Biotin Labeling for Sickle Cell Anemia

Overseen By John F Tisdale, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Disqualifiers: Biotin supplements, Chronic transfusion therapy, Hemodialysis, Malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

100 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, you cannot participate if you are on chronic transfusion therapy or have consumed biotin supplements or raw eggs in the last 30 days.

What data supports the effectiveness of the treatment Biotin-labeled red blood cells for Sickle Cell Anemia?

The research shows that biotin-labeled red blood cells can be used to track the lifespan and changes in sickle cells, which helps in understanding how these cells behave in the body. This method allows for studying the survival and characteristics of sickle cells, which could be useful in managing Sickle Cell Anemia. ^{1 2 3 4 5}

Is biotin labeling of red blood cells safe for humans?

Biotin labeling of red blood cells has been used in studies to measure red cell survival and is considered a non-toxic alternative to radioactive methods. However, there have been occasional reports of antibodies forming against biotin-labeled cells, which could affect the survival of transfused cells. ^{2 3 6 7 8}

How is the biotin-labeled red blood cell treatment different from other treatments for sickle cell anemia?

Biotin-labeled red blood cells are unique because they allow for tracking the survival and lifespan of red blood cells without using radiation, which is different from traditional methods. This treatment helps in understanding how sickle cells change over time and can provide insights into the effectiveness of other therapies. ^{1 2 3 4 5}

What is the purpose of this trial?

Background: Sickle cell disease (SCD) is an inherited disorder of the blood. SCD causes red blood cells (RBCs) to die early. This can lead to a shortage of healthy cells. SCD and other blood disorders can be managed with drugs or cured with a bone marrow transplant. Researchers want to know how long RBCs survive in people with SCD and other blood disorders before and after treatment compared to those who had a bone marrow transplant. Objective: To learn how long RBCs survive in the body in people with SCD and other blood disorders compared to those whose disease was cured with a bone marrow transplant. Eligibility: People aged 18 years or older with SCD or another inherited blood disorder. People whose SCD or blood disorder was cured with a bone marrow transplant are also needed. Design: Participants will be screened. They will have a physical exam with blood and urine tests. Participants will have about 7 tablespoons of blood drawn. In the lab, this blood will be mixed with a vitamin called biotin. Biotin sticks to the outside of RBCs. This process is called "biotin labeling of RBCs." The next day, the participant s own biotin-labeled RBCs will be returned to their bloodstream. Participants will return regularly to have smaller blood samples (about 2 teaspoons) drawn. These samples will be tested to detect the percentage of cells that have biotin labels. These visits may be every 2 weeks, 4 weeks, or some other interval. Participants will continue this schedule for up to 20 weeks or until biotin can no longer be detected....

Research Team

John F Tisdale, M.D.

Principal Investigator

National Heart, Lung, and Blood Institute (NHLBI)

Eligibility Criteria

This trial is for individuals with sickle cell disease or other hemoglobin disorders like thalassemia. It's open to those who are on disease-modifying treatments or have had a stem cell transplant. The study aims to understand how long their red blood cells live using biotin labeling.

Inclusion Criteria

Provision of signed and dated informed consent form

I can have blood samples taken.

Agreement to adhere to Lifestyle Considerations (Refrain from consumption of raw eggs or biotin supplements until after the study completion) throughout study duration

Exclusion Criteria

Consumption of biotin supplements or raw eggs within the last 30 days

Pregnancy, lactation or absence of adequate contraception for fertile subjects

I am not on hemodialysis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Biotin Labeling

Participants have blood drawn and mixed with biotin, then returned to their bloodstream

1 day

1 visit (in-person)

Monitoring

Participants return regularly for blood samples to detect biotin-labeled RBCs

Up to 20 weeks

Every 2-4 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Biotin-labeled red blood cells

Trial Overview The trial tests the lifespan of red blood cells in patients with sickle cell and related disorders by marking them with biotin, a vitamin. Researchers will compare this before and after treatments like transplants, looking at how different therapies affect red cell survival.

Participant Groups

Group I: RBC survival in patients with SCD Experimental Treatment 1 Intervention

RBC lifespan, determined by the mean number of days from biotin-labeled RBC infusion until biotin-labeled RBCs are below limit of detection, in patients with inherited hemoglobinopathies prior to and post initiation of disease modifying therapy or HSCT

Biotin-labeled red blood cells is already approved in United States for the following indications:

Approved in United States as Biotin-labeled RBCs for:

• Research use in sickle cell disease and other hemoglobinopathies

Who Is Running the Clinical Trial?

National Heart, Lung, and Blood Institute (NHLBI)

Lead Sponsor

Trials

3,987

Recruited

47,860,000+

Children's National Research Institute

Collaborator

Trials

227

Recruited

258,000+

Findings from Research

Sickle red blood cells (RBC) have a significantly shorter lifespan compared to normal RBC, with biotin labeling showing that sickle RBC without fetal hemoglobin (HbF) survive for about 2 weeks, while those with HbF can last 6-8 weeks.

