Heterozygous vs. Homozygous: Definitions and Differences

Role Of Iron In Pregnant Women: Doctor Explains Its Link To Thalassemia Prevention

Doctor Speaks: What Is The Role Of Iron In Pregnant Women In Prevention Of Thalassemia? The prevalence of iron deficiency in pregnant women is among the highest in the world, which causes Thalassemia. It is crucial address the burden of this disease and providing the right treatment.

India is known as the Thalassemia capital of the world with a huge burden of an estimated 42 million thalassemia carriers and approximately 100,000 patients with a thalassemia syndrome. India has the most important number of children with Thalassemia major about 1 to 1.5 lakhs and almost 42 million carriers of (beta) thalassemia trait. In a rare genetic blood disorder, thalassemia, the body makes an abnormal form of haemoglobin. The condition also leads to excessive destruction of red blood cells causing anaemia. Thus, it is crucial to address the burden of the disease and providing the right treatment is essential.

Dr Rahul Bhargava, The Principal Director & Chief BMT at Fortis Memorial Research Institute, Gurugram speaks about preventing thalassemia in pregnant women and the role of iron content in it.

Why Is Iron Deficiency Common Among Pregnant Women?

The prevalence of iron deficiency in pregnant women is among the highest in the world, which causes Thalassemia. It is due to a defect in the rate of globin chain synthesis, leading to ineffective blood cell formation and reduced life span of red blood cells. The disease may range from minimal suppression of synthesis of affected genes or complete absence. The most prevalent single-gene condition in India is beta-thalassemia and each year, over 9,000 babies are born with the disease. As per a report released by the National Health Mission (NHM), in 2016, India has the largest number of children with Thalassemia major in the world about 1 to 1.5 lakhs and almost 42 million carriers of (beta) thalassemia trait.

What Happens When An Expectant Mother Is Deficient In Iron?

During pregnancy, the demand for iron increases to support the growth and development of the fetus. If a pregnant woman is iron deficient, she may experience anemia, fatigue, and weakness. The baby may also be born with low birth weight or premature birth. Iron is the new gold, especially for pregnant women. The deficiency of iron can make thalassemia worse. This is because iron is needed to produce hemoglobin. If a person with thalassemia is also iron deficient, they may have more severe symptoms of the disease.

How Much Iron Should A Mother Consume And How?

It is very much crucial for pregnant women to consume 27 milligrams of iron per day. This can be obtained through a healthy diet, which includes iron-rich foods such as meat, poultry, fish, beans, and leafy green vegetables. Pregnant women may also need to take an iron supplement. Women with thalassemia should also consume enough iron. The specific amount of iron that is needed will depend on the severity of the disease. They may need to take an iron supplement in addition to getting iron from their diet. Thus, women should start consuming iron as they get married, so that when they conceive, they give birth to a healthy baby. With proper intake of iron, pregnant women can help in prevention of Thalassemia.

Reactivating Silenced Fetal Hemoglobin Genes Could Counter Sickle Cell–related Diseases

Researchers from multiple institutions in China have found a way to use gene editing to reactivate dormant fetal oxygen-transporting proteins in adult blood cells to potentially reverse a wide range of blood disorders.

In a paper, "Base editing of the HBG promoter induces potent fetal hemoglobin expression with no detectable off-target mutations in human HSCs," published in Cell Stem Cell, the team compares gene editing techniques while formulating a method that could have important clinical applications.

Fetal gamma (γ) globin is normally replaced by adult (β) hemoglobin during development. In an odd quirk of evolution, only humans and a few types of monkeys are known to switch from γ to β gene expression.

The genes producing the fetal hemoglobin become silenced and dormant after the genetic switch by repressors such as BCL11A and ZBTB7A, whose binding motifs have been identified as targets for reactivation.

β-hemoglobinopathies, including β-thalassemia and sickle cell disease, result from mutations in the HBB gene, leading to impaired β-globin production and resulting in anemia, impaired oxygen delivery to tissues and possible multi-organ tissue damage.

The researchers experimentally discovered that reactivating γ-globin expression could be developed into a universal therapeutic strategy for these conditions.

Six regulatory motifs (BCL11A enhancer and HBG1/2 promoter regions) were targeted using a recently developed cytosine base editor—transformer base editor (tBE). The team compared tBE with other base editors and Cas9 nuclease for efficiency and off-target effects.

In the study, tBE exhibited comparable or higher editing efficiency than other editors across the targeted motifs. Comprehensive analysis revealed no detectable off-target mutations in tBE-edited cells, indicating the potential of tBE as a safer and more potent treatment strategy for β-hemoglobinopathies.

Experiments conducted with patient-derived cells highlighted that disrupting the BCL11A binding sites within the HBG1/2 promoters led to the highest levels of γ-globin expression. Xenotransplantation in mice showed persistent editing in HSCs and their progenies, maintaining engraftment potential and differentiation ability.

The increased γ-globin expression observed due to tBE-mediated editing signifies a promising therapeutic avenue for β-hemoglobinopathies.

While editing methods and not direct clinical outcomes were the focus of the study, the substantial enhancement in γ-globin expression levels strongly suggests potential clinical benefits, including symptom alleviation and improved disease management for individuals affected by β-hemoglobinopathies.

More information: Wenyan Han et al, Base editing of the HBG promoter induces potent fetal hemoglobin expression with no detectable off-target mutations in human HSCs, Cell Stem Cell (2023). DOI: 10.1016/j.Stem.2023.10.007

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Vertex/CRISPR Win FDA Approval For Gene Therapy Casgevy

The US Food and Drug Administration (FDA) has approved Vertex's CRISPR/Cas9 gene-edited therapy Casgevy (exagamglogene autotemcel [exa-cel]), a few weeks after regulators in the UK.

In November, the UK's Medicines and Healthcare products Regulatory Agency (MHRA) granted marketing authorization for Vertex and CRISPR Therapeutics' sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT) treatment Casgevy.

Now, the gene-edited therapy has won authorization from the US regulatory body and Casgevy has become the first FDA-approved SCD treatment to use CRISPR/Cas9 technology. The organization said this has signalled "an innovative advancement in the field of gene therapy."

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Last month, Vertex Pharmaceuticals and CRISPR Therapeutics selected UK-based contract development and manufacturing organization (CDMO) RolsinCT – a spinout from the Roslin Institute –  to commercially manufacture the world's first CRISPR-based gene-edited therapy.

RoslinCT announced it will also be the manufacturing partner of choice following the FDA approval.

The CDMO will use its MHRA commercially approved facility in Edinburgh, Scotland to manufacture Casgevy and the site has already produced over 100 batches of the therapy.

Vertex and CRISPR Therapeutics have collaborated for a number of years, but first partnered on exa-cel in April 2021, with Vertex paying CRISPR $900 million upfront for the commercialization rights. Exa-cel is an autologous, ex vivo CRISPR/Cas9 (a Nobel Prize winning technology) gene-edited therapy in which a patient's hematopoietic stem cells are edited to produce high levels of fetal hemoglobin (HbF; hemoglobin F) in red blood cells.

HbF is a form of the oxygen-carrying hemoglobin that is naturally present at birth, which then switches to the adult form of hemoglobin.

"Sickle cell disease is a rare, debilitating and life-threatening blood disorder with significant unmet need, and we are excited to advance the field especially for individuals whose lives have been severely disrupted by the disease by approving two cell-based gene therapies today," said Nicole Verdun, director of the office of therapeutic products within the FDA's Center for Biologics Evaluation and Research (CBER).

"Gene therapy holds the promise of delivering more targeted and effective treatments, especially for individuals with rare diseases where the current treatment options are limited."

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