Clinical trial NCT04137692: Red Blood Cell Exchange Transfusion as a Novel Treatment for GLUT1 Deficiency Syndrome
Official title: Red Blood Cell Exchange Transfusion as a Novel Treatment for GLUT1 Deficiency Syndrome
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Glucose Transporter Type 1 Deficiency Syndrome
GLUT1DS1
Keywords: G1D
Glucose transporter
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
First posted: 2019-10-24
Enrollment: 5
Sex: ALL
Minimum age (years): 16
Maximum age (years): 64
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief 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.

Detailed 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.

Eligibility criteria: Inclusion Criteria:

* Male or Female
* Age 16 years to 64 years old.
* Diagnosed with genetically-confirmed glucose transporter type 1 disorder
* Patients not currently receiving dietary therapy, including ketogenic diet or other dietary therapy, due to failure of these diets to achieve seizure remission or due to patient preference, including compliance or tolerance issues. Patients currently on Modified Atkins Diet (MAD) and / or taking Medium Chain Triglyceride (MCT) oil are allowed.

Exclusion Criteria:

* Currently on the ketogenic diet or taking triheptanoin (C7) oil
* No genetic confirmation of G1D diagnosis
* Unable to return for follow up visits
* Weak peripheral veins, such that IV placement is contraindicated (required for transfusion)
* Serious chronic medical conditions, such as congestive heart failure, renal failure, liver failure, or any other medical conditions that preclude large volume transfusions.
* Patients currently pregnant or breast-feeding are excluded from participating in this research. Patients who plan on getting pregnant during this research or who are unwilling to use birth control, including abstinence, during the course of this research are also excluded due to safety concerns for the fetus.

Primary outcomes:
measure: Change in electroencephalogram (EEG)
timeFrame: Baseline, during transfusion, and 60 days after transfusion
Secondary outcomes:
measure: Change in neuropsychological receptive language test battery
timeFrame: Baseline, immediately after transfusion, and 60 days after transfusion
measure: Change in neuropsychological expressive language test battery
timeFrame: Baseline, immediately after transfusion, and 60 days after transfusion
measure: Change in neuropsychological attention scores
timeFrame: Baseline, immediately after transfusion, and 60 days after transfusion
measure: Changes in biochemical assay
timeFrame: Baseline, immediately after transfusion, and 60 days after transfusion
measure: Change in General Medical & Neurological Examination
timeFrame: Baseline and 60 days after transfusion
Other outcomes:
Locations:
city: Dallas
country: United States
facility: UT Southwestern
state: Texas
Study officials:
affiliation: UT Southwestern Medical Center
name: Juan Pascual, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lee EE, Ma J, Sacharidou A, Mi W, Salato VK, Nguyen N, Jiang Y, Pascual JM, North PE, Shaul PW, Mettlen M, Wang RC. A Protein Kinase C Phosphorylation Motif in GLUT1 Affects Glucose Transport and is Mutated in GLUT1 Deficiency Syndrome. Mol Cell. 2015 Jun 4;58(5):845-53. doi: 10.1016/j.molcel.2015.04.015. Epub 2015 May 14.