The study validated a biotin RBC label against the standard 51Cr label, confirming that both methods yield equivalent results, and revealed that sickle RBCs experience rapid loss from circulation shortly after reinfusion, particularly in reticulocytes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Time-dependent changes in the density and hemoglobin F content of biotin-labeled sickle cells. Franco, RS., Lohmann, J., Silberstein, EB., et al.[2018]

Biotinylation of red blood cells (B-RBCs) does not appear to make them immunogenic, as none of the 20 healthy subjects developed antibodies before transfusion, and only 3 showed transient antibody production after receiving autologous B-RBCs.

While the antibodies produced were not linked to any changes in red blood cell kinetics, their presence suggests that monitoring for these antibodies is advisable during multiple B-RBC transfusions to ensure safety and understand potential biological effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibodies provoked by the transfusion of biotin-labeled red cells. Cordle, DG., Strauss, RG., Lankford, G., et al.[2019]

In vivo biotin labeling of erythrocytes using biotin-N-hydroxysuccinimide ester (BNHS) and caproylamidobiotin-N-hydroxysuccinimide ester (C-BNHS) allows for accurate estimation of red blood cell survival without damaging the cells or affecting their production.

This method demonstrated a consistent daily disappearance rate of biotin-labeled red cells (2.5%-3.3%), making it a reliable technique for studying red cell lifespan in small animal models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct in vivo biotinylation of erythrocytes as an assay for red cell survival studies. Hoffmann-Fezer, G., Maschke, H., Zeitler, HJ., et al.[2019]

A new closed-system procedure for biotinylating red blood cells (RBCs) has been developed, ensuring safety and compliance with current good manufacturing practices (cGMP), which is crucial for clinical applications.

Biotinylated RBCs can be reliably tracked in the bloodstream using flow cytometry, demonstrating stability for up to 50 days, which is important for optimizing RBC storage and understanding factors affecting transfusion outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current good manufacturing practices-compliant manufacture and measurement of biotin-labeled red blood cells. Donnenberg, AD., Kanias, T., Triulzi, DJ., et al.[2023]

A standardized method for labeling red blood cell concentrates (RCCs) with biotin was developed, allowing for accurate tracking of donor RBCs in recipients without compromising the biological activity of the cells.

This biotin labeling process can be completed in under 2 hours in a sterile, closed system, making it suitable for clinical research and compliant with Good Practice Guidelines for blood establishments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A method for red blood cell biotinylation in a closed system. de Back, DZ., Vlaar, R., Beuger, B., et al.[2018]

Re-exposure to biotin-labeled red blood cells (BioRBC) in previously immunized adults led to an increase in specific antibodies, which can affect the accuracy of red cell survival measurements.

No adverse clinical events were reported during the study, but to reduce the risk of antibody induction and ensure accurate red cell survival assessments, it is recommended to limit the initial BioRBC exposure volume to ≤10 mL and use label densities of ≤18 μg/mL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antibodies against biotin-labeled red blood cells can shorten posttransfusion survival. Mock, DM., Stowell, SR., Franco, RS., et al.[2022]

Biotin labeling using BxNHS allows for the detection of red blood cells for nearly 100 days post-infusion, making it a reliable method for studying cell survival compared to water-soluble biotin compounds, which lose effectiveness after about 4 weeks.

The study found that BxNHS labeling provides a nonradioactive and nontoxic alternative for red cell survival studies, with survival times comparable to traditional 51Cr labeling, indicating its potential for safe and effective use in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of biotin labeling for red cell survival testing. Hoffmann-Fezer, G., Trastl, C., Beisker, W., et al.[2019]

A new method using biotin-labeled red blood cells (BioRBCs) allows for safe and accurate measurement of red blood cell survival in vivo, which is particularly beneficial for infants, children, and pregnant women who cannot use traditional chromium-51 methods.

This biotin labeling technique enables multiple independent measurements of red blood cell survival without exposing subjects to radiation and requires only small blood volumes, making it a significant advancement in studying anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Red blood cell (RBC) survival determined in humans using RBCs labeled at multiple biotin densities. Mock, DM., Matthews, NI., Zhu, S., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Time-dependent changes in the density and hemoglobin F content of biotin-labeled sickle cells. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Antibodies provoked by the transfusion of biotin-labeled red cells. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

Direct in vivo biotinylation of erythrocytes as an assay for red cell survival studies. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Current good manufacturing practices-compliant manufacture and measurement of biotin-labeled red blood cells. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

A method for red blood cell biotinylation in a closed system. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

Antibodies against biotin-labeled red blood cells can shorten posttransfusion survival. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Preclinical evaluation of biotin labeling for red cell survival testing. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Red blood cell (RBC) survival determined in humans using RBCs labeled at multiple biotin densities. [2021]