Query: gene therapy sickle cell disease

title: Curative options for sickle cell disease: haploidentical stem cell transplantation or gene therapy?
abstract: Haematopoietic stem cell transplantation (HSCT) is curative in sickle cell disease (SCD) however, the lack of available matched donors makes this therapy out of reach for the majority of patients with SCD. Alternative donor sources such as haploidentical HSCT expand the donor pool to nearly all patients with SCD, with recent data showing high overall survival, limited toxicities, and effective reduction in acute and chronic graft versus host disease (GVHD) Simultaneously, multiple gene therapy strategies are entering clinical trials with preliminary data showing their success, theoretically offering all patients yet another curative strategy without the morbidity and mortality of GVHD. As improvements are made for alternative donors in the allogeneic setting and as data emerge from gene therapy trials, the optimal curative strategy for any individual patient with SCD will be determined by many critical factors including efficacy, transplant morbidity and mortality, safety, patient disease status and preference, cost and applicability. Haploidentical may be the preferred choice now based mostly on availability of data; however, gene therapy is closing the gap and may ultimately prove to be the better option. Progress in both strategies, however, makes cure more attainable for the individual with SCD.

title: Gene therapy for sickle cell disease.
abstract: Sickle cell disease encompasses a group of genetic disorders characterized by the presence of at least one hemoglobin S (Hb S) allele, and a second abnormal allele that could allow abnormal haemoglobin polymerisation leading to a symptomatic disorder. Autosomal recessive disorders (such as sickle cell disease) are good candidates for gene therapy because a normal phenotype can be restored in diseased cells with only a single normal copy of the mutant gene. This is an update of a previously published Cochrane Review.  The objectives of this review are: to determine whether gene therapy can improve survival and prevent symptoms and complications associated with sickle cell disease; to examine the risks of gene therapy against the potential long term gain for people with sickle cell disease.  We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises of references identified from comprehensive electronic database searches and searching relevant journals and abstract books of conference proceedings. We also searched online trial registries, Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 21 September 2020.  All randomised or quasi randomised clinical trials (including any relevant phase 1, 2 or 3 trials) of gene therapy for all individuals with sickle cell disease, regardless of age or setting.  No trials of gene therapy for sickle cell disease were found.  No trials of gene therapy for sickle cell disease were reported.  No randomised or quasi randomised clinical trials of gene therapy for sickle cell disease were reported. Thus, no objective conclusions or recommendations in practice can be made on gene therapy for sickle cell disease. This systematic review has identified the need for well designed, randomised controlled trials to assess the benefits and risks of gene therapy for sickle cell disease.

title: In Vivo HSC Gene Therapy Using a Bi modular HDAd5/35+ Vector Cures Sickle Cell Disease in a Mouse Model.
abstract: We have recently reported that, after in vivo hematopoietic stem cell/progenitor (HSPC) transduction with HDAd5/35+ vectors, SB100x transposase mediated g globin gene addition achieved 10% 15% g globin of adult mouse globin, resulting in significant but incomplete phenotypic correction in a thalassemia intermedia mouse model. Furthermore, genome editing of a g globin repressor binding site within the g globin promoter by CRISPR Cas9 results in efficient reactivation of endogenous g globin. Here, we aimed to combine these two mechanisms to obtain curative levels of g globin after in vivo HSPC transduction. We generated a HDAd5/35+ adenovirus vector (HDAd combo) containing both modules and tested it in vitro and after in vivo HSPC transduction in healthy CD46/b YAC mice and in a sickle cell disease mouse model (CD46/Townes) Compared to HDAd vectors containing either the g globin addition or the CRISPR Cas9 reactivation units alone, in vivo HSC transduction of CD46/Townes mice with the HDAd combo resulted in significantly higher g globin in red blood cells, reaching 30% of that of adult human a and bS chains and a complete phenotypic correction of sickle cell disease.

title: Primary caregiver decision making in hematopoietic cell transplantation and gene therapy for sickle cell disease
abstract: Improved outcomes and the availability of clinical trials of hematopoietic cell transplantation (HCT) from alternate donors and genetically modified autologous hematopoietic progenitor cells have expanded the applicability of HCT for sickle cell disease (SCD) To understand the perspective of primary caregivers exploring HCT in the current milieu, we asked the research question "What motivates primary caregivers to decide to consider HCT and to seek, and to attend, an HCT consultation?"

title: Myelodysplastic syndrome unrelated to lentiviral vector in a patient treated with gene therapy for sickle cell disease.
abstract: Ability to accurately attribute adverse events post gene therapy is required to describe the benefit risk of these novel treatments.A SCD patient developed myelodysplastic syndrome post LentiGlobin treatment; we show how insertional oncogenesis was excluded as the cause.

