A couple of weeks ago CASGEVY (https://crisprtx.com/therapies) and Lyfgenia (https://www.lyfgenia.com/) were approved for treatment of sickle cell disease in patients 12 years and older. These drugs represent the first cell-based gene therapies for treatment of sickle cell disease.
Approval of these gene therapies is a major milestone in advancing usage of gene editing technologies to treat genetic disorders that currently have no cure.
Sickle cell disease is a group of inherited blood disorders affecting approximately 10 million people globally.
Sickle cell disease
The primary defect in sickle cell disease is a mutation in the HBB gene which encodes B-subunits of hemoglobin. An individual with a single/ heterozygous mutation in a HBB gene will have sickle cell trait (HbS). A double/homozygous mutation in a HBB gene will have sickle cell disease (HbSS).
Hemoglobin is a protein found in red blood cells that helps in delivery of oxygen to body tissues. The mutation causes red blood cells to develop a crescent/sickle shape that restricts efficient blood flow and limit delivery of oxygen to body tissues. This can usually present as severe pain and organ damage (vaso-occlusive crises). Recurrent organ damage leads to severe disability and or early death.
The sub-saharan burden of sickle cell trait is between 20% and 40% of the population. Sickle cell trait is a largely benign condition besides conferring protection against severe malaria. Sickle cell disease on the other hand is a lifelong severely disabling disease with low quality of life and nearly guaranteed early death.
In Uganda, burden of sickle cell trait stands at average 13.3% ranging from 5% in the southwestern region to 20% in the east and central regions. The burden of sickle cell disease follows the same pattern 0.2% in the southwestern region to over 1.5% in the east and central regions. (Grace Ndeezi et al 2016, https://www.sciencedirect.com/science/article/pii/S2214109X15002880).
Casgevy
Casgevy is a cell-based gene therapy that uses CRISPR/Cas9 gene editing technology. Patient's blood stem cells are modified by the gene editing technology. Modified stem cells are transplanted back to the patient where they attach and multiply in the bone marrow and produce fetal hemoglobin (HbF). HbF facilitates delivery of oxygen to tissues preventing sickling crises in sickle cell disease patients.
Lyfgenia
Lfygenia is a cell-based gene therapy that uses a lentiviral vector (gene delivery vehicle) for gene editing. Patient's blood stem cells are modified to produce HbAT87Q, a gene therapy derived hemoglobin A which similarly functions as the normal adult hemoglobin. Modified blood stem cells are transplanted back to the patient.
Both therapies are made from the patient's own blood stem cells which are modified and given to the patient as a single dose one time blood stem cell transplant treatment.
Approval of these gene therapies is an important step in advancing innovative gene therapies to treat various life threatening genetic diseases. Although access to these therapies is still very expensive; Casgevy $2.2m per patient and Lyfgenia $3.1m per patient, there's hope these technologies could be spread out to bring the cost down for the benefit of many patients across the globe.
Approval of these therapies provides a ray of hope for many patients living with various genetic diseases especially muscle dystrophies and other genetic diseases.
We'll have to wait and see how this gene therapy landscape unfolds in the coming months and years.
