Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2024 May 27;13(11):920.
doi: 10.3390/cells13110920.

Towards a Cure for Diamond-Blackfan Anemia: Views on Gene Therapy

Matilde Vale  1 , Jan Prochazka  1   2 , Radislav Sedlacek  1   2
Affiliations
Review

Towards a Cure for Diamond-Blackfan Anemia: Views on Gene Therapy

Matilde Vale et al. Cells. .

Abstract

Diamond-Blackfan anemia (DBA) is a rare genetic disorder affecting the bone marrow's ability to produce red blood cells, leading to severe anemia and various physical abnormalities. Approximately 75% of DBA cases involve heterozygous mutations in ribosomal protein (RP) genes, classifying it as a ribosomopathy, with RPS19 being the most frequently mutated gene. Non-RP mutations, such as in GATA1, have also been identified. Current treatments include glucocorticosteroids, blood transfusions, and hematopoietic stem cell transplantation (HSCT), with HSCT being the only curative option, albeit with challenges like donor availability and immunological complications. Gene therapy, particularly using lentiviral vectors and CRISPR/Cas9 technology, emerges as a promising alternative. This review explores the potential of gene therapy, focusing on lentiviral vectors and CRISPR/Cas9 technology in combination with non-integrating lentiviral vectors, as a curative solution for DBA. It highlights the transformative advancements in the treatment landscape of DBA, offering hope for individuals affected by this condition.

Keywords: CRISPR/Cas9; Diamond–Blackfan anemia; gene therapy; hematopoietic stem cell transplantation; lentiviral vector; non-integrating lentiviral vector; rare genetic disorder; ribosomal protein genes; ribosomopathy.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Clinical manifestations of DBA. Created with BioRender.com (accessed on 18 April 2024).
Figure 2
Figure 2
Molecular mechanism of DBA. (a) RP mutations lead to activation of p53, cell cycle arrest, and apoptosis; (b) Unbalanced globin/heme synthesis leads to accumulation of ROS in erythroid precursors; (c) Translation dysfunction caused by RP mutations; (d) Abnormal inflammatory signaling caused by RP mutations. Created with BioRender.com (accessed on 22 May 2024).
Figure 3
Figure 3
Existing treatment options for DBA patients. Created with BioRender.com (accessed on 18 April 2024).
Figure 4
Figure 4
Gene therapy as a therapeutic alternative for DBA treatment. (a) Traditional gene therapy employes integrating lentiviral vectors carrying the functional gene (e.g., RPS19), which are delivered to the patients HSCs ex vivo. (b) A more novel approach includes correcting the mutation ex vivo using non-integrating lentiviral vectors (NILVs) that carry CRISPR/Cas9 tools specific for the DBA mutation. Created with BioRender.com (accessed on 18 April 2024).
See this image and copyright information in PMC

References

    1. Liu Y., Karlsson S. Perspectives of current understanding and therapeutics of Diamond-Blackfan anemia. Leukemia. 2024;38:1–9. doi: 10.1038/s41375-023-02082-w. - DOI - PMC - PubMed
    1. Kang J., Brajanovski N., Chan K.T., Xuan J., Pearson R.B., Sanij E. Ribosomal proteins and human diseases: Molecular mechanisms and targeted therapy. Signal Transduct. Target. Ther. 2021;6:323. doi: 10.1038/s41392-021-00728-8. - DOI - PMC - PubMed
    1. Ulirsch J.C., Verboon J.M., Kazerounian S., Guo M.H., Yuan D., Ludwig L.S., Handsaker R.E., Abdulhay N.J., Fiorini C., Genovese G., et al. The Genetic Landscape of Diamond-Blackfan Anemia. Am. J. Hum. Genet. 2018;103:930–947. doi: 10.1016/j.ajhg.2018.10.027. - DOI - PMC - PubMed
    1. Maceckova Z., Kubickova A., De Sanctis J.B., Hajduch M. Effect of Glucocorticosteroids in Diamond-Blackfan Anaemia: Maybe Not as Elusive as It Seems. Int. J. Mol. Sci. 2022;23:1886. doi: 10.3390/ijms23031886. - DOI - PMC - PubMed
    1. Bartels M., Bierings M. How I manage children with Diamond-Blackfan anaemia. Br. J. Haematol. 2019;184:123–133. doi: 10.1111/bjh.15701. - DOI - PMC - PubMed

Publication types

Substances