Betibeglogene Autotemcel Gene Therapy for Non-β⁰/β⁰ Genotype β-Thalassemia

BACKGROUND: Betibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent β-thalassemia contains autologous CD34+ hematopoietic stem cells and progenitor cells transduced with the BB305 lentiviral vector encoding the β-globin (βA-T87Q) gene. METHODS: In this open-label, phase 3 study, we evaluated the efficacy and safety of beti-cel in adult and pediatric patients with transfusion-dependent β-thalassemia and a non-β0/β0 genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously. The primary end point was transfusion independence (i.e., a weighted average hemoglobin level of ≥9 g per deciliter without red-cell transfusions for ≥12 months). RESULTS: A total of 23 patients were enrolled and received treatment, with a median follow-up of 29.5 months (range, 13.0 to 48.2). Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter (range, 9.5 to 12.8). Twelve months after beti-cel infusion, the median level of gene therapy-derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q) was 8.7 g per deciliter (range, 5.2 to 10.6) in patients who had transfusion independence. The safety profile of beti-cel was consistent with that of busulfan-based myeloablation. Four patients had at least one adverse event that was considered by the investigators to be related or possibly related to beti-cel; all events were nonserious except for thrombocytopenia (in 1 patient). No cases of cancer were observed. CONCLUSIONS: Treatment with beti-cel resulted in a sustained HbAT87Q level and a total hemoglobin level that was high enough to enable transfusion independence in most patients with a non-β0/β0 genotype, including those younger than 12 years of age. (Funded by Bluebird Bio; HGB-207 ClinicalTrials.gov number, NCT02906202.)

Fast calculation of thermodynamic and structural parameters of solutions using the 3DRISM model and the multi-grid method

In the paper a new method to solve the tree-dimensional reference interaction site model (3DRISM) integral equations is proposed. The algorithm uses the multi-grid technique which allows to decrease the computational expanses. 3DRISM calculations for aqueous solutions of four compounds (argon, water, methane, methanol) on the different grids are performed in order to determine a dependence of the computational error on the parameters of the grid. It is shown that calculations on the grid with the step 0.05\Angstr and buffer 8\Angstr give the error of solvation free energy calculations less than 0.3 kcal/mol which is comparable to the accuracy of the experimental measurements. The performance of the algorithm is tested. It is shown that the proposed algorithm is in average more than 12 times faster than the standard Picard direct iteration method.Comment: the information in this preprint is not up to date. Since the first publication of the preprint (9 Nov 2011) the algorithm was modified which allowed to achieve better results. For the new algorithm see the JCTC paper: DOI: 10.1021/ct200815v, http://pubs.acs.org/doi/abs/10.1021/ct200815

A structured low-rank wavelet solver for the Ornstein-Zernike integral equation

In this article, we present a new structured wavelet algorithm to solve the Ornstein-Zernike integral equation for simple liquids. This algorithm is based on the discrete wavelet transform of radial distribution functions and different low-rank approximations of the obtained convolution matrices. The fundamental properties of wavelet bases such as the interpolation properties and orthogonality are employed to improve the convergence and speed of the algorithm. In order to solve the integral equation we have applied a combined scheme in which the coarse part of the solution is calculated by the use of wavelets and Newton-Raphson algorithm, while the fine part is solved by the direct iteration. Tests have indicated that the proposed procedure is more effective than the conventional method based on hybrid algorithms

Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency.

Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up. Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade. Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.)