Red Blood Cell Disorders

Red blood cells (RBCs, also called erythrocytes) are the most common cell type in the blood, with the primary duty of carrying oxygen from the lungs to the body’s tissues using the iron-containing molecule hemoglobin, which also gives blood its red color. Most RBC diseases are lifelong, chronic conditions that result in anemia, a reduction in the ability to carry oxygen to tissues due to reduced numbers of RBCs in blood, or a reduction in the amount or function of hemoglobin in the RBCs. The latter diseases are also known as hemoglobinopathies, and include sickle cell disease (SC, common in people of African descent, caused by a less functional hemoglobin beta, selected via malaria parasite resistance advantage over many generations), as well as beta and alpha thalassemia (from the Greek word Thalassa, meaning “sea”). The Nobel Prize-winning pathologist George Whipple coined the term thalassemia in 1932, alluding to the relatively high occurrence of the disease in people from the Mediterranean, such as Italians and Greeks. This region was once also endemic for malaria, and the presence of thalassemia minor (like sickle trait in Africa) afforded protection against malaria, enabling this condition to thrive.

In August 2017, ASGCT partnered with the Hemophilia Federation of America to produce a pair of patient education webinars: Gene Therapy Basics and Gene Therapy in Bleeding Disporders - Hemophilia. We're proud to offer replays of those essential sessions on
Watch the Webinar

Hemoglobinopathies are often monogenic diseases of the hemoglobin alpha and beta genes and can be corrected by replacing the missing/malfunctioning gene (most commonly hemoglobin beta, as with SC and beta-thalassemia). Additional diseases such as Diamond-Blackfan anemia and Fanconi anemia (FA) also cause decreased RBCs, but are more difficult to treat by gene and cell therapy since they are often not caused by a mutation in a single gene in all patients, hence making it difficult to target for gene replacement therapy. For example, FA involves loss of not just RBCs but other blood cells, and can be caused by mutations in many different genes involved in DNA repair. 

In order to treat monogenic RBC disorders, stem cells are typically isolated from the patient and gene therapy is used to render them capable of forming functional RBCs that can carry oxygen, typically through the restoration of hemoglobin function. One strategy is to reactivate the gamma chain of hemoglobin, which is produced in the fetal stage in all humans but replaced by beta hemoglobin after birth. Two gamma chains can pair with two alpha chains to create HbF (fetal hemoglobin), which is even more effective in carrying oxygen than the adult hemoglobin (two alpha chains and two beta chains). The gamma chain can be reactivated by targeting molecules that suppress its activation in adults, such as BCL11A, through genetic engineering using zinc finger nucleases (ZFNs) and other DNA-modifying molecular tools to selectively edit the BCL11A gene. With this gene rendered non-functional, the gamma chain can be re-expressed again, restoring RBC function via formation of HbF.

Human stem cells can be isolated from bone marrow or mobilized leukapheresis (often simply called “apheresis”). The latter is a way to increase stem cells in the blood by infusing the patient (donor) with combinations of immune-stimulating factors such as plerixafor and G-CSF (granulocyte-colony stimulating factor), then using an instrument to collect large amount of cells over several hours by the bedside, while reinfusing the plasma back into the donor to replace lost blood volume. These stem cells are then transported to a manufacturing facility, purified, often with magnetic nanoparticles, then genetically engineered using gene therapy (for example, using lentiviruses or electroporation) to introduce a functional gene in place of one that is not working properly. Another strategy is to remove a gene to express a beneficial one, such as the gamma globin re-expression strategy described above. These engineered stem cells can then be introduced back into the same donor patient to correct the monogenic deficiency via production of functional RBCs that are able to efficiently carry oxygen. These ex-vivo gene therapy approaches, while uniquely promising, still have many challenges which require further research and development. It may be difficult to harvest sufficient number of hematopoietic stem cells from donor bone marrow or mobilized apheresis, and maintain their “stemness” during the genetic manipulation. There is often considerable stem cell loss during genetic manipulation and therefore a lot more hematopoietic stem cells need to be harvested at the beginning of treatment. At the other end, during administration of the engineered stem cells the patient often needs to be given sufficient chemotherapy to give the transplanted genetically modified cells a survival advantage.

Most patients who suffer from RBC disorders require life-long transfusions; there are currently no proven cures for these diseases. Gene and cell therapy offers the greatest hope in restoring RBC function to these patients. The recent approval of Strimvelis for the treatment of ADA-SCID (severe combined immunodeficiency, also known as “bubble boy disease”, due to the lack of ADA, a key DNA modifying enzyme called adenosine deaminase) is just one recent demonstration of the potential of ex-vivo gene therapy to overcome monogenic blood cell diseases. Several groups are now working on ex-vivo gene therapies for hemoglobinopathies, and Phase 1 trials are expected to commence in 2018.


Hemophilia Webinars

ASGCT and the Hemophilia Federation of America (HFA) have partnered to produce a series of patient education webinars.

22nd Annual Meeting
April 29 – May 2 | Washington D.C.