title: Has the time come to implement gene therapy for sickle cell disease?
abstract: Sickle cell disease (SCD) is the consequence of the formation of hemoglobin S (HbS) typically resulting from homozygosity for sickle cell gene defects. Under low oxygen pressure, sickle hemoglobin molecules affected by the sickle cell gene pathogenic variants interact with one another to deform the red cell and give the cell its classic "sickle" appearance. This defect in the beta chain forms a hump that fits into another complimentary spot on another hemoglobin molecule thereby allowing them to hook together forming tetrahedral crystals. These ridged aggregates go on to precipitate out of solution and lead to collapse of erythrocyte and the resulting loss of function and ensuing anemia. The main determinant of cell deformation is the rate and extent of HbS formation  In a quest to understand the defect in sickle cell disease, Vernon Ingram in London in 1956 investigated one amino acid at a time on the beta chain of hemoglobin. The discovery of a difference in the 6th amino acid position in the beta chain as being consistently associated with the sickle cell disease (SCD) phenotype, thereby providing a genetic etiology for this condition. Along with W.E Roger Jr. whose use of high resolution crystallography illuminated the structural differences in the beta, but not alpha chain, in affected individuals, the genomic and molecular characterizations of sickle cell disease provided the foundation for diagnosis  Despite our understanding of the molecular defect and the pathophysiological process that leads to clinical morbidity and associated adverse clinical outcomes, management of SCD patients remains quite rudimentary without any targeted pharmacotherapies that specifically address the pathophysiology of the disease. Pain and tissue damage is postulated to originate from acute vaso occlusion from entrapped erythrocytes and leukocytes in the microcirculation. Hypoxia and inflammation further increase adhesion in the post capillary veins and exacerbate the vascular occlusive process  A second pathological process in this cascade is hemolysis, which in turn leads to anemia. Hemolysis also releases intracellular chemicals, which contribute to a hypercoagulable state associated with multiorgan damage  Adverse clinical events of SCD are frequently associated with the following complications: bone marrow infarction that leads to fat embolization to the lungs, potentiating acute chest syndrome. Pulmonary hypertension, proliferative changes in blood vessels, cholelithiasis, cutaneous leg ulcers, infection, neurologic problems and stroke are all consequences of SCD as result of the generalized vasculopathy. Once a stroke has occurred, which most likely occurs in people in their 20 s or 30 s, the likelihood of recurrence is 60%  Acute chest syndrome is the most common reason for hospitalization. Severity varies, but approximately 13% will require mechanical ventilation and 3% will go on to expire. Pulmonary hypertension is an increasingly recognized complication in about 6% of SCD patients. The vast majority of SCD patients who develop pulmonary hypertension will expire from this complication. Left sided heart disease is seen in 13% of SCD patients and is mainly caused by diastolic dysfunction. Some level of renal dysfunction is observed in almost all SCD patients. The effect is mostly in the medulla of the kidney where the erythrocytes become dehydrated and are under low oxygen tension. Papillary necrosis and fibrosis occurs in the medulla, leading to renal failure in approximately 30% of subjects  Norman Ginsberg cvsguy1@aol.com

title: Safety of Autologous Hematopoietic Stem Cell Transplantation with Gene Addition Therapy for Transfusion Dependent b Thalassemia, Sickle Cell Disease, and Cerebral Adrenoleukodystrophy
abstract: Allogeneic hematopoietic stem cell (HSC) transplantation (allo HSCT) is a treatment option for several monogenic diseases; however, its use is limited by the need for a matched donor and risk of HSCT related complications. Autologous HSC gene addition does not have some of these limitations and may have similar efficacy with an improved safety profile. Ex vivo gene addition therapy using lentiviral vectors (LVV) is being evaluated in patients with transfusion dependent b thalassemia (TDT) using betibeglogene autotemcel (beti cel, LentiGlobin for TDT) in the HGB 204, 205, 207, and 212 studies, sickle cell disease (SCD) using LentiGlobin for SCD in HGB 205 and 206, and cerebral adrenoleukodystrophy (CALD) using Lenti D in ALD 102. The safety outcomes following autologous gene modified HSCT in these ongoing studies are summarized.  HSCs are collected using disease appropriate procedures, then CD34+ cells are transduced with LVV encoding disease specific therapeutic transgenes. After myeloablation with busulfan (SCD, TDT) or busulfan/cyclophosphamide (CALD) patients are infused with LVV transduced CD34+ HSCs. Patients are followed for two years and offered participation in long term follow up studies (LTF 303  Patients have been followed for 2 years follow up. No patient experienced primary or secondary graft failure. One patient with CALD experienced disease progression and died 22 months after drug product (DP) infusion of disease complications. Two additional patients with CALD withdrew from the study after DP infusion and were referred for allo HSCT. All other patients with CALD, TDT, and SCD remain alive. Most (107/110) patients had one grade 3 or 4 adverse event (AE) attributed to conditioning; most common AEs were cytopenia, febrile neutropenia, and stomatitis. Myelodysplastic syndrome was reported in one patient with SCD. After investigation for LVV insertion in malignant cells, the AE was assessed as not related to LentiGlobin insertion or transgene expression. AEs reported as related to the DP are shown in Table 1. There was no GVHD and no clinically relevant clonal dominance or LVV mediated replication competent lentivirus.  Data from 110 patients followed for up to 5 years supports that the safety profile of gene modified autologous HSCT does not carry the risks of GVHD, graft rejection, and long term immunosuppression attendant to allo HSCT. While the safety profile beyond 5 years is still being established, these data suggest that HSC gene therapy may be an acceptable therapy for patients with TDT, SCD, and CALD, particularly in patients at increased risk of complications from allo HSCT, such as those who lack a suitable donor or are more advanced in age.

