Management of thalassemia

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Treatment of the inherited blood disorder thalassemia depends upon the level of severity. For mild forms of the condition, advice and counseling are often all that are necessary. For more severe forms, treatment may consist in blood transfusion; chelation therapy to reverse iron overload, using drugs such as deferoxamine, deferiprone, or deferasirox; medication with the antioxidant indicaxanthin to prevent the breakdown of hemoglobin; or a bone marrow transplant using material from a compatible donor, or from the patient's mother. Removal of the spleen (splenectomy) could theoretically help to reduce the need for blood transfusions in people with thalassaemia major or intermedia but there is currently no reliable evidence from clinical trials about its effects. [1] Population screening has had some success as a preventive measure.[ citation needed ]

Contents

Levels of severity

Medication

Patients with thalassemia gradually accumulate high levels of iron (Fe) in their bodies. This build-up of iron may be due to the disease itself, from irregular hemoglobin not properly incorporating adequate iron into its structure, or it may be due to the many blood transfusions received by the patient. This overload of iron brings with it many biochemical complications.[ citation needed ]

Two key substances involved in iron transport and storage in the body are ferritin and transferrin. Ferritin is a protein present within cells that binds to Fe (II) and stores it as Fe (III), releasing it into the blood whenever required. Transferrin is an iron-binding protein present in blood plasma; transferrin acts as a transporter, carrying iron through blood and providing cells with the metal through endocytosis. Transferrin is highly specific to iron (III), and binds to it with an equilibrium constant of 1023 M−1 at a pH of 7.4. [5]

Thalassemia results in nontransferrin-bound iron being available in blood as all the transferrin becomes fully saturated. This free iron is toxic to the body since it catalyzes reactions that generate free hydroxyl radicals. [6] These radicals may induce lipid peroxidation of organelles like lysosomes, mitochondria, and sarcoplasmic membranes. The resulting lipid peroxides may interact with other molecules to form cross links, and thus either cause these compounds to perform their functions poorly, or render them non-functional altogether. [6] This iron overload may be treated with chelation therapy. Deferoxamine, deferiprone and deferasirox are the three most widely used iron-chelating agents.[ citation needed ]

Deferoxamine

Structure and coordination

The drug deferoxamine, also known as desferoxamine B and DFO-B, is a trihydroxamic acid that is produced by the actinobacterium Streptomyces pilosus . It binds iron, decreasing the toxic reactions catalysed by the unbound metal, and it also decreases the uptake of iron by tissues. Deferoxamine achieves this by acting as a hexadentate iron-chelating ligand: it binds to all six coordination sites on nontransferrin-bound iron, effectively deactivating it. [7] Deferoxamine is mostly specific to ferric iron (Fe3+) and coordinates to Fe3+ using the oxygen atoms on its multiplehydroxyl and carbonyl groups, forming a structure called ferrioxamine. This drug-iron complex is mostly excreted by the kidneys as it is water-soluble. [8] Approximately one-third of ferrioxamine could also be excreted through the feces in bile. [6]

Administration and action

Deferoxamine is administered via intravenous, intramuscular, or subcutaneous injections. Oral administration is not possible as deferoxamine is rapidly metabolized by enzymes and is poorly absorbed from the gastrointestinal tract. The required parenteral administration represents one of deferoxamine's downfalls as it is harder for patients to follow up with their therapy due to the financial and emotional burdens experienced. [9] Deferoxamine was proven to cure many clinical complications and diseases that result from iron overload. It beneficially affects cardiac disease, such as myocardial disease which occurs as a result of iron accumulation in the heart. [10] Deferoxamine was also shown to improve liver function by arresting the development of hepatic fibrosis which occurs as a result of iron accumulation in the liver. [11] Deferoxamine also has positive effects on endocrine function and growth. Endocrine abnormalities in thalassemic patients involve the overloaded iron interfering with the production of insulin-like growth factor (IGF-1), as well as stimulating hypogonadism, both of which cause poor pubertal growth. A study showed that 90% of patients who were regularly treated with deferoxamine since childhood had normal pubertal growth, which fell to 38% for patients treated only with low doses of deferoxamine since their teens. [6] Another endocrine abnormality that thalassemic patients face is diabetes mellitus, which results from iron overload in the pancreas impairing insulin secretion. Studies have shown that patients who were regularly treated with deferoxamine have a reduced risk of developing diabetes mellitus. [12]

