CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia
Did you know that the most common monogenic diseases, that is, concerning a single gene, are beta-thalassemia (TDT) and sickle cell disease (SCD)? Affecting around 360 000 people worldwide, up until recently these diseases were largely non-treatable or had ineffective treatment plans. Both of them concern the hemoglobin β subunit gene (HBB). TDT has deformed or absent beta chains, while SCD replaces the sixth amino acid, glutamic acid, for valine. Now, treatments using gene editing represent a pivotal point. Both TDT and SCD treatments primarily focus on pain management and reducing side effects of blood transfusions such as iron buildup. What is intriguing is that symptoms emerge one year after birth. Why is that? A baby’s hemoglobin in their first year of life still has significant levels of gamma globin. This is a chain that binds oxygen strongly. It discharges it to tissues less effectively than beta globin. All this is in relation to the ever increasing oxygen needs of developing bodies. Babies are asymptomatic in the beginning because their hemoglobin has no beta chains, an observation that became the foundation for treating the cause of these blood ailments. Beta chains, as a key component for hemoglobin function, support the quaternary structure of the oxygen-binding molecule. As adults we have a transcription factor called BCL11A. It suppresses gene expression of gamma globin chains, therefore we lack fetal globin. So, why do we stop producing it when it protects us from symptoms of TDT and SCD? Unfortunately, it’s packed with a plethora of risks such as blood clots and visceral ischemia. A fascinating phenomenon appears in adults with higher expression of BCL11A locus on chromosome 2, which has less severe manifestations. This occurs because they produce more fetal hemoglobin. This, in turn, protects them against these blood ailments. What is CRISPR-Cas9 gene editing? CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats. It represents a family of DNA sequences of prokaryotic organisms. This DNA is derived from bacteriophages, viruses that infect bacteria. It can be used by prokaryotes to halt future attacks. Cas9 is an enzyme that links itself to CRISPR sequences. This serves as a guide to recognize and open up specific strands of DNA complementary to CRISPR making gene editing possible for living organisms. This technique allows for gene manipulation within a bacterial DNA which is then placed in a patient’s cell to activate gamma globin synthesis. This aspect made gene manipulation possible in humans, specifically in the BCL11A locus by reducing its function and restoring γ-globin synthesis. As far as the treatment goes, the target groups underwent myeloablation, suppression of erythroid cells, and received gene altered bone marrow from healthy subjects increasing their levels of fetal hemoglobin. Bone marrow extraction allows patients to produce gamma globin on their own. This decreases the need for blood transfusions and other treatments. Scientific discoveries can only happen through commitment and perseverance. As a result of innovative studies and team effort we get to connect with one another all around the world. The field of gene editing, especially, is growing at a fast pace. If you found this article helpful and believe that knowledge is power, keep up to date with our work. Also, read the full text here! About the author… Hello, my name is Cristi, and I am a fourth year medical student passionate about research and trying to build a career in the medical field I can be proud of. Oh and I also play tennis and I have a chinchilla that loves apples.
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