Page 79 - GPD-4-1

Gene & Protein in Disease Sickle cell disease’s journey

matching and determining the optimal regimen before for SCD patients aged 12 years or above. Casgevy was
HSCT availability as a curative option could be made approved by Vertex Pharmaceuticals Inc., whereas Lyfgenia
public. Usually, a fully matched donor such as a sibling was approved by Bluebird Bio Inc. Both drugs were granted
is sought. However, in select cases, alternate donors such priority review, as well as designations as an orphan drug and
as haploidentical and matched unrelated donors can be fast track and tegenerative medicine advanced therapy.
114
considered. It has been estimated that in the U.S., there Both drugs are made from autologous hematopoietic
is only a 10 – 15% chance of finding an HLA-identical stem cells which are modified and transplanted back into
donor. 112 SCD patients as a one-time single-dose infusion. Once
Third, concern regarding patient autonomy in the stem cells are collected from patients for genome-editing,
pediatric setting is a limitation of recommending HSCT patients undergo myeloablative conditioning to remove the
as a curative option. The socioeconomic barrier to defective stem cells from the bone marrow for replacement
transplantation also needs to be considered during the with the modified Casgevy or Lyfgenia cells.
HSCT option discussion. 112,113 7.1. Casgevy
The myeloablative procedure, a commonly used Casgevy is a cell-based therapy and is approved for SCD
regimen, combines whole-body irradiation and patients aged 12 years or above and with recurrent vaso-
chemotherapy (busulfan + cyclophosphamide, or busulfan occlusive episodes. It is the first FDA-approved treatment
+ fludarabine, are most commonly employed). Following involving the genome editing technology CRISPR/Cas9.
transfusion, the patient is assessed for engraftment and With this technology, the patient’s hematopoietic stem cells
donor chimerism (≥20% is considered an assurance for are genome-edited by directing CRISPR/Cas9 to cleave
cure). Thereafter, recipients are immunized and initiated targeted regions of DNA and edit the DNA at the cleaved
on prophylaxis against graft-versus-host disease and region. These genome-edited cells are transplanted back
infections. The use of granulocyte-colony stimulating into the patient for engrafting within the bone marrow
factor is a contraindication post-transplantation as it is and increasing the production of fetal hemoglobin HbF. 114
reported to cause fatal sickle cell crisis. Children younger
112
than 16 years old with sickle cell are recommended curative Casgevy was approved after an ongoing single-arm
treatment through myeloablative allo-HSCT. 115,116 There multicenter trial involving 44 adult and adolescent SCD
are no reliable indicators that a patient should undergo patients. The included subjects had a history of at least two
myeloablative allo-HSCT, and hence it is performed severe vaso-occlusive episodes as defined by the protocols,
in pediatric patients who are not expected to or did not during each of the two years before the screening. The efficacy
benefit from hydroxyurea. Myeloablative allo-HSCT outcome was a complete resolution of severe vaso-occlusive
116
presents high risks in adults, such as graft failure and organ episodes for a year during the 2-year follow-up period.
toxicity. Of the 44 patients enrolled in the study, 31 were evaluable

Non-myeloablative stem cell–cell transplantation has with sufficient follow-up time. Of these, 29 patients (93.5%)
been developed to provide treatment to adults because achieved the efficacy outcome. Successful engraftment
of fewer transplant complications while having the same was seen in all treated patients and graft failure/rejection
114
results as myeloablative allo-HSCT, offering an alternative was not detected. Nausea and vomiting, headache,
to patients who are not able to find HLA-matched musculoskeletal pain, abdominal pain, mouth sores, itching,
donors. Patients not only receive hydroxyurea, total body thrombocytopenia, leukocytopenia, and febrile neutropenia
irradiation, immunosuppressive therapy, and standard were the most commonly reported side effects.
antimicrobial prophylaxis with penicillin V potassium 7.2. Lyfgenia
but also platelet transfusions as preparation for non-
myeloablative stem cell transplantation. 117 Lyfgenia, like Casgevy, is a cell-based therapy approved for
SCD patients aged 12 years or above and with recurrent
6.2.2. Gene therapy vaso-occlusive episodes. This therapy, like Casgevy,
As a very recent development in the history of SCD genome-modifies a patient’s stem cells to produce HbA T87Q ,
treatments, gene therapy is singled out for discussion in a a genetically modified hemoglobin functionally similar
separate section. to HbA. Erythrocytes with HbA T87Q have a lower risk of
sickling, and hence patients treated with Lyfgenia are freed
7. Gene therapy in SCD from vaso-occlusive episodes. 114

In a landmark decision on December 8, 2023, the U.S. FDA Lyfgenia was approved for gene therapy of SCD after
approved two gene therapies, namely, Casgevy and Lyfgenia, a 24-month single-arm multicenter study involving SCD

Volume 4 Issue 1 (2025) 10 doi: 10.36922/gpd.4361