HbS and gene therapy

Published on 2 Apr 2017

HbS refers to the sickle hemoglobin. Quick intro here: hemoglobin is the red protein responsible for transporting oxygen in the blood. HbS is associated with the disease known as sickle cell anemia (SCA). There are many variants of Hb protein, namely the fetal hemoglobin (HbF), hemoglobin A (HbA), and hemoglobin B (HbB). In a patient with SCA, there is a problem with certain subunits of the Hb protein, therefore giving rise to the sickle cell blood phenotype.

SCA results from the homozygous missense mutation in the β-globin gene that causes polymerization of hemoglobin S. This disease has been a great interest in the scientific community because we know enough about the genetic and pathway of this disease. We know enough to carry out experiments to cure this disease.

Let’s get to the gene therapy part. A group of researchers from Necker Children’s Hospital in central Paris, France, performed a gene therapy procedure on a patient suffering from SCA. In this report, a boy suffered from homozygous HbS. In May 2014, he was enrolled in a clinical study to first fully determine the nature of his HbS. In October 2014 when he was about 13 years old, he received an infusion of the drug product LentiGlobin BB305.

So what’s LentiGlobin BB305?

It is a viral vector carrying a modified variant HbB, I believe. It is described as a self-inactivating lentiviral vector, capable of inhibiting the HbS polymerization. First, the researchers obtained bone marrow from the patient to collect sufficient stem cells for gene transfer. After a select bone-marrow cell type was enriched, the cells were then transduced with the LentiGlobin BB305 vector. The patient was discharged on day 50 and about 15 months after transplantation, no SCA-related clinical events were reported afterward.

I have to admit that I do not really understand this paper. There are a number of things I need to learn more:

  • What is meant by engraftment
  • How the lentiviral vector was made
  • What is busulfan and why it is necessary
  • The dynamics of all Hb variants

By the way, do you know that if a person is heterozygous for HbS, he/she is protected from malaria (P. falciparum) infection? That’s pretty cool.

Literature sources:

  • Ribeil et al., 2017, NEJM 376:848-855, doi:10.1056/NEJMoa1609677
  • Kwiatkowski, 2005, Am. J. Hum. Genet. 77:171-190, doi:10.1086/432519

More update(s) will come soon in the future!