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Under our new strategic plan, a multidisciplinary team of scientists and clinical researchers from Hematology and other departments will focus on the development of curative treatments for #sicklecell disease. Take a look. ow.ly/WXpk50Fefcq #WorldSickleCellDay

Sickle cell disease is the most common inherited blood disorder in the U.S. About 900 patients turn to St. Jude for treatment. Since #sicklecell disease is caused by a single mutation, could gene-editing techniques cure it? ow.ly/D7xm50FefbI #WorldSickleCellDay

Sickle cell disease is the first genetic disease to be understood at the molecular level, but therapies have lagged behind. However, the field has come together in the last 10 years with great progress. —St. Jude Hematology Dept. Chair Dr. Mitch Weiss #WorldSickleCellDay

The progress we've made includes several clinical trials for new drugs. We have the ability to make more progress because technologies are accelerating. This says the future is bright for #sicklecell disease. —Hematology Dept. Chair Dr. Mitch Weiss #WorldSickleCellDay

St. Jude has had a long history with #sicklecell disease research and treatment. In the next several years, because of the field coming together, more people will experience less suffering and more will be cured. —Hematology Dept. Chair Dr. Mitch Weiss #WorldSickleCellDay

Sickle cell disease results from a mutation that causes pliable red blood cells to become brittle & sickle shaped. Scientists used base editing to change the mutation. The resulting cells were less prone to sickling. ow.ly/Qn0X50FxTj4 Jonathan Yen nature #NowInPrint

Great work led by Kelcee Everette with David R. Liu, Gregory Newby, and my TGEn team: RML, Kalin Mayberry, Yoonjeong Jang, Thiyagaraj Mayuranathan, Nikitha Nimmagadda, Erin Dempsey. Also congrats to Yichao Li, @senthilprime, Xiong Liu, Yong Cheng, John Tisdale, and Mitch Weiss.

Gene therapy that alters hemoglobin genes may cure blood diseases that afflict millions of individuals. Scientists at St. Jude and Broad Institute used potentially curative base editing technology to restart fetal hemoglobin production in patient cells. bit.ly/434cpGB

Today we report in Nature Genetics a study led by the team of Jonathan Yen and Mitch Weiss St. Jude that characterizes Cas9 nuclease and adenine base editing strategies to induce fetal hemoglobin expression, clinical approaches to treat sickle-cell disease & beta-thalassemia. 1/10

We treated HSPCs with ABEs programmed to install 1 of 3 naturally occurring mutations that restores fetal hemoglobin expression from its silenced state following the HBG-to-HBB switch. Each base edit creates binding sites for KLF1, TAL1, or GATA1 transcriptional activators. 2/10

Cas9 nuclease targeting either the BCL11A binding motif in the HBG promoter, or the BCL11A erythroid enhancer (two strategies currently in clinical trials), disrupted their respective target sites via indel formation and also stimulated HbF production. 4/10

However, Cas9 nuclease generated a complex mixture of indel outcomes that varied in their ability to induce fetal hemoglobin production. Analysis of individual clones showed most increased HbF levels, but some did ~nothing, while others DECREASED HbF levels vs no treatment. 5/10

In contrast, the –175A>G base edit resulted in highly potent and uniform induction of HbF that was linearly proportional to editing efficiency, consistent with much more homogenous outcomes of base editing at the target site. 6/10

These findings show that in addition to undesired cellular & chromosomal consequences of double-strand DNA breaks, the heterogeneity of biological outcomes from on-target indel mixtures generated by nucleases can attenuate and complicate desired therapeutic editing outcomes. 8/10

Congrats Thiyagaraj, Gregory Newby, Ruopeng, Yu, Kalin, Cicera, Yichao, Rachel, Nikitha, Erin, Guolian, Shaina, Phillip, Jingjing Z., Yoonjeong, Jingjing C., Henry, Merlin, Senthil, Akshay, John, Shondra, Yong, Shengdar, Mitch, and Jonathan Yen for this in-depth study. 9/10

PDF for free download: drive.google.com/file/d/1UoL_6J… Paper on the Nature Genetics website: nature.com/articles/s4158… 10/10

Great work led by Thiyagaraj Mayuranathan, Gregory Newby in collaboration with David R. Liu and Mitch Weiss anr my TGEn team: RML, Kalin Mayberry, Yoonjeong Jang, Thiyagaraj Mayuranathan, Nikitha Nimmagadda, Erin Dempsey. You can access the article here: nature.com/articles/s4158…

🚨 ONLINE Nature Genetics 📰 Potent and uniform fetal hemoglobin induction via base editing 🧑🏾‍🤝‍🧑🏽 Jonathan Yen David R. Liu Mitch Weiss, Thiyagaraj Mayuranathan and colleagues 👇🏻 go.nature.com/3pxh2eE

#PublicationAlert Incredibly proud to share our manuscript in NEJM describing the first 3 #SickleCell dz patients who got hematopoietic stem cells #CRISPR Cas9 edited at the globin locus 🙏 to Seredev James LaBelle, M.D., Ph.D. Jaap J Boelens 🇳🇱🇺🇸 Jane Hankins, MD, MS Maria Cancio nejm.org/doi/full/10.10…

#StJudeGrowingScience research in sickle cell disease has helped improve the cure of this disease. We have come a long way from where we were two decades ago! St. Jude Research Jonathan Yen