Advances in the gene therapy of monogenic blood cell diseases

Bueren, Juan A.; Quintana-Bustamante, Óscar; Almarza, Elena; Navarro, Susana; Rı́o, Paula; Segovia, José C.; Güenechea, Guillermo

doi:10.1111/cge.13593

Cited by 21 publications

(17 citation statements)

References 176 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recent progress in genome editing (Zinc finger nucleases (ZFNs), Transcription activator-like effector nuclease (TALEN), and CRISPR/Cas9) is also promising in the treatment of the clinical disorders in ribosomopathies. CRISPR/Cas9 technology has been used to target cells from various tissues, such as hematopoietic stem cells [ 140 ], skeletal muscle cells [ 141 ], or inner ear cells [ 142 ]. We can speculate that in the next few years, new strategies using gene editing to correct the disorders found in ribosomopathies will appear by correcting mutations in specific tissues.…”

Section: Discussionmentioning

confidence: 99%

Ribosomopathies: New Therapeutic Perspectives

Orgebin

Lamoureux

Isidor

et al. 2020

Cells

View full text Add to dashboard Cite

Ribosomopathies are a group of rare diseases in which genetic mutations cause defects in either ribosome biogenesis or function, given specific phenotypes. Ribosomal proteins, and multiple other factors that are necessary for ribosome biogenesis (rRNA processing, assembly of subunits, export to cytoplasm), can be affected in ribosomopathies. Despite the need for ribosomes in all cell types, these diseases result mainly in tissue-specific impairments. Depending on the type of ribosomopathy and its pathogenicity, there are many potential therapeutic targets. The present manuscript will review our knowledge of ribosomopathies, discuss current treatments, and introduce the new therapeutic perspectives based on recent research. Diamond–Blackfan anemia, currently treated with blood transfusion prior to steroids, could be managed with a range of new compounds, acting mainly on anemia, such as L-leucine. Treacher Collins syndrome could be managed by various treatments, but it has recently been shown that proteasomal inhibition by MG132 or Bortezomib may improve cranial skeleton malformations. Developmental defects resulting from ribosomopathies could be also treated pharmacologically after birth. It might thus be possible to treat certain ribosomopathies without using multiple treatments such as surgery and transplants. Ribosomopathies remain an open field in the search for new therapeutic approaches based on our recent understanding of the role of ribosomes and progress in gene therapy for curing genetic disorders.

show abstract

Section: Discussionmentioning

confidence: 99%

Ribosomopathies: New Therapeutic Perspectives

Orgebin

Lamoureux

Isidor

et al. 2020

Cells

View full text Add to dashboard Cite

show abstract

“…In some cases, rather than discussing HCT as a treatment option, in a child with minimal SCD‐related complications, traditional therapy with hydroxyurea or enrolment in clinical drug trials may be preferred over referral for HCT (Bakshi et al , ). Additionally, with gene editing therapies also on the horizon, University‐based providers, who tend to have greater access to advanced therapies, may prefer to await the opportunity to potentially refer a patient for gene editing in the future, rather than to have them undergo HCT (Ribeil et al , ; Bueren et al , ; Ikawa et al , ). This may be particularly true for providers with more negative perspectives about HCT.…”

Section: Discussionmentioning

confidence: 99%

Paediatric haematologists’ attitudes regarding haematopoietic cell transplantation as treatment for sickle cell disease

et al. 2019

View full text Add to dashboard Cite

Summary Beginning early in childhood, patients with sickle cell disease [SCD; a group of genetic haemoglobin disorders characterized by the sickle or HbS mutation (HBB E7V)] are at risk of life‐threatening and debilitating health events. Despite the high morbidity and mortality of this disease, haematopoietic cell transplantation (HCT), a curative therapy for SCD, remains underutilized. A variety of factors, including the limited availability of suitable donors, play a role in this trend, but do not fully explain the low frequency with which this therapy is employed. The objective of this study was to identify paediatric haematologists’ attitudes about HCT as a treatment option for SCD, and to describe the impact of these attitudes on their practices of discussing HCT with families of children affected by this disease. A nationwide survey of paediatric haematologists in the United States was conducted between February and May 2016. Two hundred and eighty‐seven surveys were included in the final analysis (response rate 20%). On average, respondents reported informing 42% of families about HCT as a treatment option (N = 248, 95% confidence interval: 38–46). Clinician attitudes about the cost and safety of HCT were associated with practices of discussing this therapy with families. These findings suggest that clinician attitudes and referral practices may play a role in the underutilization of this therapy in the SCD population.

show abstract

“…Two clinical trials are being conducted with  AS3 -globin LVVs (NCT02247843 [171] and NCT03964792) but no data have yet been published.…”

Section: Clinical Studiesmentioning

confidence: 99%

Innovative Therapies for Hemoglobin Disorders

Sii-Felice¹,

Nègre²,

Brendel³

et al. 2020

BioDrugs

View full text Add to dashboard Cite

-globin gene transfer has been used as a paradigm for hematopoietic stem cell (HSC) gene therapy, but is subject to major difficulties, such as the lack of selection of genetically corrected HSCs, the need for high-level expression of the therapeutic gene, and cell-specific transgene expression. It took more than 40 years for scientists and physicians to advance from the cloning of globin gene and discovering globin gene mutations to improving our understanding of the pathophysiological mechanisms involved, the detection of genetic modifiers, the development of animal models and gene transfer vectors, comprehensive animal testing, and demonstrations of phenotypic improvement in clinical trials, culminating in the authorization of the first gene therapy product for -thalassemia in 2019. Research has focused mostly on the development of lentiviral gene therapy vectors expressing variants of the -globin gene, or more recently targeting a -globin repressor, some of which have entered clinical testing and should soon diversify the available treatments and promote price competition. These results are encouraging, but we have yet to reach the end of the story. New molecular and cellular tools, such as gene editing or the development of induced pluripotent stem cells, are being developed, heralding the emergence of alternative products, the efficacy and safety of which are being studied. Hemoglobin disorders constitute an important model for testing the pros and cons of these advanced technologies, some of which are already in the clinical phase. In this review, we focus on the development of the advanced products, and recent technological innovations which could lead to clinical trials in the near future, and provide hope for a definitive cure of these severe conditions.

show abstract

Advances in the gene therapy of monogenic blood cell diseases

Cited by 21 publications

References 176 publications

Ribosomopathies: New Therapeutic Perspectives

Ribosomopathies: New Therapeutic Perspectives

Paediatric haematologists’ attitudes regarding haematopoietic cell transplantation as treatment for sickle cell disease

Innovative Therapies for Hemoglobin Disorders

Contact Info

Product

Resources

About