Ready for Repair? Gene Editing Enters the Clinic for the Treatment of Human Disease DOI Creative Commons
Martijn P. T. Ernst, Mike Broeders,

Pablo Herrero-Hernandez

et al.

Molecular Therapy — Methods & Clinical Development, Journal Year: 2020, Volume and Issue: 18, P. 532 - 557

Published: July 4, 2020

We present an overview of clinical trials involving gene editing using clustered interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9), transcription activator-like effector nucleases (TALENs), or zinc finger (ZFNs) and discuss the underlying mechanisms. In cancer immunotherapy, is applied ex vivo in T cells, transgenic cell receptor (tTCR)-T chimeric antigen (CAR)-T cells to improve adoptive therapy for multiple types. This involves knockouts immune checkpoint regulators such as PD-1, components endogenous TCR histocompatibility leukocyte (HLA) complex generate universal allogeneic CAR-T CD7 prevent self-destruction therapy. cervix carcinoma caused by human papillomavirus (HPV), E6 E7 genes are disrupted topically machinery. HIV infection, CCR5 co-receptor HIV-resistant hematopoietic stem cells. β-thalassemia sickle disease, engineered induce production fetal hemoglobin. AAV-mediated exploit liver systemic therapeutic proteins hemophilia mucopolysaccharidoses, eye restore splicing CEP920 Leber's congenital amaurosis. Close consideration safety aspects education stakeholders will be essential a successful implementation technology clinic.

Language: Английский

A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease DOI Open Access
Elliott Vichinsky, Carolyn Hoppe, Kenneth I. Ataga

et al.

New England Journal of Medicine, Journal Year: 2019, Volume and Issue: 381(6), P. 509 - 519

Published: June 14, 2019

Deoxygenated sickle hemoglobin (HbS) polymerization drives the pathophysiology of cell disease. Therefore, direct inhibition HbS has potential to favorably modify disease outcomes. Voxelotor is an inhibitor.

Language: Английский

Citations

519
Antibodies to watch in 2019 DOI Open Access
Hélène Kaplon, Janice M. Reichert

mAbs, Journal Year: 2018, Volume and Issue: 11(2), P. 219 - 238

Published: Dec. 5, 2018

For the past 10 years, annual 'Antibodies to watch' articles have provided updates on key events in late-stage development of antibody therapeutics, such as first regulatory review or approval, that occurred year before publication were anticipated occur during publication. To commemorate 10th anniversary article series and celebrate 2018 Nobel Prizes Chemistry Physiology Medicine, which given for work is highly relevant therapeutics research development, we expanded scope data presented include an overview all commercial clinical approval success rates this class molecules. Our indicate that: 1) are entering study, being approved, record numbers; 2) pipeline robust, with over 570 at various phases, including 62 studies; 3) Phase 1 favorable, ranging from 17-25%, depending therapeutic area (cancer vs. non-cancer). In 2018, a number (12) antibodies (erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality), burosumab (Crysvita), lanadelumab (Takhzyro), caplacizumab (Cablivi), mogamulizumab (Poteligeo), moxetumomab pasudodox (Lumoxiti), cemiplimab (Libtayo), ibalizumab (Trogarzo), tildrakizumab (Ilumetri, Ilumya), emapalumab (Gamifant)) treat wide variety diseases granted either European Union (EU) United States (US). As November 4 (sacituzumab govitecan, ravulizumab, risankizumab, romosozumab) considered their marketing EU US, additional 3 developed by Chinese companies (tislelizumab, sintilimab, camrelizumab) China. addition, our show product candidates (leronlimab, brolucizumab, polatuzumab vedotin) may enter end least 12 (eptinezumab, teprotumumab, crizanlizumab, satralizumab, tanezumab, isatuximab, spartalizumab, MOR208, oportuzumab monatox, TSR-042, enfortumab vedotin, ublituximab) 2019. Finally, found approximately half (18 33) cancer immune checkpoint modulators antibody-drug conjugates. Of these, 7 (tremelimumab, BCD-100, omburtamab, mirvetuximab soravtansine, trastuzumab duocarmazine, depatuxizumab mafodotin) evaluated studies primary completion dates late 2019, thus 'antibodies watch'. We look forward documenting progress made these other next installment series.

Language: Английский

Citations

418
Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease DOI Open Access
Julie Kanter, Mark C. Walters, Lakshmanan Krishnamurti

et al.

New England Journal of Medicine, Journal Year: 2021, Volume and Issue: 386(7), P. 617 - 628

Published: Dec. 12, 2021

Sickle cell disease is characterized by the painful recurrence of vaso-occlusive events. Gene therapy with use LentiGlobin for sickle (bb1111; lovotibeglogene autotemcel) consists autologous transplantation hematopoietic stem and progenitor cells transduced BB305 lentiviral vector encoding a modified β-globin gene, which produces an antisickling hemoglobin, HbAT87Q.

Language: Английский

Citations

262
Sickle Cell Disease DOI
Patricia L. Kavanagh, Titilope Fasipe, Ted Wun

et al.

