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Akshay Sharma

Publications and source records attributed to Akshay Sharma.

3 recordsLinked to original sources
PubMed2026

Project Sickle Cure: A Prospective, International Observational Study of Hematopoietic Cell Transplantation for Sickle Cell Disease.

BACKGROUND: Sickle cell disease (SCD) is a chronic and life-limiting hemoglobin and systemic vascular disease. While over 1000 people have undergone hematopoietic cell transplantation (HCT) over the last 40 years, long-term disease-specific and health-related quality of life data are lacking. The American Society of Hematology 2021 Guidelines for SCD emphasized the need for more detailed registry data to inform patients and providers with decision-making and practice recommendations. PROCEDURES: In January 2021, the Sickle Cell Transplant Advocacy and Research Alliance (STAR) launched Project Sickle Cure (PSC). This multi-center, prospective study of patients who have undergone HCT for SCD includes baseline demographics and SCD-specific post-HCT outcomes, serial neurocognitive testing, health-related quality of life measures, health equity evaluations, a neuroimaging bank, detailed evaluation of neurologic status pre- and post-transplant, and chronic pain evaluation. A biorepository is in the planning stage of development. RESULTS: As of November 2025, 115 participants have enrolled at 18 STAR sites with enrollment ongoing. CONCLUSIONS: PSC is a STAR prospective study which will address a major gap in our understanding of outcomes post-HCT specific to SCD. WeDecide, a larger study comparing HCT health-related quality of life outcomes to those who receive non-transplant disease modifying therapy (NT-DMT) is in development, and PSC will provide the HCT comparator data. These data will also be highly relevant as other curative and transformative therapies, such as gene therapy, become more widely used.

Humans↗
PubMed2026

Exa-cel in Children with Transfusion-Dependent β-Thalassemia or Sickle Cell Disease.

BACKGROUND: Exagamglogene autotemcel (exa-cel) is a cell therapy in which autologous CD34+ hematopoietic cells are engineered through ex vivo clustered regularly interspaced short palindromic repeats-Cas9 editing of the erythroid-specific enhancer region of BCL11A to express fetal hemoglobin. In phase 3 studies involving participants 12 to 35 years of age with sickle cell disease or transfusion-dependent β-thalassemia, exa-cel eliminated vaso-occlusive crises and the need for red-cell transfusions. METHODS: In two ongoing, phase 3, open-label, single-group studies, we evaluated exa-cel in children 5 to 11 years of age with transfusion-dependent β-thalassemia or sickle cell disease. Before exa-cel infusion, participants underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end points were transfusion independence for at least 12 consecutive months in children with transfusion-dependent β-thalassemia and freedom from severe vaso-occlusive crises for at least 12 consecutive months in children with sickle cell disease. RESULTS: A total of 15 children with transfusion-dependent β-thalassemia and 11 with sickle cell disease received exa-cel; median follow-up was 16.0 months (range, 2.2 to 32.1) and 16.9 months (range, 7.6 to 33.1), respectively. Of 8 children with transfusion-dependent β-thalassemia who were followed to at least 16 months, 8 were transfusion independent; the status of the remaining 7 was not yet evaluable. Of 8 children with sickle cell disease who were followed to at least 16 months, 8 were free of vaso-occlusive crises; the status of the remaining 3 was not yet evaluable. All the children had at least one grade 3 or 4 adverse event; 2 children with transfusion-dependent β-thalassemia had severe veno-occlusive liver disease that was assessed as being related to busulfan conditioning, 1 of whom died. CONCLUSIONS: Exa-cel therapy resulted in transfusion independence or freedom from severe vaso-occlusive crises in participants with transfusion-dependent β-thalassemia or sickle cell disease, respectively, who were followed for at least 16 months. All the participants had grade 3 or 4 adverse events. (Funded by Vertex Pharmaceuticals and CRISPR Therapeutics; CLIMB THAL-141 ClinicalTrials.gov number, NCT05356195; CLIMB SCD-151 ClinicalTrials.gov number, NCT05329649.).

Child↗
PubMed2025

NFATc1 drives Orai3 transcription and proteolysis by harnessing epigenome differences in the MARCH8 promoter.

Several autonomous mechanisms regulate protein expression, such as transcription, translation, post-translational modifications, and epigenetic changes. Rarely, these processes are controlled by the same molecular player with overlapping roles. Here, we reveal that transcription factor NFATc1 regulates both transcription and degradation of the Ca2+ channel Orai3 in a context-dependent manner. We demonstrate that NFATc1 drives Orai3 transcription in non-metastatic pancreatic cancer cells. In invasive and metastatic pancreatic cancer cells, NFATc1 induces Orai3 lysosomal degradation by transcriptionally enhancing MARCH8 E3-ubiquitin ligase. We show that MARCH8 physically interacts with Orai3 intracellular loop eventually resulting in its ubiquitination at the N-terminal. Mechanistically, the dichotomy in the regulation of Orai3 expression emerges from the differences in MARCH8 epigenetic landscape. We uncover that MARCH8 promoter is hyper-methylated in non-metastatic cells. Importantly, we demonstrate that MARCH8 restricts pancreatic cancer metastasis by targeting Orai3 degradation, thereby highlighting the pathophysiological importance of this signaling module. Taken together, we report a unique and clinically relevant scenario wherein the same transcription factor both enhances and curtails the expression of a target protein in cancer.

Humans↗