Innovative cell-based gene therapy to treat sickle cell disease
Sickle cell disease is a rare, debilitating, and life-threatening blood disorder. In 2021, over half a million babies were born with sickle cell disease. This disorder was ranked as the 12th leading cause of mortality in children under 5 years of age, resulting in over 81,000 deaths worldwide.
In December 2023, the FDA approved the first gene therapies to treat sickle cell disease.
A recent study reports the follow-up of the first nine patients who received one of these treatments, the lovo-cel gene therapy, now commercialised under the name LYFGENIA.
The disease
Sickle cell disease is caused by a mutation, or error, in the two copies of the gene setting the precise instructions for making haemoglobin, the protein in red blood cells that carries oxygen around the body. This mutation results in the production of abnormal haemoglobin (HbS), and sickle-shaped red blood cells that recurrently block blood vessels restrict the flow of blood to organs (vaso-occlusive crises), leading to the progressive development of blood vessels disease. The abnormal shape also results in an excessive breakdown of red blood cells.
In the lovo-cel gene therapy, researchers take stem cells from a patient’s bone marrow. They use a lentivirus vector, a modified virus, to insert a new gene that codes for a unique type of haemoglobin (HbAT87Q) that helps decrease the expression and clumping of HbS. After removing all the cells in the bone marrow through chemotherapy, the modified blood stem cells are infused back to the patient as a transplant.
Purpose and findings of the study
In this study, researchers focused on the monitoring of nine patients who received the gene therapy in the initial phases of development to determine efficacy and safety over time (up to 60 months). The gene therapy results for the first seven patients (Group A) suggested that a higher expression of HbAT87Q would increase clinical benefits. The next two patients (Group B) received a modified lovo-cel process greatly improving the transplant quality (higher number of stem cells transduced with more viral vector).
Production of blood cells began and stabilized in all patients within 6 months after therapy, and the production of HbAT87Q remained stable up to the last follow-up visit at 60 months. While patients in Group A had modest HbAT87Q levels with moderate clinical benefits, both patients in Group B produced more HbAT87Q leading to HbS reduction, decreased breakdown of red blood cells, and fewer vaso-occlusive crises and acute chest pain.
The most common adverse events for patients were related to the production of blood cells from the transplant. Patients had low levels of blood platelets (85.7% in Group A), low levels of neutrophils, a type of white blood cell (71.5% in Group A, and 100% in Group B), and low levels of white blood cells (100% in Group B). Patients also suffered from inflammation of the oral mucosa (71.5% in Group A, and 100% in Group B). Finally, two patients (Group A) developed cancer of the white blood cells (or Acute Myeloid Leukaemia, AML) at 3 and 5.5 years after lovo-cel therapy, leading to death in both cases.
Not so fast
Only nine patients received the lovo-cel therapy in this phase 1/2 clinical study, so these data are only descriptive. Long-term monitoring also uncovered two AML cases several years after treatment. After thorough examination, these cases were deemed likely unrelated to the gene therapy. In the first case, the viral vector was absent from cancerous cells. In the second, although present, the viral vector was inserted in a non-coding region of a gene (VAMP4) unrelated to cellular proliferation or oncogenesis. Other patients who received the lovo-cel therapy had the same viral vector insertion with no harmful effects or complications.
Why does it matter?
The lovo-cel therapy is a milestone treatment for patients with sickle cell disease as few patients with sickle cell disease have matched sibling donors.
Before the approval of gene therapy, sickle cell disease had only one curative treatment based on the transplantation of stem cells from a sibling with matched immune system proteins. However, this approach has important limitations. The transplanted cells can mistakenly attack the body because the patient’s tissues are seen as foreign, or vice versa, potentially leading to graft rejection.
Take home messages
1. Gene therapy offers a treatment for sickle cell disease by promoting the stable production of anti-sickle cell haemoglobin. This effect persists long-term, up to 60 months after the treatment.
2. Changes made during development of the lovo-cel therapy resulted in considerable improvements for patients.
3. Long-term monitoring in gene therapies is vital and sequencing tools have a key role in evaluating their potential contribution to mutagenesis / cancer development.
Guest author: Solène Grosdidier, PharmD, PhD.
This article was written as part of a series of ‘journal club’ summaries for Scientific Writers Ltd., and is based on the following publication:
First Author: Kanter J, et al.
Journal: American Journal of Hematology
Date online: 10 October 2022
Other references:
FDA press announcement – first gene therapies to treat sickle cell disease
https://clinicaltrials.gov/study/NCT02140554
Acute Myeloid Leukemia Case after Gene Therapy for Sickle Cell Disease