Side effects

Deferoxamine could lead to toxic side effects if doses greater than 50 mg/kg body weight are administered. These side effects may include auditory and ocular abnormalities, pulmonary toxicity, sensorimotor neurotoxicity, as well as changes in renal function. [6] Another toxic effect of deferoxamine mostly observed in children is the failure of linear growth. This reduction in height may occur as a result of deferoxamine chelating metals other than iron which are required for normal growth. Deferoxamine has an affinity constant (Ka) of 1031 for Fe3+, 1014 for Cu2+ and 1010 for Zn2+, and so may coordinate to zinc and copper when little iron is available for chelation. Zinc is needed for the proper functioning of various metalloenzymes involved in bone formation. Zinc chelation may cause zinc deficiency in the body, which can thus lead to a reduced growth rate, reduced collagen formation and defective bone mineralization. Similarly, copper functions as an enzyme cofactor in bone formation. Copper chelation may result in copper deficiency as well, leading to metaphyseal cupping and osteoporosis. For example, abnormal collagen is formed when copper is deficient as the enzyme lysyl oxidase, which uses copper as a cofactor and catalyzes the oxidative deamination step that is important for cross-linking of collagen, cannot function properly. Studies have shown that even though the blood serum of patients receiving deferoxamine was not deficient in copper and zinc, deficiencies of the metals in the metaphyseal matrix were observed.[ citation needed ]

The toxic effect of deferoxamine on linear growth could also be due to excess deferoxamine accumulating in tissues and interfering with iron-dependent enzymes which are involved in the post-translational modification of collagen. [13]

Patients who receive vitamin C supplements have shown improved iron excretion by deferoxamine. This occurs due to the expansion of the iron pool brought about by vitamin C, which deferoxamine subsequently has access to. However, vitamin C supplementation could also worsen iron toxicity by promoting the formation of free radicals. Therefore, only 100 mg of vitamin C should be taken 30 minutes to one hour after deferoxamine administration. [14]

It has also been proven that combined treatment with deferoxamine and deferiprone leads to an increased efficiency in chelation and doubles iron excretion. [15]

Deferiprone

Structure and coordination

Deferiprone Deferiprone.svg
Deferiprone

Deferiprone (DFP) is a bidentate iron-chelator. Three molecules of the drug therefore coordinate to one iron atom, forming an orthorhombic structure. [16]

DFP is synthetically made and is highly selective to Fe(III). [16] [17] Physical properties that allow this compound to be effective as a drug include its water solubility, low molecular weight (139 Da), neutral charge, and lipophilicity. [16] These physio-chemical properties allow facile crossing of cell membranes throughout the body, including the blood–brain barrier, facilitating removal of excess iron from within organs. [16] [18]

Although the mechanism for the removal of iron by DFP is not well understood, however, a study by Viroj Wiwanitkit in 2006 proposed a possible mechanism: the coordination to the iron was thought to occur through the cleavage of either a C-C bond or a C-O bond in the drug. Wiwanitkit concluded that the mechanism goes through the cleavage of the C-C bond because this bond requires less energy to be cleaved. The total energy for the cleavage was found to be negative, suggesting spontaneity and thermodynamic favourability of the cleavage. The resulting structure of the product also resembled the observed tertiary structure of the drug-iron complex. [19]

Administration and action

Deferiprone is an iron chelator that is orally active, its administration thus being much easier than that for deferoxamine. [16] Plasma levels for the iron-drug complex climax after one hour of intake and the drug has a half-life of 160 minutes. Most of the iron-drug complex is therefore excreted within three to four hours following administration, the excretion occurring mostly in urine (90%). [16]

When comparing deferiprone to deferoxamine, they both bind iron with similar efficiency. However, drugs with different properties are able to access different iron pools. DFP is smaller than deferoxamine and can thus enter cells more easily. Also, at the pH of blood, the affinity of DFP for iron is concentration dependent: at low DFP concentrations, the iron-drug complex breaks down and the iron is donated to another competing ligand. This property accounts for the observed tendency of DFP to redistribute iron in the body. For the same reason, DFP can 'shuttle' intracellular iron out to the plasma, and transfer the iron to deferoxamine which goes on to expel it from the body. [17]

