FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4310107735> ?p ?o ?g. }

• W4310107735 endingPage "1908" @default.
• W4310107735 startingPage "1906" @default.
• W4310107735 abstract "Introduction: Increased levels of fetal hemoglobin (HbF; encoded by γ-globin [HBG1/HBG2]) are protective against complications of sickle cell disease (SCD). BCL11A is a transcription factor that binds to HBG1/HBG2 promoters and produces a γ-to-β globin (fetal-to-adult hemoglobin) switch. Inhibiting BCL11A binding to its target can reverse the switch and induce HbF expression in adult red blood cells (RBCs). OTQ923 is an autologous, ex vivo, CRISPR/Cas9-edited, CD34+ cellular product with a targeted disruption of the HBG1/HBG2 promoters on chromosome 11. Targeting this region in preclinical models led to HbF induction, phenotypically recapitulating hereditary persistence of fetal hemoglobin (a naturally occurring condition whose co-inheritance ameliorates SCD severity). This approach is more targeted than complete elimination of BCL11A expression in erythrocyte precursors for treating hemoglobinopathies. Additionally, unlike lentiviral vector gene addition, induction of endogenous γ-globin transcription could concur with reduction of βS-globin expression to avoid α- and β-like globin chain imbalance. Methods: Subjects with severe SCD, defined by a history of stroke, recurrent vaso-occlusive events (VOE), acute chest syndrome (ACS), chronic transfusions, recurrent priapism or red cell alloimmunization, were eligible to participate in the adult cohort (≥18-≤40 years old) of this clinical trial (NCT04443907). OTQ923 was manufactured from cryopreserved, peripheral blood derived CD34+ cells, collected after plerixafor mobilization. Prior to infusion, participants received myeloablative busulfan. Primary endpoints are to evaluate engraftment, long-term safety, and efficacy of HbF expression. Results: As of the data cut-off (July 8, 2022), 2 participants had received OTQ923, with follow-ups of 9 months (mos) and 3 mos, respectively. Here, we present initial clinical data from these 2 participants; additional data will be presented at the meeting. Both participants were homozygous for the sickle mutation. Participant 1 is a 22-year-old male with a history of silent cerebral infarcts, ACS, and priapism. At study entry, he was receiving chronic transfusions. He received 2.8x106 CD34+ cells/kg of OTQ923 (2 combined manufacturing batches). Participant 2 is a 21-year-old male with a history of ACS, and a silent cerebral infarct and was receiving hydroxyurea. He received 5.99x106 CD34+ cells/kg of OTQ923 (3 combined manufacturing batches). Time to neutrophil engraftment (the first of 3 consecutive days of absolute neutrophil count above 500 cells/mL after cell infusion) was 26 and 20 days for Participants 1 and 2, respectively. No OTQ923-related adverse events (AEs) were reported in either participant. All observed AEs were consistent with busulfan conditioning. Participants received RBC transfusions around conditioning and have received none after engraftment. For Participant 1, HbF level increased in the 6 mos after infusion and was stable at data cut-off (22.1% HbF at 9 mos after infusion). Induction of HbF was pancellular, with an F-cell percentage around 91% at 6 mos after infusion (Fig. 1A). Participant 2 had achieved an HbF level of 15.9% at 3 mos after infusion, the latest evaluable timepoint at data cut-off. Neither participant had any SCD-related VOEs after infusion of the cellular product. The proportion of edited alleles in the peripheral blood of Participant 1 was maintained at over 60% until Mo 6, which was the last evaluable timepoint (Fig. 1B). The indels were diverse, except for a predominant, large 5 kb deletion arising from simultaneous double-stranded DNA cleavage at HBG1 and HBG2 on-target sites, similar to previous reports. Conclusion: Preliminary data demonstrate clinically meaningful increases in HbF and evidence of benefit for both Participants 1 and 2 after OTQ923 infusion. Edited alleles were stable and maintained in the peripheral blood for >6 mos. The safety profile of OTQ923 was as expected after myeloablative busulfan and autologous hematopoietic stem cell transplantation. Taken together, these data suggest that this approach is safe and offers a potentially curative option for patients with severe SCD. Using cryopreserved, CD34+ cells as a starting material offers the advantage of centralizing manufacturing, scaling up the process to allow for improved patient access around the globe. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal" @default.
• W4310107735 created "2022-11-30" @default.
• W4310107735 creator A5001390394 @default.
• W4310107735 creator A5009145909 @default.
• W4310107735 creator A5015934798 @default.
• W4310107735 creator A5024939834 @default.
• W4310107735 creator A5026667594 @default.
• W4310107735 creator A5035243936 @default.
• W4310107735 creator A5035304815 @default.
• W4310107735 creator A5045032985 @default.
• W4310107735 creator A5046975210 @default.
• W4310107735 creator A5050407540 @default.
• W4310107735 creator A5052192469 @default.
