LXR and DR: Liver X Receptor (LXR) as a Novel Therapeutic Target in Diabetic Retinopathy (DR)

Sponsor
University of Alabama at Birmingham (Other)
Overall Status
Recruiting
CT.gov ID
NCT03403686
Collaborator
(none)
104
1
59.6
1.7

Study Details

Study Description

Brief Summary

Results from large clinical trials demonstrate a strong association between lipid abnormalities and progression of the most common microvascular complication, diabetic retinopathy (DR). We found that activation of a master regulator of cholesterol metabolism, the nuclear hormone receptors liver X receptors (LXRα/LXRβ), prevents DR in rodent models. In this application, we seek to understand the mechanisms responsible for the beneficial effects of LXR agonists on retina and on bone marrow (BM) to preserve the function of reparative cells while reducing inflammatory cell.

Condition or Disease Intervention/Treatment Phase
  • Biological: blood draw

Detailed Description

Diabetic retinopathy (DR) is a disabling microvascular complication. Despite recent advances using pharmacotherapy, a cure for DR has yet to be realized. Thus, a conceptual and technical breakthrough to identify novel targets, and a strategy to cure this complication is paramount. We believe that the recent clinical evidence from large clinical trials demonstrating a strong association between lipid abnormalities and DR progression and the discovery that activation of the nuclear hormone receptors liver X receptors (LXRα/LXRβ) prevents DR in rodent models offers such a breakthrough. The detrimental effect of dyslipidemia is not limited to the vasculature but also leads to dysfunction of circulating angiogenic cells (CAC) and of macrophages. The endogenous ligands for LXRs are oxidative metabolites of cholesterol that serve as intracellular cholesterol "sensors". LXR agonists operate, in part, by transcriptional upregulation of genes involved in promoting cholesterol efflux and inhibition of cholesterol uptake; and by inhibiting inflammation. Our published studies and new preliminary data show that pharmacological LXR activation prevents DR development in both T1D and T2D rodent models. In this application, we seek to understand the mechanisms involved in this beneficial effect. We put forth the hypothesis that LXR activation will restore cholesterol homeostasis in the diabetic retina and correct diabetes-induced bone marrow dysfunction to sustain CAC levels and function and to reduce of myeloid cell production.

Study Design

Study Type:
Observational
Anticipated Enrollment :
104 participants
Observational Model:
Cohort
Time Perspective:
Other
Official Title:
LXR as a Novel Therapeutic Target in DR
Actual Study Start Date :
Jan 11, 2018
Anticipated Primary Completion Date :
Dec 31, 2022
Anticipated Study Completion Date :
Dec 31, 2022

Arms and Interventions

Arm Intervention/Treatment
Controls

Any man or woman between the ages of 21- 98 years of age will be eligible to participate. To participate in the study as a study subject we will require that the subject must carry the diagnosis of healthy control.

Biological: blood draw
Blood sample will be obtained and CD34+ cells will be isolated for functional testing.

Diabetic no retinopathy

Patients with diabetes but with no evidence of diabetic retinopathy

Biological: blood draw
Blood sample will be obtained and CD34+ cells will be isolated for functional testing.

Diabetic with mild retinopathy

Diabetics with mild non proliferative diabetic retinopathy (NPDR).

Biological: blood draw
Blood sample will be obtained and CD34+ cells will be isolated for functional testing.

Diabetic with moderate retinopathy

Diabetics with moderate NPDR

Biological: blood draw
Blood sample will be obtained and CD34+ cells will be isolated for functional testing.

Diabetics with severe retinopathy

Diabetic with severe NPDR.

Biological: blood draw
Blood sample will be obtained and CD34+ cells will be isolated for functional testing.

Diabetics with proliferative diabetic retinopathy (PDR)

Diabetics with proliferative diabetic retinopathy (PDR)

Biological: blood draw
Blood sample will be obtained and CD34+ cells will be isolated for functional testing.

Outcome Measures

Primary Outcome Measures

  1. Assessing CD34+ cells function [from blood draw to 48 hours]

    We are isolating CD34+ cells from peripheral blood and then examining the cell membrane characteristics of CD34+ cells and their in vitro function.

Eligibility Criteria

Criteria

Ages Eligible for Study:
21 Years to 98 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
Yes
Inclusion Criteria:
  • Any man or woman between the ages of 21- 98 years of age will be eligible to participate. To participate in the study as a study subject we will require: a) the subject must either carry the diagnosis of diabetes or be a healthy aged control and
  1. the patient be willing and have the ability to cooperate with the protocol.
Exclusion Criteria:
  • Exclusion criteria: We will apply the following exclusion criteria: a) evidence of ongoing acute or chronic infection (HIV, Hepatitis B or C, tuberculosis); b) ongoing malignancy; c) cerebral vascular accident or cerebral vascular procedure; d) current pregnancy; e) history of organ transplantation; f) presence of a graft (to avoid any effect of the graft on inflammatory parameters; g) uremic symptoms, an estimated glomerular filtration rate of less than 20 cc/min (by Modification of Diet in Renal Disease equation), or an albumin of less than 3.6 (to avoid malnutrition as a confounding variable); h) be unwilling to abstain from drinking alcohol and i) patients with anemia. Subjects with AMD, glaucoma, uveitis, known hereditary degenerations or other significant ocular complications other than diabetic retinopathy will be excluded.

Contacts and Locations

Locations

Site City State Country Postal Code
1 University of Alabama at Birmingham Birmingham Alabama United States 35294

Sponsors and Collaborators

  • University of Alabama at Birmingham

Investigators

  • Principal Investigator: Maria B Grant, MD, University of Alabama at Birmingham

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Maria Grant, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier:
NCT03403686
Other Study ID Numbers:
  • 300000068
First Posted:
Jan 19, 2018
Last Update Posted:
Aug 16, 2021
Last Verified:
Aug 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Maria Grant, Principal Investigator, University of Alabama at Birmingham
Additional relevant MeSH terms:

Study Results

No Results Posted as of Aug 16, 2021