DFP was also found to be significantly more effective than deferoxamine in treating myocardial siderosis in patients with thalassemia major: [16] DFP is thought to improve the function of mitochondria in the heart by accessing and redistributing labile iron in cardiac cells.[ citation needed ]

Thalassemia patients may also be faced with potential oxidative damage to brain cells as the brain has high oxygen demands, but contains relatively low levels of antioxidant agents for protection against oxidation. The presence of excess iron in the brain may lead to higher concentrations of free radicals. Hexadentate chelators, like deferoxamine, are large molecules, and are thus unlikely to be able to cross the blood–brain barrier to chelate the excess iron. DFP, however, can do so and forms a soluble, neutral iron-drug complex that can cross cell membranes by non-facilitated diffusion. Attaching the drug to sugars may additionally enhance the penetration of the blood–brain barrier, as the brain uses facilitated transport for its relatively high levels of sugar intake. [20]

Side effects

DFP can be subjected to glucuronidation in the liver, which may expel as much as 85% of the drug from the body before it has had a chance to chelate iron. DFP also has a well-known safety profile, with agranulocytosis being the most serious side effect. [16] While agranulocytosis has been reported in less than 2% of patients treated, it is potentially life-threatening and thus requires close monitoring of the white blood cell count. [18] Less serious side effects include gastrointestinal symptoms, which were found in 33% of patients in the first year of administration, but fell to 3% in following years; arthralgia; and zinc deficiency, with the latter being a problem especially for individuals with diabetes. [16]

Deferasirox

Structure and coordination

Deferasirox Deferasirox.svg
Deferasirox

Deferasirox is an N-substituted bis-hydroxyphenyl-triazole. It is capable of removing iron from the blood through the coordination of two molecules of the deferasirox to a single iron ion, which forms the iron chelate (Fe-[deferasirox]2). [21] Each molecule of the tridentate chelator deferasirox binds to the iron at three sites, using one nitrogen atom and two oxygen atoms. This results in a stable octahedral geometry around the iron centre. The ability of deferasirox to remove iron stems directly from its relatively small size, which is what allows it to access the iron contained within the blood and inside tissues. Also, an important feature of deferasirox is that it has been shown to be highly selective for iron in the +3 oxidation state, and use of the drug does not lead to a significant decrease in the levels of other important metals in the body. [22]

Administration and action

Deferasirox-Iron (III) complex Deferasirox-iron(III) complex.png
Deferasirox-Iron (III) complex

Deferasirox is most commonly marketed under the brand name Exjade. It has one key advantage over desferoxamine in that it can be taken orally in pill form, and so does not require intravenous or subcutaneous administration. With a terminal elimination half life of 8–16 hours, the deferasirox pill can be taken just once each day. A once-daily dose of 20 mg/kg of body weight has been found to be sufficient for most patients for the maintenance of liver iron concentration (LIC) levels, which are usually measured as mg of iron per g of liver tissue. Larger doses may be required for some patients in order to reduce LIC levels. [23] The ability of deferasirox to effectively reduce LIC levels has been well documented. One study demonstrated that after 4–5 years of deferasirox treatment the mean LIC levels of patients decreased from 17.4 ± 10.5 to 9.6 ± 8.0 mg Fe/g. This study showed that long-term treatment did result in a sustainable reduction in the iron burden faced by patients receiving blood transfusions for thalassemia. [24] An additional benefit of the use of deferasirox instead of desferoxamine is that, unlike desferoxamine, early studies have indicated that deferasirox does not have a significant impact on the growth and development of pediatric thalassemia patients. In a study by Cappellini et al. it was shown that children receiving the treatment displayed continual near-normal growth and development over a 5-year study period. [24]

Side effects

Deferasirox can, however, have a wide variety of side effects. These may include headaches, nausea, vomiting, and joint pains. [25] Some evidence has been shown of a link to gastrointestinal disorders experienced by some people who have received the treatment. [24]

Indicaxanthin

Structure

Indicaxanthin, the yellow pigment of the cactus pear fruit Indicaxanthin.svg
Indicaxanthin, the yellow pigment of the cactus pear fruit

