Genetic Correction
Gene Therapy
Correcting the genetic defect at its source. The history, the process, the promise — and the honest caveats — of gene therapy in inherited blood disorders.
The Promise
Forty years of trying to correct the gene
To try and correct the genetic defect, if possible, in inherited diseases seemed like an intuitive approach. Scientists have tried to achieve this over the last four decades. The problem has centred around the method to achieve this.
Certain viruses have the tendency to incorporate their genetic element into the human DNA. Utilising this principle, many viruses of the adenovirus or retrovirus clans were tried as agents or vectors to correct the defective gene. Most were unsuccessful or led to cancers in later years.
However, it is only in the last 5–10 years that safe and effective viral vectors have been identified. These are either Lentivirus or Adeno-associated Virus. In addition, by understanding how bacteria correct their genetic elements through an enzymatic cleavage method, scientists applied another method of deleting and/or adding genetic elements called CRISPR-Cas9. Based on these developments, successful gene therapy trials have taken place in both Thalassemia and Sickle Cell Anemia.
The Process
The Nine Steps of Gene Therapy
Stem cells are mobilised into the peripheral blood and collected by apheresis — similar to dialysis.
The true stem cells (CD34+) are separated from other blood cells using magnetic beads coated with CD34 antibody.
A safe Lentivirus or Adeno-associated Virus is engineered to carry the corrective gene.
The corrective gene is delivered into the patient's stem cells via the viral vector.
Laboratory testing confirms the gene has been successfully integrated and is being expressed.
The patient's existing bone marrow stem cells are destroyed with high-dose Busulfan to make room for the genetically corrected cells.
The corrected stem cells are returned to the patient via a transfusion through a central line.
The patient is managed in a clean room while waiting for haematopoietic recovery, with attention to the complications of high-dose chemotherapy.
Long-term follow-up tracks the durability of the genetic correction and watches for any late effects.
Honest Caveats
Points to be noted for Gene Therapy
Similar to Autologous BMT
The process is similar to that of an Autologous BMT — including the conditioning, the clean-room phase, and the engraftment timeline.
Limited to the transfected cell type
The genetic correction is limited to the transfected cell type. It does not prevent the vertical transmission of the defective gene to the patient's progeny.
Long-term safety still being learned
The follow-up of these patients is currently short, and the long-term probability of a cancer developing due to aberrant genetic integration is unclear.