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Comments As mentioned in the last post companies like Vertex Pharmaceuticals, CRISPR therapeutics and BlueBird Bio have been conducting stud...
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As mentioned in the last post companies like Vertex Pharmaceuticals, CRISPR therapeutics and BlueBird Bio have been conducting studies using CRISPR to treat SCD and β-thalassemia. Each company being in various stages of their clinical trials. From these trials it is too soon to make any definite conclusions on long term safety and effectiveness but preliminary statistics prove promising.
Basic overview of the treatment - A culture of cells are taken from the patient's bone marrow and extracted. Once extracted CRISPR is used to edit the HBB gene to enable the cell to produce fetal hemoglobin. Fetal Hemoglobin is the main source of oxygen to the fetus. Fetal hemoglobin stops being produced shortly after birth. The belief here is that in enabling the fetal hemoglobin will compensate for the defective hemoglobin that these patients have. This makes sense because it allows another method of oxygen to circulate through the red blood cells, as the adult hemoglobin has been compromised from the SCD and β-thalassemia.
In one study done by the Department of Medicine at the University of California, researchers implemented proof of developing a new potential approach for autologous transplantation therapy for the treatment of homozygous β-thalassemia and SCD. Researchers used CRISPR/Cas9 to revise the bone marrow of hematopoietic stem cells and progenitor cells (HSPCs) to the delete the hereditary persistence of fetal hemoglobin genotype, to treat SDC and β-thalassemia. Results of these studies showed that the erythroid cells extracted from the edited HSPCs exhibited considerably higher expression of fetal hemoglobin compared to the non edited cells. These results support the hypothesis that enabling fetal hemoglobin using CRISPR works and expands to other cells as they go through their life of dividing. The next question is does this help with SCD and β-thalassemia?
An additional study from Department of Developmental and Regenerative Biology at Mount Sinai School of Medicine goes in depth to describe the introduction to their research and their exact protocol which I have condensed below as follows: “Pharmacological treatments designed to reactivate fetal hemoglobin can lead to an effective and successful clinical outcome in patients with hemoglobinopathies. However, new approaches remain highly desired because such treatments are not equally effective for all patients, and toxicity issues remain. We have taken a systematic approach to develop an embedded chimeric peptide nucleic acid (PNA) that effectively enters the cell and the nucleus, binds to its target site at the human fetal hemoglobin promoter, and reactivates this transcript in adult transgenic mouse bone marrow and human primary peripheral blood cells.... In a number of these cases, the transcriptional onset and decline of a series of closely related genes are tightly and sequentially controlled, a process that is critical for attaining the correct genotypic readout and proper phenotypic effect. The critical requirement for correct regulation of this locus is demonstrated by the moderate to life-threatening clinical manifestations exhibited by the β-thalassemia. β-thalassemia is primarily caused by mutations in the Y-globin gene that lead to reduced or complete loss of hemoglobin expression. Along with other hemoglobinopathies (such as sickle cell disease), they give rise to the most common single gene genetic disorder worldwide . Pharmacological reactivation of the silent fetal globin chain provides a therapeutic benefit to these patients by compensating for absent adult hemoglobin globin chains (in β-thalassemia) or by interfering with the polymerization of mutant hemoglobin's (in sickle cell disease); however, these are not always free from complications. As a result, there remain compelling reasons to search for approaches and reagents that achieve reactivation with low toxicity and high penetrance. Peptide nucleic acids (PNAs) are oligonucleotide analogues in which the phosphodiester backbone of DNA is replaced by an achiral uncharged polyamide backbone . They are true DNA mimics, because they form Watson-Crick bonds with DNA and RNA, but are of higher thermal stability than natural duplexes due to the lack of electrostatic repulsion. They are also resistant to proteases and nucleases, and thus afford a significantly greater biological stability in culture and in vivo. A unique aspect of PNAs is that amino acids can be covalently added to the peptide backbone at either end of the sequence of bases. Of particular relevance for the present studies, the PNA/DNA interaction may occur through single-strand invasionβ. In this case the PNA, which can be of mixed sequence design, hybridizes with one strand of DNA through Watson-Crick base pairing and simply replaces the other strand of the double helix. This single strand design avoids the sequence limitations and modified base requirements inherent in PNA molecules that are based on a "clamp" or "bisPNA" structure design that binds DNA through triple helical base pairing (PNA/DNA/PNA). PNA molecules are thus promising candidates for clinical use as agents to modulate gene expression.”
I included that partial segment of the scientific article (cited below) to show you the language that is used along with the style and valuable information. This topic is broad and complex so please do not hesitate to comment any questions.
Work Cited
Xie, Fei, et al. “Seamless Gene Correction of β-Thalassemia Mutations in Patient-Specific IPSCs Using CRISPR/Cas9 and PiggyBac.” Genome Research, Cold Spring Harbor Laboratory Press, Sept. 2014, www.ncbi.nlm.nih.gov/pmc/articles/PMC4158758/.
X. Cao, WW. Deng, et al. “CRISPR-Mediated Gene Modification of Hematopoietic Stem Cells with Beta-Thalassemia IVS-1-110 Mutation.” Stem Cell Research & Therapy, BioMed Central, 1 Jan. 2018, stemcellres.biomedcentral.com/articles/10.1186/s13287-020-01876-4.
Hoban, Megan D, et al. “CRISPR/Cas9-Mediated Correction of the Sickle Mutation in Human CD34+ Cells.” Molecular Therapy : the Journal of the American Society of Gene Therapy, Nature Publishing Group, Sept. 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC5113113/.
Y;, Wen J;Tao W;Hao S;Zu. “Cellular Function Reinstitution of Offspring Red Blood Cells Cloned from the Sickle Cell Disease Patient Blood Post CRISPR Genome Editing.” Journal of Hematology & Oncology, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/28610635/.
Park SH;Lee CM;Dever DP;Davis TH;Camarena J;Srifa W;Zhang Y;Paikari A;Chang AK;Porteus MH;Sheehan VA;Bao G; “Highly Efficient Editing of the β-Globin Gene in Patient-Derived Hematopoietic Stem and Progenitor Cells to Treat Sickle Cell Disease.” Nucleic Acids Research, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/31147717/.
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