Indicaxanthin is a pigment derived from the cactus pear fruit and can be used as an antioxidant. Dietary indicaxanthin has been shown to have protective effects on RBCs in people with beta thalassemia. [26] It has a structure similar to that of amino acids, and is amphiphilic: it is able to bind to cell membranes through charge-related interactions with polar head groups of membrane constituents, as well through adsorption to the lipid aggregates. Upon ex vivo introduction to thalassemic blood, indicaxanthin was shown to accumulate within RBCs. [26]

Function

Hb undergoes the following oxidation reaction during normal controlled breakdown of RBCs:[ citation needed ]

Hb → Oxy-Hb → Met-Hb → [Perferryl-Hb] → Oxoferryl → further oxidation steps

This reaction is experienced by thalassemic RBCs to a greater extent because, not only are there more oxidative radicals in thalassemic blood, but thalassemic RBCs also have limited antioxidant defense. Indicaxanthin is able to reduce the perferryl-Hb, a reactive intermediate, back to met-Hb. The overall effect of this step is that Hb degradation is prevented, which helps prevent accelerated breakdown of RBCs. [26]

In addition, indicaxathin has been shown to reduce oxidative damage in cells and tissues and does so by binding to radicals. The mechanism of its function, however, is still unknown. [26]

Indicaxanthin has high bioavailability and minimal side effects, like vomiting or diarrhea.[ citation needed ]

Carrier detection

In 2008, in Spain, a baby was selectively implanted in order to be a cure for his brother's thalassemia. The child was born from an embryo screened to be free of the disease before implantation with In vitro fertilization. The baby's supply of immunologically compatible cord blood was saved for transplantation to his brother. The transplantation was considered successful. [29] In 2009, a group of doctors and specialists in Chennai and Coimbatore registered the successful treatment of thalassemia in a child using a sibling's umbilical cord blood. [30]

Bone marrow transplant

It is possible to be cured, by a bone marrow transplantation (BMT) from compatible donor. In low-risk young people, the thalassemia-free survival rate is 87%; the mortality risk is 3%. [31] The drawback is that this method requires an HLA-matched compatible donor.[ citation needed ]

If the person does not have an HLA-matched compatible donor, there is another method called bone marrow transplantation from haploidentical mother to child (mismatched donor), in which the donor is the mother. The results are these: thalassemia-free survival rate 70%, rejection 23%, and mortality 7%. The best results are with very young people. [32]

Gene therapy

Betibeglogene autotemcel, sold under the brand name Zynteglo, is a gene therapy for the treatment for beta thalassemia. [33] It was approved for medical use in the European Union in May 2019, [34] and in the United States in August 2022. [35] [36] Betibeglogene autotemcel is indicated for the treatment of people twelve years and older with transfusion-dependent beta thalassemia who do not have a β0/β0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate but a human leukocyte antigen (HLA)-matched related HSC donor is not available.

The procedure involves collecting hematopoietic stem cells (HSCs) from the affected person's blood. The HSCs then have a beta-globin gene added using a lentiviral vector. After destroying the affected person's bone marrow with a dose of chemotherapy (a myeloablative conditioning regimen), the altered HSCs are infused back into the affected person where they become engrafted in the bone marrow where they proliferate. This potentially results in a progressive increase in hemoglobin A2 synthesis in all subsequent developing red blood cells, with resultant resolution of the anemia. [37]

HbF induction

Exagamglogene autotemcel, sold under the brand name Casgevy, is a gene therapy for the treatment of transfusion-dependent beta thalassemia. It was developed by Vertex Pharmaceuticals and CRISPR Therapeutics. [38]

The treatment was approved in the United Kingdom for the treatment of transfusion-dependent beta thalassemia in November 2023 [39] [40] [41] and in the United States in January 2024. [42] [43] [44]

Exagamglogene autotemcel is the first cell-based gene therapy treatment utilizing CRISPR/Cas9 gene editing technology to be approved by the US Food and Drug Administration (FDA). [42]

The gene therapy is made from the recipient's own blood stem cells, which are modified, and are given back as a one-time, single-dose infusion as part of a hematopoietic stem cell transplant. Prior to treatment, the recipient's own stem cells are collected, and then the recipient must undergo myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow so they can be replaced with the modified cells in exagamglogene autotemcel. The modified blood stem cells are transplanted back into the recipient where they engraft within the bone marrow and increase the production of fetal hemoglobin (HbF), a type of hemoglobin that facilitates oxygen delivery.

