scholarly journals 702. Successful Correction of Human Beta Thalassemia Major Using a Self-Inactivating Lentiviral Vector

2004 ◽  
Vol 9 ◽  
pp. S267
Keyword(s):  
Lentiviral Vector ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Beta Thalassemia Major

First US Phase I Clinical Trial Of Globin Gene Transfer For The Treatment Of Beta-Thalassemia Major

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 716-716 ◽  
Author(s):  
Farid Boulad ◽  
Isabelle Riviere ◽  
Xiuyan Wang ◽  
Shirley Bartido ◽  
Susan E. Prockop ◽  
...  
Keyword(s):  
Copy Number ◽  
Lentiviral Vector ◽  
Globin Gene ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Myeloablative Conditioning ◽  
Gradual Rise ◽  
Beta Thalassemia Major ◽  
Cd34 Cells ◽  
Vector Copy Number

Abstract To date, the only curative therapeutic approach for beta-thalassemia major has been allogeneic stem cell transplantation (SCT) for patients with HLA-matched siblings. For the majority of patients who do not have a matched sibling, allogeneic SCT is associated with major risks of morbidity and mortality. The stable transfer of a functional globin gene into the patient’s own hematopoietic progenitor cells (HPCs) yields a perfectly matched graft that does not require immunosuppression to engraft. We previously demonstrated successful globin gene therapy in murine thalassemia models, using a lentiviral vector that encodes the human ß-globin promoter and arrayed regulatory elements uniquely combined to achieve high level and erythroid-specific globin expression. In vivo in thalassemic mice, the vector termed TNS9.3.55, increased hemoglobin levels by an average 4-6 g/dL per vector copy. We obtained in 2012 the first US Food and Drug Administration (FDA) approval to proceed to a clinical study in adult subjects with beta-thalassemia major (NCT01639690). We have to date enrolled 5 patients and recently treated the first three, administering the transduced HPCs after non-myeloablative conditioning. Engraftment data are available for the first two patients. Patient 3 was recently infused with CD34+ cells and is at this time too early to evaluate. Patient 1 is a 23 year old female with a ß039 – IVS1,110 mutation. Patient 2 is an 18 year old female with a ß039 – IVS1,6 mutation. Both patients underwent mobilization of peripheral blood stem cells (PBSCs) with filgrastim and mobilized 25 x 10^6 and 9.9 x 10^6 CD34 cells/Kg respectively. CD34+ PBSCs were transduced with the lentiviral vector TNS9.3.55 encoding the normal human beta-globin gene. The average vector copy number (VCN) in bulk CD34+ cells for these two patients was respectively 0.39 and 0.21 copies per cell. Both patients underwent non-myeloablative cytoreduction with busulfan administered at 2 mg/Kg/dose Q12H x 4 doses (total 8 mg/Kg), followed by reinfusion of 11.8 x 10^6 and 8.4 x 10^6 CD34+ cells/Kg, respectively. Both patients tolerated cytoreduction well and recovered their blood counts. While they continue to be transfusion dependent, both patients show a gradual rise in vector copy number in peripheral blood white blood cells and neutrophils, steadily increasing by 1-2% every month, reaching an average VCN of 5-7% 3-6 months after transplantation. In summary, patients with thalassemia major underwent safe and effective mobilization followed by excellent transduction of mobilized CD34+ cells. The transplant non-myeloablative conditioning was well tolerated, and followed by rapid engraftment and gradual rise in VCN. Continued clinical and molecular monitoring is on-going and will be presented. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Assessment of Subclinical Renal Glomerular and Tubular Dysfunction in Children with Beta Thalassemia Major

Children ◽  
2021 ◽  
Vol 8 (2) ◽  
pp. 100
Author(s):  
Asmaa A. Mahmoud ◽  
Doaa M. Elian ◽  
Nahla MS. Abd El Hady ◽  
Heba M. Abdallah ◽  
Shimaa Abdelsattar ◽  
...  
Keyword(s):  
Cystatin C ◽  
Kidney Injury ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Good Survival ◽  
Control Group ◽  
Healthy Children ◽  
Serum Cystatin C ◽  
Serum Cystatin ◽  
Beta Thalassemia Major

