 12 months (5). Alternative efforts for modulating antigenicity to insulin in a costeffective manner are highly desirable. Here I propose oral gene therapy as a non-invasive and potentially safer immunomodulatory strategy. Although intriguing, DNA is rapidly degraded in the stomach, preventing an efficient oral DNA delivery protocol (6). If plasmid DNA can be effectively protected from degradation in the stomach, the ingested DNA could reach the intestine where DNA can be taken up by cells, which will express any DNA-encoded proteins. Nanoparticles made from chitosan, a natural polysaccharide often found in foodstuff (7), protect plasmid DNA from degradation in the stomach to enhance its uptake by the small intestine. Using chitosan nanoparticles, we have achieved low but therapeutic levels of coagulation human factor VIII (FVIII) in hemophilia A mice (8). Further, and unlike viral vectors, re-administration of nanoparticles is possible. Interestingly, there was no detectable FVIII-specific IgG in the treated mice, even following a FVIII challenge. Of note, transplantation of lymphocytes from the spleen (adoptive transfer) is able to confer reduced immunogenicity in a recipient mouse, suggesting tolerance (9). The general hypothesis to be tested is that insulin peptide B9-23 presentation following oral delivery of formulated DNA can induce immune tolerance to insulin and can delay the onset of diabetes in NOD mice. The insulin peptide B9-23 is the equivalent target of T cells in NOD mice (10), and thus a suitable peptide to use in this strategy to induce immune tolerance. The purpose of the proposed experiments is to generate enough data to evaluate the efficacy of various oral formulations of DNA coding for insulin peptides in chitosan nanoparticles as a potential novel strategy to reduce or eliminate unwanted immune responses to insulin. This proposal specifically will attempt to reduce or prevent the onset in non-obese diabetic (NOD) mice. While oral tolerance has been widely studied, oral delivery of DNA is a novel approach that might open new therapeutic possibilities, and hence worth pursuing, particularly considering the extraordinary cost of diabetes to the health care system. If the proposed hypothesis is confirmed, clinical trials using the proposed strategy may be contemplated.
Status | Active |
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Effective start/end date | 1/1/22 → 12/31/24 |
Keywords
- oral
- nanoparticles
- insulin
- immune modulation
- diabetes
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