Related Research Articles

<span class="mw-page-title-main">Hemoglobinopathy</span> Any of various genetic disorders of blood

Hemoglobinopathy is the medical term for a group of inherited blood disorders involving the hemoglobin, the protein of red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits.

<span class="mw-page-title-main">Myelodysplastic syndrome</span> Diverse collection of blood-related cancers

A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may include fatigue, shortness of breath, bleeding disorders, anemia, or frequent infections. Some types may develop into acute myeloid leukemia.

<span class="mw-page-title-main">Thalassemia</span> Family of inherited blood disorders

Thalassemias are inherited blood disorders that result in abnormal hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe. Often there is mild to severe anemia as thalassemia can affect the production of red blood cells and also affect how long the red blood cells live. Symptoms of anemia include feeling tired and having pale skin. Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine. Slow growth may occur in children. Symptoms and presentations of thalassemia can change over time. Older terms included Cooley's anemia and Mediterranean anemia for beta-thalassemia. These have been superseded by the terms Transfusion-Dependent Thalassemia (TDT) and non-Transfusion-Dependent Thalassemia (NTDT). Patients with TDT require regular transfusions, typically every two to five weeks. TDTs include Beta-thalassemia major, nondeletional HbH disease, survived Hb Bart's disease, and severe HbE/beta-thalassemia.

<span class="mw-page-title-main">Iron overload</span> Human disease

Iron overload is the abnormal and increased accumulation of total iron in the body, leading to organ damage. The primary mechanism of organ damage is oxidative stress, as elevated intracellular iron levels increase free radical formation via the Fenton reaction. Iron overload is often primary but may also be secondary to repeated blood transfusions. Iron deposition most commonly occurs in the liver, pancreas, skin, heart, and joints. People with iron overload classically present with the triad of liver cirrhosis, secondary diabetes mellitus, and bronze skin. However, due to earlier detection nowadays, symptoms are often limited to general chronic malaise, arthralgia, and hepatomegaly.

<span class="mw-page-title-main">Microcytic anemia</span> Medical condition

Microcytic anaemia is any of several types of anemia characterized by smaller than normal red blood cells. The normal mean corpuscular volume is approximately 80–100 fL. When the MCV is <80 fL, the red cells are described as microcytic and when >100 fL, macrocytic. The MCV is the average red blood cell size.

Deferoxamine (DFOA), also known as desferrioxamine and sold under the brand name Desferal, is a medication that binds iron and aluminium. It is specifically used in iron overdose, hemochromatosis either due to multiple blood transfusions or an underlying genetic condition, and aluminium toxicity in people on dialysis. It is used by injection into a muscle, vein, or under the skin.

<span class="mw-page-title-main">Alpha-thalassemia</span> Thalassemia involving the genes HBA1and HBA2 hemoglobin genes

Alpha-thalassemia is a form of thalassemia involving the genes HBA1 and HBA2. Thalassemias are a group of inherited blood conditions which result in the impaired production of hemoglobin, the molecule that carries oxygen in the blood. Normal hemoglobin consists of two alpha chains and two beta chains; in alpha-thalassemia, there is a quantitative decrease in the amount of alpha chains, resulting in fewer normal hemoglobin molecules. Furthermore, alpha-thalassemia leads to the production of unstable beta globin molecules which cause increased red blood cell destruction. The degree of impairment is based on which clinical phenotype is present.

<span class="mw-page-title-main">Deferasirox</span> Oral iron chelator

Deferasirox, sold under the brand name Exjade among others, is an oral iron chelator. Its main use is to reduce chronic iron overload in patients who are receiving long-term blood transfusions for conditions such as beta-thalassemia and other chronic anemias. It is the first oral medication approved in the United States for this purpose.

