Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease

Kanter, Julie; Walters, Mark C.; Krishnamurti, Lakshmanan; Mapara, Markus Y.; Kwiatkowski, Janet L.; Rifkin-Zenenberg, Stacey; Aygün, Banu; Kasow, Kimberly A.; Pierciey, Francis J.; Bonner, Melissa; Miller, Alex; Zhang, Xinyan; Lynch, Jessie; Kim, Dennis; Ribeil, Jean-Antoine; Asmal, Mohammed; Goyal, Sunita; Thompson, Alexis A.; Tisdale, John F.

doi:10.1056/nejmoa2117175

Cited by 233 publications

(191 citation statements)

References 34 publications

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“…On the other hand, Itgb3 overexpression in the BM of aged mice via BMT reduces plasma TNFα and thus, prevents the clonal expansion of multiple SMC-derived progenitors in the plaque and attenuates plaque burden (Figure 7). It is intriguing to consider this result in light of a recent study demonstrating efficacy of autologous transplantation of genetically modified hematopoietic stem and progenitor cells as a treatment for patients with sickle cell disease (Kanter et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Age of the bone marrow dictates clonality of smooth muscle-derived cells in the atherosclerotic plaque

Kabir

Zhang

Dave

et al. 2022

Preprint

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Aging is the predominant risk factor for atherosclerosis, the leading cause of death. Rare smooth muscle cells (SMCs) clonally expand giving rise to up to ~70% of atherosclerotic plaque cells; however, the effect of age on SMC clonality is not known. Our results indicate that aging induces SMC polyclonality and worsens atherosclerosis through non-cell autonomous effects of aged bone marrow-derived cells. Indeed, in myeloid cells from aged mice and humans, TET2 levels are reduced which epigenetically silences integrin beta-3 resulting in increased cytokine (e.g., tumor necrosis factor [TNF]-alpha) signaling. In turn, TNF-alpha induces recruitment and expansion of multiple SMCs into the atherosclerotic plaque. Recent studies demonstrate that normal aging is characterized by somatic mutations and clonal expansion of epithelial cells of diverse tissues (e.g., esophagus, endometrium, skin); extrapolating beyond atherogenesis, our results call for future studies evaluating the role of aged myeloid cells in regulating this epithelial cell clonal expansion.

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Section: Discussionmentioning

confidence: 99%

Age of the bone marrow dictates clonality of smooth muscle-derived cells in the atherosclerotic plaque

Kabir

Zhang

Dave

et al. 2022

Preprint

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“…Hybrid Additive gene therapy that introduces a fetal-like HBB (HbA T87Q ) achieves about 40% HbA T87Q with excellent clinical results. 1 HbA T87Q in mice had an O 2 affinity like that of HbA. 23 In two patients with sickle cell disease treated with LentiGlobin gene therapy, and achieving HbA T87Q levels of about 46%, P 50 was 27-29 torr compared with 32 torr in untreated sickle cell disease controls.…”

Section: Effects Of 40% Hbf On P 5 0 In Sickle Cell Anemiamentioning

confidence: 98%

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mentioning

confidence: 99%

Fetal hemoglobin in β hemoglobinopathies: Is enough too much?

Steinberg

2022

American J Hematol

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Cell-based therapies inducing about 40% fetal hemoglobin (HbF), or a HbF-like hemoglobin in most erythrocytes, can-at least in the shortterm-effect a cure or near-cure of β hemoglobinopathies, which are humankind's most common Mendelian diseases. [1][2][3] In sickle cell disease, a point mutation in the normal β-globin gene (HBB) directs the synthesis of sickle hemoglobin (HbS), which polymerizes on deoxygenation, damaging the red cell and triggering a complex pathophysiology. HbF exerts a powerful anti-polymerization effect because the chances of both the HbF tetramer (α 2 γ 2 ) and the hybrid tetramer α 2 γβ S entering the polymer phase are nearly nil. 4 Hundreds of different HBB mutations cause β thalassemia where insufficient β-globin synthesis allows free unpaired α globin to accumulate, leading to ineffective erythropoiesis and severe anemia. γ-Globin pairs with α globin forming HbF and preventing, at its earliest stage, the pathophysiology of the β thalassemia phenotype.

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“…If regular blood transfusion is not applicable, therapy with hydroxyurea is recommended as a better choice than no therapy at all [69]. Very recently, published results of a phase 1-2 study showed the promising biological and clinical efficacy of SCD gene therapy with the use of LentiGlobin [70].…”

Section: Autosomal Recessive Inheritancementioning

confidence: 99%

The Genetic Basis of Strokes in Pediatric Populations and Insight into New Therapeutic Options

Janković

Petrović²,

Novaković

et al. 2022

IJMS

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Strokes within pediatric populations are considered to be the 10th leading cause of death in the United States of America, with over half of such events occurring in children younger than one year of life. The multifactorial etiopathology that has an influence on stroke development and occurrence signify the importance of the timely recognition of both modifiable and non-modifiable factors for adequate diagnostic and treatment approaches. The early recognition of a stroke and stroke risk in children has the potential to advance the application of neuroprotective, thrombolytic, and antithrombotic interventions and rehabilitation strategies to the earliest possible timepoints after the onset of a stroke, improving the outcomes and quality of life for affected children and their families. The recent development of molecular genetic methods has greatly facilitated the analysis and diagnosis of single-gene disorders. In this review, the most significant single gene disorders associated with pediatric stroke are presented, along with specific therapeutic options whenever they exist. Besides monogenic disorders that may present with stroke as a first symptom, genetic polymorphisms may contribute to the risk of pediatric and perinatal stroke. The most frequently studied genetic risk factors are several common polymorphisms in genes associated with thrombophilia; these genes code for proteins that are part of the coagulation cascade, fibrolysis, homocystein metabolism, lipid metabolism, or platelets. Single polymorphism frequencies may not be sufficient to completely explain the stroke causality and an analysis of several genotype combinations is a more promising approach. The recent steps forward in our understanding of the disorders underlying strokes has given us a next generation of therapeutics and therapeutic targets by which to improve stroke survival, protect or rebuild neuronal connections in the brain, and enhance neural function. Advances in DNA sequencing and the development of new tools to correct human gene mutations have brought genetic analysis and gene therapy into the focus of investigations for new therapeutic options for stroke patients.

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Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease

Cited by 233 publications

References 34 publications

Age of the bone marrow dictates clonality of smooth muscle-derived cells in the atherosclerotic plaque

Age of the bone marrow dictates clonality of smooth muscle-derived cells in the atherosclerotic plaque

Fetal hemoglobin in β hemoglobinopathies: Is enough too much?

The Genetic Basis of Strokes in Pediatric Populations and Insight into New Therapeutic Options

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