• W4310107735 creator A5053797796 @default.
• W4310107735 creator A5055838753 @default.
• W4310107735 creator A5068720519 @default.
• W4310107735 creator A5068817584 @default.
• W4310107735 creator A5080913846 @default.
• W4310107735 creator A5084937471 @default.
• W4310107735 date "2022-11-15" @default.
• W4310107735 modified "2023-09-28" @default.
• W4310107735 title "Treatment of Individuals with Severe Sickle Cell Disease with OTQ923, an Autologous, <i>Ex Vivo</i>, CRISPR/Cas9-Edited, CD34+ Hematopoietic Stem and Progenitor Cell Product, Leads to Durable Engraftment and Fetal Hemoglobin Induction" @default.
• W4310107735 doi "https://doi.org/10.1182/blood-2022-166254" @default.
• W4310107735 hasPublicationYear "2022" @default.
• W4310107735 type Work @default.
• W4310107735 citedByCount "2" @default.
• W4310107735 countsByYear W43101077352023 @default.
• W4310107735 crossrefType "journal-article" @default.
• W4310107735 hasAuthorship W4310107735A5001390394 @default.
• W4310107735 hasAuthorship W4310107735A5009145909 @default.
• W4310107735 hasAuthorship W4310107735A5015934798 @default.
• W4310107735 hasAuthorship W4310107735A5024939834 @default.
• W4310107735 hasAuthorship W4310107735A5026667594 @default.
• W4310107735 hasAuthorship W4310107735A5035243936 @default.
• W4310107735 hasAuthorship W4310107735A5035304815 @default.
• W4310107735 hasAuthorship W4310107735A5045032985 @default.
• W4310107735 hasAuthorship W4310107735A5046975210 @default.
• W4310107735 hasAuthorship W4310107735A5050407540 @default.
• W4310107735 hasAuthorship W4310107735A5052192469 @default.
• W4310107735 hasAuthorship W4310107735A5053797796 @default.
• W4310107735 hasAuthorship W4310107735A5055838753 @default.
• W4310107735 hasAuthorship W4310107735A5068720519 @default.
• W4310107735 hasAuthorship W4310107735A5068817584 @default.
• W4310107735 hasAuthorship W4310107735A5080913846 @default.
• W4310107735 hasAuthorship W4310107735A5084937471 @default.
• W4310107735 hasBestOaLocation W43101077351 @default.
• W4310107735 hasConcept C104317684 @default.
• W4310107735 hasConcept C109159458 @default.
• W4310107735 hasConcept C201750760 @default.
• W4310107735 hasConcept C203014093 @default.
• W4310107735 hasConcept C207001950 @default.
• W4310107735 hasConcept C26291073 @default.
• W4310107735 hasConcept C2778086970 @default.
• W4310107735 hasConcept C28328180 @default.
• W4310107735 hasConcept C54355233 @default.
• W4310107735 hasConcept C71924100 @default.
• W4310107735 hasConcept C86803240 @default.
• W4310107735 hasConcept C98108389 @default.
• W4310107735 hasConceptScore W4310107735C104317684 @default.
• W4310107735 hasConceptScore W4310107735C109159458 @default.
• W4310107735 hasConceptScore W4310107735C201750760 @default.
• W4310107735 hasConceptScore W4310107735C203014093 @default.
• W4310107735 hasConceptScore W4310107735C207001950 @default.
• W4310107735 hasConceptScore W4310107735C26291073 @default.
• W4310107735 hasConceptScore W4310107735C2778086970 @default.
• W4310107735 hasConceptScore W4310107735C28328180 @default.
• W4310107735 hasConceptScore W4310107735C54355233 @default.
• W4310107735 hasConceptScore W4310107735C71924100 @default.
• W4310107735 hasConceptScore W4310107735C86803240 @default.
• W4310107735 hasConceptScore W4310107735C98108389 @default.
• W4310107735 hasIssue "Supplement 1" @default.
• W4310107735 hasLocation W43101077351 @default.
• W4310107735 hasOpenAccess W4310107735 @default.
• W4310107735 hasPrimaryLocation W43101077351 @default.
• W4310107735 hasRelatedWork W1812483684 @default.
• W4310107735 hasRelatedWork W1977103373 @default.
• W4310107735 hasRelatedWork W1994790910 @default.
• W4310107735 hasRelatedWork W2015681352 @default.
• W4310107735 hasRelatedWork W2022468097 @default.
• W4310107735 hasRelatedWork W2024796495 @default.
• W4310107735 hasRelatedWork W2038672919 @default.
• W4310107735 hasRelatedWork W2052381154 @default.
• W4310107735 hasRelatedWork W2508891881 @default.
• W4310107735 hasRelatedWork W4311268005 @default.
• W4310107735 hasVolume "140" @default.
• W4310107735 isParatext "false" @default.
• W4310107735 isRetracted "false" @default.
• W4310107735 workType "article" @default.