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

Weill Medical College of Cornell University12 enrolled

Overview

Pathogenic mutations of the brain glucose transporter type I lead to glucose transporter deficiency syndrome (G1D), which is most often associated with medication-refractory epilepsy and movement dysfunction. At present, G1D is only alleviated by interventions such as the ketogenic diet, which can be poorly tolerated and afford only an incomplete restoration of neural function. A better understanding of G1D can uncover new fundamental aspects of brain function while facilitating the development of new therapies aimed to restore brain metabolism and excitability. We will conduct a mechanistic trial that will utilize a mechanism-testing framework broadly applicable to metabolic interventions. The trial will investigate red blood cell exchange (i.e., the replacement of human G1D circulating red cells, which are deficient in GLUT1) with healthy donor cells as a novel means to augment blood-to-brain glucose transport. The hypothesis is that electroencephalography post treatment will display an increase in beta brain activity. Additional measures of brain activity will also be secondarily tested.

Glucose Transporter 1 (GLUT1) is a protein that helps move glucose (sugar) into cells. Most tissues in the body have only small amounts of this protein. Red blood cells, however, have very large amounts of GLUT1, far more than they need for their own energy use. Because of this, red blood cells can take in and carry glucose at extremely high rates, much higher than they can actually use themselves. Some scientists believe that red blood cells may serve as a temporary storage system for glucose, especially when blood sugar levels are low. If this idea can be proven, it would change how we understand an important part of human biology. This study may also lead to new treatment options for people with Glucose Transporter Type 1 Deficiency (G1D). G1D is a condition where the brain does not get enough glucose because the GLUT1 protein does not work properly. Right now, the only treatment is the ketogenic diet. This diet helps some patients with seizures, but it does not work well for long-term brain development or overall health, so better treatments are needed. It is usually believed that G1D mainly affects the cells in the brain's blood vessels, which help control what gets into the brain. However, many G1D patients also have low levels of GLUT1 in their red blood cells, meaning their red blood cells may not carry enough glucose. This may also play a role in the disease. Animal models, like mice with GLUT1 deficiency, do not accurately mimic the human condition, so they cannot fully answer this question. Red blood cell exchange (RBCx) is already used safely and at reasonable cost for patients with sickle cell disease to prevent strokes and blood vessel problems. Because RBCx replaces a person's red blood cells with donor cells, it could be a promising new approach for treating G1D.

Eligibility

Sex: ALLMin age: 16 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Male or Female 2. Age 16 years to 80 years old. 3. Diagnosed with genetically confirmed glucose transporter type 1 disorder 4. Patients not currently receiving ketogenic dietary therapy, due to failure of this diet to achieve seizure remission or due to patient preference, including compliance or tolerance issues. 5. Subjects must be able to provide informed consent for themselves or have a parent or legally authorized representative (LAR) provide permission if the subject is a minor or lacks capacity to consent. 6. Spanish and English speakers will be eligible for participation. Spanish-speaking participants may be enrolled, and the study team is equipped to conduct the consent process in Spanish. The Principal Investigator (PI) is fluent in Spanish and will conduct the consent process in Spanish when applicable. 7. IHD-RBCx is determined to be a safe and appropriate procedure for the subject by the transfusion medicine physician based on clinical and laboratory assessment. Exclusion Criteria: 1. Currently on the ketogenic diet or taking triheptanoin (C7) oil 2. No genetic confirmation of G1D diagnosis 3. Unable to return for follow up visits 4. Weak peripheral veins, such that IV placement is contraindicated (required for transfusion) 5. Serious chronic medical conditions, such as congestive heart failure, renal failure, liver failure, or any other medical conditions that preclude large volume transfusions. 6. 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. 7. An evaluation by the transfusion physician as to whether IHD-RBCx is a safe option will be part of the screening assessment. If IHD-RBCx is deemed unsafe based on laboratory parameters such as a low red blood cell count, then the subject will not be eligible to participate in this study.

Outcomes

Primary Outcomes

Change from baseline in electroencephalography (EEG) measures during transfusion.

Electroencephalography measures number of seizures recorded during the transfusion. Number of seizures will be assessed using standard observation of the electroencephalogram (EEG).

Time frame: Baseline: During Transfusion

Change from baseline in electroencephalography (EEG) measures 60 days after transfusion.

Electroencephalography measures number of seizures recorded 60 days after the transfusion. Number of seizures will be assessed using standard observation of the electroencephalogram (EEG).

Time frame: Baseline - 60 Days After Transfusion

Secondary Outcomes

Change from baseline in Peabody Picture Vocabulary Test (PPVT) standard scores immediately after transfusion

The Peabody Picture Vocabulary Test (PPVT) measures receptive vocabulary skills. Total scores range from 20 to 160, with higher scores indicating stronger receptive language ability.

Time frame: Baseline - Immediately after transfusion

Change from baseline in Peabody Picture Vocabulary Test (PPVT) standard scores 60 days after transfusion

The Peabody Picture Vocabulary Test (PPVT) measures receptive vocabulary skills. Total scores range from 20 to 160, with higher scores indicating stronger receptive language ability.

Time frame: Baseline - 60 days after transfusion

Change from baseline in Expressive Vocabulary Test (EVT) standard scores immediately after transfusion

The Expressive Vocabulary Test (EVT) evaluates expressive vocabulary and word retrieval abilities. Total Standard scores typically range from 20 to 160, with higher scores indicating stronger expressive language skills.

Time frame: Baseline - Immediately after transfusion

Change from baseline in Expressive Vocabulary Test (EVT) standard scores 60 days after transfusion

Time frame: Baseline - 60 days after transfusion

Change from Baseline in T-scores on the Connors Continuous Performance Test Immediately After Transfusion

T-scores will be obtained from the Connors Continuous Performance Test (CPT). Minimum T-score is \<30 and maximum is 90. For the Hit Reaction Time domain, higher T-scores indicate slower reaction time. For detectability, omissions, commissions, and perseverations, higher T-scores indicate elevated performance.

Time frame: Baseline - Immediately after transfusion

Change from Baseline in T-scores on the Connors Continuous Performance Test 60 Days After Transfusion

Time frame: Baseline - 60 days after transfusion

Number of participants immediately after transfusion with erythrocyte Glut1 levels increased by over 40% from baseline

Baseline erythrocyte Glut1 levels are used as the reference point. This measure captures the number of participants whose Glut1 levels increase by more than 40% immediately after transfusion compared to their baseline value.

Time frame: Immediately after transfusion

Number of participants 60 days after transfusion with erythrocyte Glut1 levels increased by over 40% from baseline

Baseline erythrocyte Glut1 levels are used as the reference point. This measure captures the number of participants whose Glut1 levels increase by more than 40% 60 days after transfusion compared to their baseline value.

Time frame: 60 days after transfusion

Change from Baseline in General Medical & Neurological Examination 60 Days After Transfusion

This measure assesses change from baseline in the standardized clinical physical examination, which includes 12 domains scored as normal or abnormal. Minimum total score is 0. Maximum total score is 76. Higher total scores indicate a more normal examination and better outcomes, while lower scores indicate more abnormalities.

Time frame: Baseline - 60 days after transfusion

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes