Genes and chromosomes 4: common genetic conditions
Complications Of Beta Thalassemia
The blood disorder beta thalassemia can bring complications that include things like bone damage, heart problems, and slow growth in children. Treatment can help you or your child avoid many of these problems.
Beta thalassemia lowers the amount of a protein in your body called hemoglobin. Hemoglobin helps red blood cells carry oxygen to your organs and tissues. If you or your child doesn't have enough hemoglobin, you can get anemia, which makes you tired and short of breath.
Low oxygen and too much iron cause most beta thalassemia complications. Iron is a mineral your body uses to carry oxygen and keep your muscles healthy. In beta thalassemia, your intestines absorb more iron than normal. The blood transfusions you get to treat the disease also contain iron. All of that extra iron builds up in your heart, liver, and the glands that make hormones and damages these organs.
The complications you or your child get depend in part on the type of beta thalassemia. "Beta thalassemia minor" is mild and usually doesn't cause problems. Anemia from "beta thalassemia intermedia" causes slowed growth in children, weak bones, and an enlarged spleen. "Beta thalassemia major" is the most serious type, and it can cause many complications, including slow growth in children, an enlarged spleen, heart and liver problems, and bone damage.
If you're the parent of a child who has complications from beta thalassemia, talk to your friends and family to get the emotional backing you may need as you help your child manage their symptoms. If you find yourself getting anxious or stressed out, talk to your doctor. They can put you in touch with social workers or mental health professionals who can help.
Your child's body needs lots of energy to grow. Cells need oxygen to create that energy.
Without enough oxygen, a child will grow more slowly. Puberty may also start late in kids with beta thalassemia.
Your spleen is an organ that makes new infection-fighting white blood cells and filters out the old ones that your body doesn't need anymore. Beta thalassemia makes your spleen make more new blood cells and break down more old blood cells than usual, so it has to work harder.
Just like a muscle grows when you use it more, overuse makes your spleen get bigger. If your spleen gets too large, you may need an operation called a splenectomy to remove it.
Your spleen is part of your body's defense system against germs. It makes the white blood cells that protect you from infections.
An enlarged spleen doesn't work as well as it should, which could make you more likely to get sick. And if you have surgery to remove your spleen, you or your child will be more likely to catch infections like the flu and pneumonia.
Getting all of your recommended vaccines and taking antibiotics will help to protect you from some of these illnesses. Let your doctor know if your child with beta thalassemia runs a fever. This could be a sign of a serious infection.
In severe beta thalassemia, both anemia and iron overload can damage the heart and cause problems like:
Heart problems can get worse without causing any symptoms. You or your child should get tests like echocardiograms, a chest X-ray, and a stress test each year to watch for any problems. Medicine to remove extra iron in your body, called chelation therapy, can help prevent heart problems from too much iron.
Your liver helps keep the right balance of iron in your body. Extra iron due to beta thalassemia or blood transfusions can build up and damage the liver.
Although it's rare, it is possible to get hepatitis B from a blood transfusion, which can also damage the liver.
Eventually your liver can become so scarred that it doesn't work right, a condition called cirrhosis.
Your body makes new blood cells in bone marrow, the spongy area inside your bones. When you have anemia, your bone marrow has to work overtime to make enough red blood cells to meet your body's needs.
As the bone marrow works harder, it stretches. Your bones become thinner, wider, and weaker than usual. They can break easily.
Extra bone growth may also cause your forehead, cheekbones, or jaw to stick out more than usual.
Your doctor will monitor you or your child for complications and treat any problems. One way to avoid complications is to follow the treatment plan your doctor prescribed.
If you have severe beta thalassemia, blood transfusions can help you avoid some of these problems.
Chelation therapy helps prevent extra iron from damaging your organs. You get this treatment as a pill or shot. The medicine binds to iron in your body and removes it through your urine or a bowel movement.
Base Editing Shows Promise For Treating Sickle Cell Disease And Beta Thalassemia
Gene therapy that alters hemoglobin genes may be an answer to curing sickle cell disease (SCD) and beta thalassemia. These two common life-threatening anemias afflict millions of individuals across the globe. Scientists at St. Jude Children's Research Hospital and the Broad Institute of MIT and Harvard used a next-generation genome editing technology, adenosine base editing, to restart fetal hemoglobin expression in SCD patient cells. The approach raised the expression of fetal hemoglobin to higher, more stable, and more uniform levels than other genome editing technologies that use CRISPR/Cas9 nuclease in human hematopoietic stem cells. The findings were published today in Nature Genetics.
SCD and beta thalassemia are blood disorders affecting millions of people; mutations in the gene that encodes an adult version of the oxygen-carrying molecule hemoglobin cause these disorders. Restoring gene expression of an alternative hemoglobin subunit active in a developing fetus has previously shown therapeutic benefit in SCD and beta thalassemia patients. The researchers wanted to find and optimize genomic technology to edit the fetal hemoglobin gene. One alteration installed by adenosine base editing was particularly potent for restoring fetal hemoglobin expression in post-natal red blood cells.
We showed base editors meaningfully increase fetal hemoglobin levels. Now, my Therapeutic Genome Engineering team is already hard at work, starting to optimize base editing to move this technology to the clinic."
Jonathan Yen, Ph.D., lead corresponding author, St. Jude Therapeutic Genome Engineering group director
Hemoglobin holds the keyAdult hemoglobin, expressed primarily after birth, contains four protein subunits -; two beta-globin and two alpha-globin. Mutations in the beta-globin gene cause sickle cell disease and beta-thalassemia. But humans have another hemoglobin subunit gene (gamma-globin), which is expressed during fetal development instead of beta-globin. Gamma-globin combines with alpha-globin to form fetal hemoglobin. Normally around birth, gamma-globin expression is turned off, and beta-globin is turned on, switching from fetal to adult hemoglobin. Genome editing technologies can introduce mutations that turn the gamma-globin gene back on, thereby increasing fetal hemoglobin production, which can effectively substitute for defective adult hemoglobin production.
"We used a based editor to create a new TAL1 transcription factor binding site that causes particularly strong induction of fetal hemoglobin," Yen said. "Creating a new transcription factor binding site requires a precise base pair change -; something that can't be done using CRISPR-Cas9 without generating unwanted byproducts and other potential consequences from double-stranded breaks."
The gamma-globin [fetal hemoglobin] gene is a good target for base editing because there are very precise mutations that can reactivate its expression to induce expression after birth, which may provide a powerful 'one-size-fits-all' treatment for all mutations that cause SCD and beta-thalassemia."
Mitchell Weiss, M.D., Ph.D., co-corresponding author, St. Jude Department of Hematology chair
Thus, scientists want to restore fetal hemoglobin expression because it is a more universal treatment for major hemoglobin disorders than correcting the SCD mutation or hundreds of mutations that cause beta thalassemia. Increasing fetal hemoglobin expression has the potential to therapeutically benefit most patients with SCD or beta thalassemia, regardless of their causative mutations. Researchers have previously shown proof-of-principle with multiple genome editing approaches, but this study is the first to systematically compare these different strategies' efficacy.
"We looked closely at the individual DNA sequence outcomes of nucleases and base editors used to make therapeutic edits of fetal hemoglobin genes. Since nucleases often generate complex, uncontrolled mixtures of many different DNA sequence outcomes, we characterized how each nuclease-edited sequence affects fetal hemoglobin expression. Then we did the same for base editing outcomes, which were much more homogeneous," said co-corresponding author David Liu, Ph.D., Richard Merkin, Professor at Broad Institute of MIT and Harvard, whose lab invented base editing in 2016.
The study discovered that using base editing at the most potent site in the gamma-globin promoter achieved 2- to 4-fold greater HbF levels than Cas9 editing. They further demonstrated that these base edits could be retained in engrafting blood stem cells from healthy donors and SCD patients by putting them into immunocompromised mice.
Addressing safety concerns"Ultimately, we showed that not all genetic approaches are equal," Yen said. "Base editors may be able to create more potent and precise edits than other technologies. But we must do more safety testing and optimization."
When compared for safety, base editing caused fewer genotoxic events, such as p53 activation and large deletions. Base editing was much more consistent in its edits and products -; a highly desirable safety property for a clinical therapy. In contrast to conventional Cas9, which generates uncontrolled mixtures of insertion and deletion mutations termed "indels," base editing generates precise nucleotide changes with few undesired byproducts.
"In our comparison, we found unanticipated problems with conventional Cas9 nucleases," Weiss said. "We were somewhat surprised that not every Cas9 insertion or deletion raised fetal hemoglobin to the same extent, indicating the potential for heterogeneous biological outcomes with that technology." The group found that individual red blood cells derived from hematopoietic stem cells treated with the same Cas9 produce a more variable amount of fetal hemoglobin compared to cells treated with base editing. Thus, base editing produced more potent, reliable, and consistent outcomes, which are desirable therapeutic properties.
Though base editing performed well, researchers have yet to determine its safety in patients. Notably, base editing may have some risks not presented by Cas9; for example, some early base editors can cause undesired changes in genomic DNA or RNA at off-target sites. The group showed that these changes are relatively small and not predicted to be harmful, but deeper studies are warranted to evaluate these risks fully.
The future of gene editing therapeuticsThroughout the study, the scientists directly compared the performance of Cas9 nucleases at two different target sites that induce fetal hemoglobin production in different ways and base editing. Base editing uses a distinct editing mechanism that directly converts one DNA base pair to another, rather than cutting the DNA double helix into two pieces.
The Cas9 nuclease approaches create mixtures of deletions and insertions that impair the expression or activity of BCL11A, a well-known gamma-globin gene repressor. In contrast, base editing creates a novel transcription factor binding motif within the gamma-globin promoter. The Cas9 nuclease approaches and a different base editing approach are being tested through clinical trials. St. Jude is participating in some of these studies.
"It is very important to test and compare different genome editing approaches for treating SCD and beta-thalassemia because the best ones are not known," said Weiss.
John Tisdale, M.D., a study co-author and the Cellular and Molecular Therapeutics Branch chief at the National Heart, Lung, and Blood Institute, agreed. "The science of gene editing is moving quickly, and we are now able to envision multiple different strategies for combating sickle cell disease," Tisdale said. "These findings bring us a step closer to our goal of broadly available cures."
Authors and fundingThe study's first authors are Thiyagaraj Mayuranathan, St. Jude and Gregory Newby, Broad Institute. Other authors are Ruopeng Feng, Yu Yao, Kalin Mayberry, Cicera Lazzarotto, Yichao Li, Rachel Levine, Nikitha Nimmagadda, Erin Dempsey, Guolian Kang, Shaina Porter, Phillip Doerfler, Jingjing Zhang, Yoonjeong Jang, Jingjing Chen, Senthil Velan Bhoopalan, Akshay Sharma, Shondra Pruett-Miller, Yong Cheng and Shengdar Tsai, all of St. Jude; Henry Bell and Merlin Crossley, University of New South Wales and John Tisdale, National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases.
The study was supported by grants from the National Institutes of Health (U01 AI142756, RM1 HG009490, R01 EB022376, R35 GM118062, R01 HL156647, R01 HL136135, P01 HL053749, U01 AI157189, R35 GM133614, HL163805, K01 DK132453 and P30 CA21765); the Bill and Melinda Gates Foundation; the Howard Hughes Medical Institute including a Helen Hay Whitney Postdoctoral Fellowship; the St. Jude Collaborative Research Consortium for SCD; the Doris Duke Foundation; the Assisi Foundation of Memphis; Cooley's Anemia Foundation Postdoctoral Research Fellowship Award; the American Society of Hematology (RTAF) and ALSAC, the fundraising and awareness organization of St. Jude.
Source:
Journal reference:
Mayuranathan, T., et al. (2023) Potent and uniform fetal hemoglobin induction via base editing. Nature Genetics. Doi.Org/10.1038/s41588-023-01434-7.
Gene Therapy Offers Possible Cure For Sickle Cell Disease
Gene therapy that alters hemoglobin genes may be an answer to curing sickle cell disease (SCD) and beta thalassemia. These two common life-threatening anemias afflict millions of individuals across the globe. Scientists at St. Jude Children's Research Hospital and the Broad Institute of MIT and Harvard used a next-generation genome editing technology, adenosine base editing, to restart fetal hemoglobin expression in SCD patient cells. The approach raised the expression of fetal hemoglobin to higher, more stable, and more uniform levels than other genome editing technologies that use CRISPR/Cas9 nuclease in human hematopoietic stem cells. The findings were published today in Nature Genetics.
SCD and beta thalassemia are blood disorders affecting millions of people; mutations in the gene that encodes an adult version of the oxygen-carrying molecule hemoglobin cause these disorders. Restoring gene expression of an alternative hemoglobin subunit active in a developing fetus has previously shown therapeutic benefit in SCD and beta thalassemia patients. The researchers wanted to find and optimize genomic technology to edit the fetal hemoglobin gene. One alteration installed by adenosine base editing was particularly potent for restoring fetal hemoglobin expression in post-natal red blood cells.
