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Red Blood Cell Exchange Transfusion as a Novel Treatment for GLUT1 Deficiency Syndrome

2019-10-29 14:36:47 | BioPortfolio

Summary

This proposal is an investigator-initiated, single-site proof of concept trial. Five patients will undergo isovolemic hemodilution-red cell exchange (IHD- RBCx) with up to 10 units of red cell antigens (Rh group, Kell, Duffy, Kidd blood group antigens) matched normal donor red cells to replace a target of 70% of the patient's red cells with donor red cells. The procedure will be performed as an outpatient according to protocols established for sickle cell anemia patients. One of the investigators is an expert on RBCx and will oversee the transfusion. Subjects will be assessed before and after transfusion, and at two months post transfusion. Outcome measures include neurological exam, electroencephalography (EEG), neuropsychological testing, and biochemical assays.

Description

As the transporter responsible for basal levels of glucose flux, Glucose transporter 1 (GLUT1) is expressed at low levels in most tissues. In contrast, GLUT1 is very highly expressed on human erythrocytes. Human erythrocytes possess up to 5x105 copies of GLUT1 in their membranes representing almost 5% of total membrane protein. This allows erythrocytes to catalyze glucose transfer at rates three orders of magnitude greater than their capacity to utilize it. It has been proposed that human erythrocytes function in glucose storage, especially when the serum carrying capacity for glucose becomes limiting. If this hypothesis could be validated experimentally, it would be of fundamental importance to the understanding of human physiology.

This proposal also has the potential to uncover a novel therapeutic option for patients with Glucose Transporter Type 1 Deficiency (G1D). Currently, the only treatment for G1D is the ketogenic diet. While the ketogenic diet improves seizures in a fraction of patients, its effects on neurodevelopment and long-term health are poor, so better treatment options for G1D are needed. Because of the hypoglycorrachia (i.e. low cerebrospinal fluid glucose) of G1D patients, the endothelial cells of the blood-brain barrier microvessels have long been assumed to be the primary site of disease pathogenesis. However, most G1D patients also have deficits in GLUT1 levels and glucose uptake in their erythrocytes and a potential contribution of this compartment to disease pathogenesis is likely. GLUT1 deficient mice are not amenable to test the hypothesis because they do not fully recapitulate the clinical presentation of G1D patients and because they exhibit metabolic adaption to G1D. Red blood cell exchange (RBCx) is a safe and cost effective treatment to prevent strokes and vascular abnormalities in patients with sickle cell anemia. RBCx has the potential to dramatically alter the treatment of G1D patients.

Study Design

Conditions

Glucose Transporter Type 1 Deficiency Syndrome

Intervention

Red Blood Cell Transfusion

Location

UT Southwestern
Dallas
Texas
United States
75390

Status

Not yet recruiting

Source

University of Texas Southwestern Medical Center

Results (where available)

View Results

Links

Published on BioPortfolio: 2019-10-29T14:36:47-0400

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Medical and Biotech [MESH] Definitions

A ubiquitously expressed glucose transporter that is important for constitutive, basal GLUCOSE transport. It is predominately expressed in ENDOTHELIAL CELLS and ERYTHROCYTES at the BLOOD-BRAIN BARRIER and is responsible for GLUCOSE entry into the BRAIN.

A glucoside-derived SODIUM-GLUCOSE TRANSPORTER 2 inhibitor that stimulates urinary excretion of glucose by suppressing renal glucose reabsorption. It is used to manage BLOOD GLUCOSE levels in patients with TYPE 2 DIABETES.

A major glucose transporter found in NEURONS.

A glucose transport protein found in mature MUSCLE CELLS and ADIPOCYTES. It promotes transport of glucose from the BLOOD into target TISSUES. The inactive form of the protein is localized in CYTOPLASMIC VESICLES. In response to INSULIN, it is translocated to the PLASMA MEMBRANE where it facilitates glucose uptake.

A glucose transport facilitator that is expressed primarily in PANCREATIC BETA CELLS; LIVER; and KIDNEYS. It may function as a GLUCOSE sensor to regulate INSULIN release and glucose HOMEOSTASIS.

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