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

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ClinicalTrials.gov Identifier: NCT03403686
Recruitment Status : Recruiting
First Posted : January 19, 2018
Last Update Posted : January 19, 2018
Sponsor:
Information provided by (Responsible Party):
Maria Grant, University of Alabama at Birmingham

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
Diabetic Retinopathy 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 Type : Observational
Estimated Enrollment : 104 participants
Observational Model: Cohort
Time Perspective: Other
Official Title: LXR as a Novel Therapeutic Target in DR
Actual Study Start Date : January 11, 2018
Estimated Primary Completion Date : January 31, 2020
Estimated Study Completion Date : January 31, 2021

Resource links provided by the National Library of Medicine


Group/Cohort 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.




Primary Outcome Measures :
  1. Assessing CD34+ cells function [ Time Frame: 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.



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Ages Eligible for Study:   21 Years to 98 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population
Patients who have retinal abnormalities other than diabetic retinopathy will be excluded. Patients who have systemic conditions that influence hematopoietic stem cell function such as cardiovascular disease, malignant disease, diabetes, hematologic disorder, or estimated glomerular filtration rate less than 60 mL/min or who have undergone treatment with erythropoietin will be excluded. We will record all medications including antihypertensive drug treatment, treatment with statins, Angiotensin-Converting Enzyme (ACE) Inhibitors, Angiotensin Receptor Blockers (ARB) or other pharmacological agents that may influence CD34+ cell function. Baseline characteristics will be recorded, including age, lipid parameters, body mass index (BMI), blood pressure, smoking history, antioxidant intake and use of nutritional supplements.
Criteria

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 b) 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03403686


Contacts
Contact: Jennifer Moorer 205 325 8674 jmoorer@uabmc.edu

Locations
United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35294
Contact: Jennifer Moorer    205-325-8674    jmoorer@uabmc.edu   
Principal Investigator: Maria B Grant, MD         
Sponsors and Collaborators
University of Alabama at Birmingham
Investigators
Principal Investigator: Maria B Grant, MD University of Alabama at Birmingham

Responsible Party: Maria Grant, Principal Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT03403686     History of Changes
Other Study ID Numbers: 300000068
First Posted: January 19, 2018    Key Record Dates
Last Update Posted: January 19, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
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, University of Alabama at Birmingham:
Liver X receptor
Circulating angiogenic cells

Additional relevant MeSH terms:
Retinal Diseases
Diabetic Retinopathy
Eye Diseases
Diabetic Angiopathies
Vascular Diseases
Cardiovascular Diseases
Diabetes Complications
Diabetes Mellitus
Endocrine System Diseases