<span class="mw-page-title-main">Beta thalassemia</span> Blood disorder

Beta thalassemias are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. Global annual incidence is estimated at one in 100,000. Beta thalassemias occur due to malfunctions in the hemoglobin subunit beta or HBB. The severity of the disease depends on the nature of the mutation.

Nancy Fern Olivieri is a prominent Toronto haematologist and researcher with an interest in the treatment of haemoglobinopathies. She is best known for a protracted struggle with the Hospital for Sick Children and the pharmaceutical company Apotex about the drug deferiprone.

<span class="mw-page-title-main">Deferiprone</span> Iron chelator

Deferiprone, sold under the brand name Ferriprox among others, is a medication that chelates iron and is used to treat iron overload in thalassaemia major. It was first approved and indicated for use in treating thalassaemia major in 1994 and had been licensed for use in the European Union for many years while awaiting approval in Canada and in the United States. On 14 October 2011, it was approved for use in the US under the FDA's accelerated approval program.

Transfusional hemosiderosis is the accumulation of iron in the body due to frequent blood transfusions. Iron accumulates in the liver and heart, but also endocrine organs. Frequent blood transfusions may be given to many patients, such as those with thalassemia, sickle cell disease, leukemia, aplastic anemia, or myelodysplastic syndrome, among others. It is diagnosed with a blood transferrin test and a liver biopsy. It is treated with venipuncture, erythrocytapheresis, and iron chelation therapy.

<span class="mw-page-title-main">Hemosiderosis</span> Iron metabolism disease

Hemosiderosis is a form of iron overload disorder resulting in the accumulation of hemosiderin.

Congenital hemolytic anemia (CHA) is a diverse group of rare hereditary conditions marked by decreased life expectancy and premature removal of erythrocytes from blood flow. Defects in erythrocyte membrane proteins and red cell enzyme metabolism, as well as changes at the level of erythrocyte precursors, lead to impaired bone marrow erythropoiesis. CHA is distinguished by variable anemia, chronic extravascular hemolysis, decreased erythrocyte life span, splenomegaly, jaundice, biliary lithiasis, and iron overload. Immune-mediated mechanisms may play a role in the pathogenesis of these uncommon diseases, despite the paucity of data regarding the immune system's involvement in CHAs.

<span class="mw-page-title-main">Congenital dyserythropoietic anemia</span> Red blood cell disorder

Congenital dyserythropoietic anemia (CDA) is a rare blood disorder, similar to the thalassemias. CDA is one of many types of anemia, characterized by ineffective erythropoiesis, and resulting from a decrease in the number of red blood cells (RBCs) in the body and a less than normal quantity of hemoglobin in the blood. CDA may be transmitted by both parents autosomal recessively or dominantly.

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<span class="mw-page-title-main">Transfusion-dependent anemia</span> Anemia which requires continuous blood transfusion

Transfusion-dependent anemia is a form of anemia characterized by the need for continuous blood transfusion. It is a condition that results from various diseases, and is associated with decreased survival rates. Regular transfusion is required to reduce the symptoms of anemia by increasing functional red blood cells and hemoglobin count. Symptoms may vary based on the severity of the condition and the most common symptom is fatigue.

<span class="mw-page-title-main">CRISPR Therapeutics</span> Swiss-American biotechnology company

CRISPR Therapeutics AG is a Swiss–American biotechnology company headquartered in Zug, Switzerland. It was one of the first companies formed to utilize the CRISPR gene editing platform to develop medicines for the treatment of various rare and common diseases. The company has approximately 500 employees and has offices in Zug, Switzerland, Boston, Massachusetts, San Francisco, California and London, United Kingdom. Its manufacturing facility in Framingham, Massachusetts won the Facilities of the Year Award (FOYA) award in 2022. The company’s lead program, exagamglogene autotemcel, or exa-cel, was granted regulatory approval by the US Food and Drug Administration (FDA) in December 2023.

Exagamglogene autotemcel, sold under the brand name Casgevy, is a gene therapy used for the treatment of sickle cell disease and transfusion-dependent beta thalassemia. It was developed by Vertex Pharmaceuticals and CRISPR Therapeutics.

Lovotibeglogene autotemcel, sold under the brand name Lyfgenia, is a lentiviral gene therapy used for the treatment of sickle cell disease.