title: Gene Therapy in a Patient with Sickle Cell Disease: Brief Report
abstract: Sickle cell disease results from a homozygous missense mutation in the b globin gene that causes polymerization of hemoglobin S. Gene therapy for patients with this disorder is complicated by the complex cellular abnormalities and challenges in achieving effective, persistent inhibition of polymerization of hemoglobin S. We describe our first patient treated with lentiviral vector mediated addition of an antisickling b globin gene into autologous hematopoietic stem cells. Adverse events were consistent with busulfan conditioning. Fifteen months after treatment, the level of therapeutic antisickling b globin remained high (approximately 50% of b like globin chains) without recurrence of sickle crises and with correction of the biologic hallmarks of the disease.

title: Gene therapy in sickle cell disease: Possible utility and impact
abstract: CRISPR Cas9 makes it possible to edit the patient's own genes, but questions remain.

title: Lentiglobin Gene Therapy in Patients with Sickle Cell Disease: Updated Interim Results from Hgb 206
abstract: b globin gene transfer may reduce or eliminate complications in patients with sickle cell disease (SCD) LentiGlobin gene therapy (GT) comprises drug product (DP) made from autologous hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV) encoding b globin with an anti sickling T87Q substitution (HbAT87Q) The safety and efficacy of LentiGlobin GT in adults with SCD is being evaluated in a phase 1 study, HGB 206 (NCT02140554) Patients were initially treated with DP made from bone marrow harvested (BMH) HSCs (Group [Grp] A, fully enrolled) then from DP made from BMH HSCs but using a refined manufacturing process (Grp B, fully enrolled) and subsequently from plerixafor mobilized HSCs (Grp C, currently enrolling)  Assess safety and feasibility of plerixafor mobilization in patients with SCD and describe outcomes of LentiGlobin GT in the HGB 206 study.  Adults with severe SCD (history of recurrent vaso occlusive crisis, acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s) were enrolled. Autologous CD34+ cells, collected by BMH or apheresis following mobilization with 240 ug/kg plerixafor, were transduced with BB305 LVV. After myeloablative busulfan conditioning (area under the curve goal of 5000 [range 4400 5400] uM*min daily) patients were infused with the transduced cells and monitored for safety and efficacy. Summary statistics are median (min max)  As of May 15, 2018, 22 patients had HSCs collected, 18 patients had DP made and 15 patients were treated. BMH was performed in 11 patients (9 in Grp A, 2 in Grp B) and mobilization/apheresis in 12 patients (1 in Grp B [also had BMH] 11 in Grp C) Median of 4.3 (0.1 10.8) x 106 and 10.4 (3.8 21.6) x 106 CD34+ cells/kg were collected per BMH (N=26) and per mobilization cycle (N=17) respectively. Eighteen grade 3 adverse events (AEs) in 6 patients were attributed to BMH and 5 grade 3 AEs in 3 patients to mobilization/apheresis. DP and treatment characteristics are shown in Table 1. DP characteristics were improved in Grp B and Grp C vs Grp A. The safety profile post DP infusion was consistent with myeloablative conditioning and underlying SCD; most common non hematologic grade =3 AEs were stomatitis, febrile neutropenia, and vaso occlusive pain. At last visit (Table 1) HbAT87Q levels were higher in Grp B (3.2 7.2 g/dL) vs Grp A (0.5 1.2 g/dL) In 4 Grp C patients at the 3 month visit, HbAT87Q (4.1 [3.2 6.0] g/dL) levels were equal to or exceeded HbS levels (3.3 [2.8 3.8] g/dL) In 1 Grp C patient at the 6 month visit, HbAT87Q was 8.8 g/dL and total Hb was 14.2 g/dL.  These data support the safety and feasibility of plerixafor mediated HSC collection in patients with SCD. HGB 206 protocol changes have improved LentiGlobin DP characteristics yielding higher HbAT87Q levels. Additional data will determine the clinical effect of increased HbAT87Q/HbS ratios.