Zynteglo

Zynteglo is a preparation of autologous, CD34-positive hematopoietic stem cells (HSCs) transduced ex vivo with the BB305 recombinant replication-defective, self-inactivating lentiviral vector encoding for an engineered form of human beta-globin (hemoglobin-beta, HBB) gene, beta-A-T87Q (B-A-T87Q). This genetic modification, where threonine at position 87 is substituted with glutamine, restores beta-globin expression and function in patients with beta-thalassemia or sickle cell anemia.

Composition

Zynteglo consists of:

CD34-positive hematopoietic stem cells:

• Autologous HSCs isolated from the patient’s own bone marrow.

BB305 Lentiviral Vector:

• A replication-defective, self-inactivating vector used to insert the B-A-T87Q beta-globin gene into the patient's HSCs.

B-A-T87Q Beta-Globin:

• An engineered beta-globin protein with a threonine-to-glutamine substitution at position 87, enhancing its antisickling activity compared to the wild-type protein.

Mechanism of Action

The therapeutic process involves:

1. Isolation of Autologous CD34-positive HSCs:

• Hematopoietic stem cells are collected from the patient’s bone marrow.

2. Ex Vivo Transduction:

• These cells are transduced with the BB305 lentiviral vector to insert the B-A-T87Q beta-globin gene.

3. Reinfusion:

• The modified HSCs, known as betibeglogene autotemcel, are re-infused into the patient.

4. Expression of Beta-Globin:

• The transduced cells produce B-A-T87Q-globin, enabling the synthesis of functional hemoglobin.

5. Restoration of Healthy Red Blood Cells:

• The expressed beta-globin allows the body to generate normal, healthy red blood cells.

Indications

Zynteglo is primarily indicated for the treatment of:

Beta-Thalassemia:

• A genetic disorder caused by mutations in the HBB gene leading to insufficient beta-globin production.

Sickle Cell Anemia:

• A condition caused by abnormal beta-globin, resulting in sickle-shaped red blood cells that impair blood flow.

Advantages

Targeted Therapy:

• Addresses the root cause of beta-globin deficiencies by correcting the genetic defect in the patient’s HSCs.

Long-Term Efficacy:

• Potential for lifelong production of normal beta-globin and healthy red blood cells.

Reduced Complications:

• The B-A-T87Q beta-globin exhibits increased antisickling activity, minimizing complications associated with sickle cell disease.

Safety and Side Effects

The use of Zynteglo may be associated with:

Myoloablatiive conditioning:

• Required before the infusion of betibeglogene autotemcel, which can lead to temporary immunosuppression.

Potential Insertional Mutagenesis:

• Though minimized by using a self-inactivating lentiviral vector, there is a theoretical risk of disrupting other genes.

Short-Term Side Effects:

• Fever, infections, and low blood counts are common immediately after infusion.

Related Concepts

Beta-Globin:

• The beta-chain of hemoglobin, essential for oxygen transport in red blood cells.

HBB Gene:

• Encodes beta-globin; mutations cause beta-thalassemia and sickle cell anemia.

Betibeglogene Autotemcel:

• - The active therapeutic component of Zynteglo.

See Also

• Hematopoietic stem cell transplantation
• Gene therapy
• Beta-thalassemia
• Sickle cell anemia