References

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  17. 1 2 Olivieri, Nancy F.; Brittenham, Gary M. (1997). "Iron-Chelating Therapy and the Treatment of Thalassemia". Blood. 89 (3): 739–61. doi: 10.1182/blood.V89.3.739 . PMID   9028304.
  18. 1 2 Galanello, R.; Campus, S. (2009). "Deferiprone Chelation Therapy for Thalassemia Major". Acta Haematologica. 122 (2–3): 155–64. doi:10.1159/000243800. PMID   19907153. S2CID   31161087.
  19. ↑ Wiwanitkit, Viroj (2006). "Quantum Chemical Analysis of the Deferiprone-Iron Binding Reaction". International Journal of Nanomedicine. 1 (1): 111–3. doi: 10.2147/nano.2006.1.1.111 . PMC   2426763 . PMID   17722270.
  20. ↑ Heli, Hossein; Mirtorabi, Siamak; Karimian, Khashayar (2011). "Advances in iron chelation: An update". Expert Opinion on Therapeutic Patents. 21 (6): 819–56. doi:10.1517/13543776.2011.569493. PMID   21449664. S2CID   41639654.
  21. ↑ Cappellini, M. D.; Cohen, A; Piga, A; Bejaoui, M; Perrotta, S; Agaoglu, L; Aydinok, Y; Kattamis, A; et al. (2006). "A phase 3 study of deferasirox (ICL670), a once-daily oral iron chelator, in patients with beta-thalassemia". Blood. 107 (9): 3455–62. doi: 10.1182/blood-2005-08-3430 . PMID   16352812.
  22. ↑ R Galanello; Piga, A; Forni, GL; Bertrand, Y; Foschini, ML; Bordone, E; Leoni, G; Lavagetto, A; et al. (2006-01-01). "Phase II clinical evaluation of deferasirox, a once-daily oral chelating agent, in pediatric patients with β-thalassemia major". Haematologica. 91 (10): 1343–51. PMID   17018383.
  23. ↑ Nisbet-Brown, Eric; Olivieri, Nancy F; Giardina, Patricia J; Grady, Robert W; Neufeld, Ellis J; Séchaud, Romain; Krebs-Brown, Axel J; Anderson, Judith R; et al. (2003). "Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: A randomised, double-blind, placebo-controlled, dose-escalation trial". The Lancet. 361 (9369): 1597–602. doi:10.1016/S0140-6736(03)13309-0. PMID   12747879. S2CID   12396225.
  24. 1 2 3 Cappellini, M. D.; Bejaoui, M.; Agaoglu, L.; Canatan, D.; Capra, M.; Cohen, A.; Drelichman, G.; Economou, M.; et al. (2011). "Iron chelation with deferasirox in adult and pediatric patients with thalassemia major: Efficacy and safety during 5 years' follow-up". Blood. 118 (4): 884–93. doi: 10.1182/blood-2010-11-316646 . PMID   21628399.
  25. ↑ "How Are Thalassemias Treated?". National Heat, Lung and Blood institute. Retrieved March 2, 2013.
  26. 1 2 3 4 Tesoriere, L.; Allegra, M.; Butera, D.; Gentile, C.; Livrea, M. A. (2006). "Cytoprotective effects of the antioxidant phytochemical indicaxanthin in β-thalassemia red blood cells". Free Radical Research. 40 (7): 753–61. doi:10.1080/10715760600554228. PMID   16984002. S2CID   25837703.
  27. ↑ Leung TN, Lau TK, Chung TKh; Lau; Chung (April 2005). "Thalassaemia screening in pregnancy". Current Opinion in Obstetrics and Gynecology. 17 (2): 129–34. doi:10.1097/01.gco.0000162180.22984.a3. PMID   15758603. S2CID   41877258.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  28. ↑ Samavat A, Modell B; Modell (November 2004). "Iranian national thalassaemia screening programme". BMJ (Clinical Research Ed.). 329 (7475): 1134–7. doi:10.1136/bmj.329.7475.1134. PMC   527686 . PMID   15539666.
  29. ↑ Spanish Baby Engineered To Cure Brother
  30. ↑ His sister's keeper: Brother's blood is boon of life, Times of India, 17 September 2009
  31. ↑ Sabloff, M; Chandy, M; Wang, Z; Logan, BR; Ghavamzadeh, A; Li, CK; Irfan, SM; Bredeson, CN; et al. (2011). "HLA-matched sibling bone marrow transplantation for β-thalassemia major". Blood. 117 (5): 1745–50. doi:10.1182/blood-2010-09-306829. PMC   3056598 . PMID   21119108.