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Subscribe for FREE"We showed base editors meaningfully increase fetal hemoglobin levels," said lead corresponding author Jonathan Yen, Ph.D., St. Jude Therapeutic Genome Engineering group director. "Now, my Therapeutic Genome Engineering team is already hard at work, starting to optimize base editing to move this technology to the clinic."
Hemoglobin holds the keyAdult hemoglobin, expressed primarily after birth, contains four protein subunits — two beta-globin and two alpha-globin. Mutations in the beta-globin gene cause sickle cell disease and beta-thalassemia. But humans have another hemoglobin subunit gene (gamma-globin), which is expressed during fetal development instead of beta-globin. Gamma-globin combines with alpha-globin to form fetal hemoglobin. Normally around birth, gamma-globin expression is turned off, and beta-globin is turned on, switching from fetal to adult hemoglobin. Genome editing technologies can introduce mutations that turn the gamma-globin gene back on, thereby increasing fetal hemoglobin production, which can effectively substitute for defective adult hemoglobin production.
"We used a based editor to create a new TAL1 transcription factor binding site that causes particularly strong induction of fetal hemoglobin," Yen said. "Creating a new transcription factor binding site requires a precise base pair change — something that can't be done using CRISPR-Cas9 without generating unwanted byproducts and other potential consequences from double-stranded breaks."
"The gamma-globin [fetal hemoglobin] gene is a good target for base editing because there are very precise mutations that can reactivate its expression to induce expression after birth, which may provide a powerful 'one-size-fits-all' treatment for all mutations that cause SCD and beta-thalassemia," said co-corresponding author Mitchell Weiss, M.D., Ph.D., St. Jude Department of Hematology chair.
Thus, scientists want to restore fetal hemoglobin expression because it is a more universal treatment for major hemoglobin disorders than correcting the SCD mutation or hundreds of mutations that cause beta thalassemia. Increasing fetal hemoglobin expression has the potential to therapeutically benefit most patients with SCD or beta thalassemia, regardless of their causative mutations. Researchers have previously shown proof-of-principle with multiple genome editing approaches, but this study is the first to systematically compare these different strategies' efficacy.
"We looked closely at the individual DNA sequence outcomes of nucleases and base editors used to make therapeutic edits of fetal hemoglobin genes. Since nucleases often generate complex, uncontrolled mixtures of many different DNA sequence outcomes, we characterized how each nuclease-edited sequence affects fetal hemoglobin expression. Then we did the same for base editing outcomes, which were much more homogeneous," said co-corresponding author David Liu, Ph.D., Richard Merkin, Professor at Broad Institute of MIT and Harvard, whose lab invented base editing in 2016.
The study discovered that using base editing at the most potent site in the gamma-globin promoter achieved 2- to 4-fold greater HbF levels than Cas9 editing. They further demonstrated that these base edits could be retained in engrafting blood stem cells from healthy donors and SCD patients by putting them into immunocompromised mice.
Addressing safety concerns"Ultimately, we showed that not all genetic approaches are equal," Yen said. "Base editors may be able to create more potent and precise edits than other technologies. But we must do more safety testing and optimization."
When compared for safety, base editing caused fewer genotoxic events, such as p53 activation and large deletions. Base editing was much more consistent in its edits and products — a highly desirable safety property for a clinical therapy. In contrast to conventional Cas9, which generates uncontrolled mixtures of insertion and deletion mutations termed "indels," base editing generates precise nucleotide changes with few undesired byproducts.
"In our comparison, we found unanticipated problems with conventional Cas9 nucleases," Weiss said. "We were somewhat surprised that not every Cas9 insertion or deletion raised fetal hemoglobin to the same extent, indicating the potential for heterogeneous biological outcomes with that technology." The group found that individual red blood cells derived from hematopoietic stem cells treated with the same Cas9 produce a more variable amount of fetal hemoglobin compared to cells treated with base editing. Thus, base editing produced more potent, reliable, and consistent outcomes, which are desirable therapeutic properties.
Though base editing performed well, researchers have yet to determine its safety in patients. Notably, base editing may have some risks not presented by Cas9; for example, some early base editors can cause undesired changes in genomic DNA or RNA at off-target sites. The group showed that these changes are relatively small and not predicted to be harmful, but deeper studies are warranted to evaluate these risks fully.
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