JAMA, Journal Year: 2022, Volume and Issue: 328(1), P. 57 - 57

Published: July 5, 2022

Importance

Sickle cell disease (SCD) is an inherited disorder of hemoglobin, characterized by formation long chains hemoglobin when deoxygenated within capillary beds, resulting in sickle-shaped red blood cells, progressive multiorgan damage, and increased mortality. An estimated 300 000 infants are born annually worldwide with SCD. Most individuals SCD live sub-Saharan Africa, India, the Mediterranean, Middle East; approximately 100 US.

Observations

diagnosed through newborn screening programs, where available, or patients present unexplained severe atraumatic pain normocytic anemia. In SCD, sickling hemolysis cells result vaso-occlusion associated ischemia. repeated episodes acute chest syndrome, other complications including stroke, chronic pain, nephropathy, retinopathy, avascular necrosis, priapism, leg ulcers. US, nearly all children survive to adulthood, but average life expectancy remains 20 years less than general population, higher mortality as transition from pediatric adult-focused health care systems. Until 2017, hydroxyurea, which increases fetal reduces sickling, was only disease-modifying therapy available for first-line most Three additional therapies, L-glutamine, crizanlizumab, voxelotor, have been approved adjunctive second-line agents. clinical trials, L-glutamine reduced hospitalization rates 33% mean length stay 11 7 days compared placebo. Crizanlizumab crises 2.98 1.63 per year Voxelotor at least 1 g/dL, significantly more placebo (51% vs 7%). Hematopoietic stem transplant curative therapy, it limited donor availability, best results seen a matched sibling donor. While not likely develop addiction medications population.

Conclusions Relevance

people hemolytic anemia, syndrome; incidence retinopathy; span that shorter hydroxyurea voxelotor US since 2017 treatments, hematopoietic now standard disease.

Language: Английский

Citations

248
Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges DOI Open Access
Marina Cavazzana, Frederic D. Bushman, Annarita Miccio

et al.

Nature Reviews Drug Discovery, Journal Year: 2019, Volume and Issue: 18(6), P. 447 - 462

Published: March 11, 2019

Language: Английский

Citations

168
History of the Plague: An Ancient Pandemic for the Age of COVID-19 DOI Creative Commons

Kathryn A. Glatter,

Paul Finkelman

The American Journal of Medicine, Journal Year: 2020, Volume and Issue: 134(2), P. 176 - 181

Published: Sept. 24, 2020

Language: Английский

Citations

143
Acute Myeloid Leukemia Case after Gene Therapy for Sickle Cell Disease DOI Open Access
Sunita Goyal, John F. Tisdale,

Manfred Schmidt

et al.

New England Journal of Medicine, Journal Year: 2021, Volume and Issue: 386(2), P. 138 - 147

Published: Dec. 12, 2021

Gene therapy with LentiGlobin for sickle cell disease (bb1111, lovotibeglogene autotemcel) consists of autologous transplantation a patient's hematopoietic stem cells transduced the BB305 lentiviral vector that encodes βA-T87Q-globin gene. Acute myeloid leukemia developed in woman approximately 5.5 years after she had received as part initial cohort (Group A) HGB-206 study. An analysis peripheral-blood samples revealed blast contained insertion site. The results an investigation causality indicated was unlikely to be related insertion, given location site, very low transgene expression cells, and lack effect on surrounding genes. Several somatic mutations predisposing acute were present diagnosis, which suggests patients are at increased risk hematologic malignant conditions transplantation, most likely because combination risks associated underlying disease, procedure, inadequate control treatment. (Funded by Bluebird Bio.).

Language: Английский

Citations

137
Past, present, and future of CRISPR genome editing technologies DOI Creative Commons

Martin Pacesa,

Oana Pelea, Martin Jínek

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(5), P. 1076 - 1100

Published: Feb. 1, 2024

Genome editing has been a transformative force in the life sciences and human medicine, offering unprecedented opportunities to dissect complex biological processes treat underlying causes of many genetic diseases. CRISPR-based technologies, with their remarkable efficiency easy programmability, stand at forefront this revolution. In Review, we discuss current state CRISPR gene technologies both research therapy, highlighting limitations that constrain them technological innovations have developed recent years address them. Additionally, examine summarize landscape applications context health therapeutics. Finally, outline potential future developments could shape coming years.

Language: Английский

Citations

131
Exagamglogene Autotemcel for Severe Sickle Cell Disease DOI
Haydar Frangoul, Franco Locatelli, Akshay Sharma

et al.

New England Journal of Medicine, Journal Year: 2024, Volume and Issue: 390(18), P. 1649 - 1662

Published: April 24, 2024

Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis by means of ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region

Language: Английский

Citations

113
Hemolysis, free hemoglobin toxicity, and scavenger protein therapeutics DOI Creative Commons
Florence Vallelian, Paul W. Buehler, Dominik J. Schaer

et al.

Blood, Journal Year: 2022, Volume and Issue: 140(17), P. 1837 - 1844

Published: June 3, 2022

During hemolysis, erythrophagocytes dispose damaged red blood cells. This prevents the extracellular release of hemoglobin, detoxifies heme, and recycles iron in a linked metabolic pathway. Complementary to this process, haptoglobin hemopexin scavenge shuttle cell toxins hemoglobin heme cellular clearance. Pathological hemolysis outpaces macrophage capacity scavenger synthesis across diversity diseases. imbalance leads hemoglobin-driven disease progression. To meet void treatment options, protein-based therapeutics are clinical development.

Language: Английский

Citations

78