  32. ↑ Sodani, P; Isgrò, A; Gaziev, J; Paciaroni, K; Marziali, M; Simone, MD; Roveda, A; De Angelis, G; et al. (2011). "T cell-depleted hla-haploidentical stem cell transplantation in thalassemia young patients". Pediatric Reports. 3 (Suppl 2): e13. doi:10.4081/pr.2011.s2.e13. PMC   3206538 . PMID   22053275.
  33. ↑ Negre, Olivier; Eggimann, Anne-Virginie; Beuzard, Yves; Ribeil, Jean-Antoine; Bourget, Philippe; Borwornpinyo, Suparerk; Hongeng, Suradej; Hacein-Bey, Salima; Cavazzana, Marina; Leboulch, Philippe; Payen, Emmanuel (February 2016). "Gene Therapy of the β-Hemoglobinopathies by Lentiviral Transfer of the β – Gene". Human Gene Therapy. 27 (2): 148–165. doi:10.1089/hum.2016.007. PMC   4779296 . PMID   26886832.
  34. ↑ "Zynteglo EPAR". European Medicines Agency (EMA). 25 March 2019. Archived from the original on 16 August 2019. Retrieved 16 August 2019. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  35. ↑ "Zynteglo". U.S. Food and Drug Administration. 17 August 2022. Archived from the original on 26 August 2022. Retrieved 26 August 2022.
  36. ↑ "FDA Approves First Cell-Based Gene Therapy to Treat Adult and Pediatric Patients with Beta-thalassemia Who Require Regular Blood Transfusions". U.S. Food and Drug Administration (FDA) (Press release). 17 August 2022. Archived from the original on 21 August 2022. Retrieved 20 August 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  37. ↑ Biffi, A (19 April 2018). "Gene Therapy as a Curative Option for β-Thalassemia". The New England Journal of Medicine. 378 (16): 1551–1552. doi:10.1056/NEJMe1802169. PMID   29669229.
  38. ↑ Stein R (31 October 2023). "FDA advisers see no roadblocks for gene-editing treatment for sickle cell disease". NPR. Archived from the original on 4 December 2023. Retrieved 4 December 2023.
  39. ↑ "MHRA authorises world-first gene therapy that aims to cure sickle-cell disease and transfusion-dependent β-thalassemia". Medicines and Healthcare products Regulatory Agency (MHRA) (Press release). 16 November 2023. Archived from the original on 25 November 2023. Retrieved 8 December 2023.
  40. ↑ Sheridan C (November 2023). "The world's first CRISPR therapy is approved: who will receive it?". Nature Biotechnology. 42 (1): 3–4. doi:10.1038/d41587-023-00016-6. PMID   37989785. S2CID   265350318. Archived from the original on 4 December 2023. Retrieved 4 December 2023.
  41. ↑ "Vertex and CRISPR Therapeutics Announce Authorization of the First CRISPR/Cas9 Gene-Edited Therapy, Casgevy (exagamglogene autotemcel), by the United Kingdom MHRA for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia" (Press release). Vertex Pharmaceuticals. 16 November 2023. Archived from the original on 22 November 2023. Retrieved 9 December 2023– via Business Wire.
  42. 1 2 "FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease". U.S. Food and Drug Administration (FDA). 8 December 2023. Archived from the original on 8 December 2023. Retrieved 8 December 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  43. ↑ "Vertex and CRISPR Therapeutics Announce US FDA Approval of Casgevy (exagamglogene autotemcel) for the Treatment of Sickle Cell Disease" (Press release). Vertex Pharmaceuticals. 8 December 2023. Archived from the original on 9 December 2023. Retrieved 9 December 2023– via Business Wire.
  44. ↑ Commissioner, Office of the (2024-01-16). "FDA Roundup: January 16, 2024". FDA. Retrieved 2024-01-19.
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