Background: A good survival rate among patients with beta thalassemia major (beta-TM) has led to the appearance of an unrecognized renal disease. Therefore, we aimed to assess the role of serum cystatin-C as a promising marker for the detection of renal glomerular dysfunction and N-acetyl beta-D-glucosaminidase (NAG) and kidney injury molecule 1 (KIM-1) as potential markers for the detection of renal tubular injury in beta-TM children. Methods: This case-control study was implemented on 100 beta-TM children receiving regular blood transfusions and undergoing iron chelation therapy and 100 healthy children as a control group. Detailed histories of complete physical and clinical examinations were recorded. All subjected children underwent blood and urinary investigations. Results: There was a significant increase in serum cystatin-C (p < 0.001) and a significant decrease in eGFR in patients with beta-TM compared with controls (p = 0.01). There was a significant increase in urinary NAG, KIM-1, UNAG/Cr, and UKIM-1/Cr (p < 0.001) among thalassemic children, with a significant positive correlation between serum cystatin-C, NAG and KIM-1 as regards serum ferritin, creatinine, and urea among thalassemic patients. A negative correlation between serum cystatin-C and urinary markers with eGFR was noted. Conclusion: Serum cystatin-C is a good marker for detection of glomerular dysfunction. NAG and KIM-1 may have a predictive role in the detection of kidney injury in beta-TM children.

scholarly journals Left Atrial Strain Identifies Increased Atrial Ectopy in Patients with Beta-Thalassemia Major

Diagnostics ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 1
Author(s):  
Maria Vlachou ◽  
Vasileios Kamperidis ◽  
Efthymia Vlachaki ◽  
Georgios Tziatzios ◽  
Despoina Pantelidou ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Left Atrial ◽  
Systolic Pressure ◽  
Thalassemia Major ◽  
Beta Thalassemia ◽  
Tape Recording ◽  
Blood Transfusions ◽  
Systolic Strain ◽  
Peak Systolic Strain ◽  
Beta Thalassemia Major

Patients with beta-thalassemia major (β-ΤΜ) may develop cardiac arrhythmias through a multifactorial mechanism. The current study evaluated the association of cardiac structure and function on echocardiography with atrial ectopic burden on 24-hour tape recording in β-ΤΜ patients. This prospective study included consecutive β-ΤΜ patients. Demographic, laboratory, echocardiographic, cardiac magnetic resonance (CMR) T2* and 24-hour tape recording data were prospectively collected. The patients were classified according to the median value of premature atrial contractions (PACs) on 24-hour tape. In total, 50 β-TM patients (37.6 ± 9.1 years old, 50% male) were divided in 2 groups; PACs ≤ 24/day and > 24/day. Patients with PACs > 24/day were treated with blood transfusion for a longer period of time (39.0 ± 8.6 vs. 32.0 ± 8.9 years, p < 0.007), compared to their counterparts. Older age (OR: 1.121, 95% CI: 1.032–1.217, p = 0.007), longer duration of blood transfusion (OR:1.101, 95% CI:1.019–1.188, p = 0.014), larger LV end-diastolic diameter (OR: 4.522, 95% CI:1.009–20.280, p = 0.049), higher values of LA peak systolic strain (OR: 0.869, 95% CI: 0.783–0.964, p = 0.008), higher MV E/E′ average (OR: 1.407, 95% CI: 1.028–1.926, p = 0.033) and higher right ventricular systolic pressure (OR: 1.147, 95% CI: 1.039–1.266, p = 0.006) were univariably associated with PACs > 24/day. LA peak systolic strain remained significantly associated with PACs > 24/day after adjusting for the duration of blood transfusions or for CMR T2*. The multivariable model including blood transfusion duration and LA peak systolic strain was the most closely associated with PACs > 24/day. Receiver operating characteristic curve analysis identified a left atrial peak systolic strain of 31.5%, as the best cut-off value (83% sensitivity, 68% specificity) for prediction of PACs > 24/day. In β-TM patients, LA peak systolic strain was associated with the atrial arrhythmia burden independently to the duration of blood transfusions and CMR T2*.

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