BLOG: Gene therapies for children with sickle cell disease
Click Here to Manage Email Alerts
Key takeaways:
- Gene therapy for sickle cell disease is approved for children aged 12 and older.
- Establishing safety of the approach could expand accessibility to younger children.
An increasing number of gene therapies correct genetic disorders, including hemoglobinopathies.
There are two FDA-approved gene therapies for sickle cell disease, and several others are in clinical trials.
Sickle cell disease gene therapy is approved for children aged 12 years or older, and clinical trials are evaluating it for younger individuals.
Gene therapy involves harvesting stem cells from peripheral blood after mobilization with plerixafor; manufacturing gene-modified stem cells; preparing patients by having them discontinue hydroxyurea, transfusing to decrease hemoglobin S to less than 30%, and planning fertility preservation measures if desired; administering high-dose busulfan; and infusing gingival mesenchymal stem cells (GMSC).
Engraftment introduces a non-sickling hemoglobin or increases hemoglobin F.
All products improve pain symptoms. Stem cell collection is more successful for younger patients — those aged younger than 30 years — with higher blood counts.
Gene modification includes introduction of an anti-sickling gene to induce trait-like status, or CRSPR-Cas 9-based gene editing, gene suppression or base editing to correct the S mutation or increase fetal hemoglobin containing erythrocytes (F cells).
Clinical benefit requires long-term engraftment/persistence of a critical number of corrected cells. Gene products should not incorporate at off-target sites and should not cause serious toxicity, such as hematologic malignancies.
The FDA mandates 15-year follow-up after gene therapy to ensure safety, especially after two initial patients who received lovotibeglogene autotemcel (Lyfgenia, Bluebird Bio) — often called lovo-cel — developed leukemia. The manufacturing process was changed and no additional GMSC recipient has developed malignant transformation to date.
Due to the nature of correction, lovo-cel is contraindicated for patients with a two-gene alpha-globin deletion. The majority of patients who have successfully received gene therapy demonstrate a decrease in hemoglobin S-to-sickle-trait levels (lovo-cel), or a high percentage of F cells (exagamglogene autotemcel [CRISPR Therapeutics, Vertex Pharmaceuticals]) with sustained persistence for more than 3 years, increase in hemoglobin levels to normal, decreased reticulocyte counts and hemolysis, and a marked reduction in pain symptoms and opioid use within the first year of treatment.
Benefits for other organ systems, currently unknown, will depend on the amount of initial damage. This will need careful tracking to identify reversibility or stabilization and allow comparison with gains from allogeneic transplantation.
The unknowns about gene therapy that require long-term monitoring are persistence of GMSC in sufficient numbers, safety, comparison between products, and risk for malignant transformation with or without genetic predisposition or underlying clonal hematopoiesis.
Cost and accessibility hopefully are surmountable barriers with time, with gene therapy benefitting patients even in countries with economic challenges.
Future advances to look forward to include newer/better sickle cell disease stem cell-mobilizing regimens with agents such as motixafortide, low-toxicity nonchemotherapy antibody-based conditioning and, better yet, easier ways to safely achieve targeted delivery of the corrective gene using injectable products with in vivo activity.
Collaboration between centers to systematically compare outcomes following allogeneic transplant and autologous gene therapy to define effects on overall health and organ preservation also are transformative treatment goals.
Establishing safety opens the door to treating younger patients before established sickle cell disease vasculopathy.
References:
- Farrell A, et al. Blood Adv. 2019;doi:10.1182/bloodadvances.2019000882.
- Frangoul H, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2309676.
- Kanter J, et al. Am J Hematol. 2023:doi:10.1002/ajh.26741.
- Sharma A, et al. Br J Haematol. 2022;doi:10.1111/bjh.18311.
- Shenoy S, et al. Biol Blood Marrow Transplant. 2017;doi:10.1016/j.bbmt.2017.01.009.
For more information:
Shalini Shenoy, MD, MBBS, can be reached at shalinishenoy@wustl.edu.
Collapse