Category Archives: Cell Therapy

TiGenix has treated the first patient in a new early-stage clinical trial to test its candidate Cx611 as a treatment for sepsis in patients with pneumonia.

TiGenix, based in Belgium, develops stem cell therapies derived from donors. This morning, the first patient was treated in a Phase Ib/IIa clinical trial for its candidate therapyCx611 in the treatment of severe sepsis.Sepsis occurs when the immune systems response to infection injures tissues and organs in the body, and it affects over 26 million people worldwide,causing up to 50% of hospital deaths and costing22B ($24B) annually.

TiGenix is testing the immunomodulatory properties of Cx611 as a method to restore normal levels of immune response in patients with severe sepsis in community-acquired pneumonia.The trial will recruit 180 patients in five European centers, who will receive either placebo or two doses of the experimental treatment in addition to the standard care with antibiotics and anti-inflammatory drugs.In aPhase Itrial completed in 2015, Cx611 proved to be safe in healthy volunteers. The treatment consists of donor-derived adipose stem cells delivered intravenously.

Researchers at TiGenix

TiGenix unique technology seems promising, but its financial situation has been tight for the past years. In addition toa5.4Mgrant from the EUsHorizon 2020, adeal with Takeda and its recent NasdaqIPOhave injected some cash that the company will use to advance its pipeline.Its leading candidate, Cx601, a treatment for perianal fistulas in Crohns disease is awaiting approval and will be commercialized by Takeda.

TiGenix has claimed fame by producing thefirst cell therapyin the European market,ChondroCelect, for the repair of defects in the knees cartilage. However, the company recently withdrew it for commercial reasons, mostly the lack of reimbursement in key European countries.By targeting a bigger indicationwith unmet clinical needs, Cx611 might perform better than TiGenix first product and bring the company the revenues it needs to keep developing more cell therapies for a wide range of diseases, from myocardial infarction to rheumatoid arthritis.

Images from Sergei Drozd/Shutterstock, TiGenix

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Stem Cell Therapy for Sepsis in Pneumonia advances to Phase II - Labiotech.eu (blog)

If reinstated, Donald Trumps order restricting travel to the US would hurt the cell therapy sector according to the International Society for Cellular Therapy (ISCT).

US President Donald Trump issued an executive order on January 27 that limited immigration from seven predominantly Muslim countries, halted refugee admission for 120 days, and barred all Syrian refugees.

Last Friday , a judge in Seattle suspended implementation of the order after lawyers representing Washington and Minnesota argued it was unconstitutional and discriminatory.

In response, Trump criticized the presiding judge and vowed to have the order reinstated. However, at the time of writing, nothing has been decided.

If reinstated, the travel restrictions will negatively impact the cell therapy sector according to the International Society for Cellular Therapy (ISCT) a Canada-based group representing doctors, regulators, researchers and industry which raised concerns in a statement today.

The US plays an essential part in cell therapy research as a leading country in the life science industry. It hosts the highest number of international conferences, critical for scientific collaboration and sharing of ideas.

The ISCT also highlighted the leading roles US investors and the FDA play in shaping the global cell therapy sector and warned against any regulations that restrict international collaboration.

ISCT views any policies that would prevent the free movement of properly credentialed scientists, patients, care givers and/or their families from entering the US, as significantly harmful to the sharing of key scientific findings and the ability to deliver cell therapy to all patients.

ISCT President Catherine Bollard told us The Executive Order may result in a loss of talented researchers being able to come and work in the US to develop cell therapeutics given how much the US relies on foreign talent in the research and development sector.

She also suggested that some researchers returning to their country of origin because they do not feel comfortable continuing to live in the US.

Bollard confirmed that ISCT has one member from a country covered by the executive order.

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Trump's travel restrictions would hurt cell therapy developers says ISCT - BioPharma-Reporter.com

Regenerative medicine company BioTime expanded its ophthalmology portfolio through the acquisition of global rights to the University of Pittsburgh Medical Centers (UPMC) stem cell-derived retinal repair platform IP. The cell therapy technology, developed in partnership with BioTime, generates 3-D retinal tissue from human pluripotent stem cells for use as implants to repair retinas in patients with advanced retinal degradation. The licensing deal has been made through UPMCs Innovation Institute.

We anticipate that this technology, co-developed with the UPMC lab for retinal repair and epigenetics, will allow us to generate three-dimensional laminated human retinal tissue in a controlled manufacturing process," said Michael D. West, Ph.D., co-CEO of BioTime. "This could lead to vision restoration treatments for a variety of blinding retinal degenerative diseases, particularly retinitis pigmentosa, macular degeneration, and diabetic retinopathy, among other diseases and conditions.

BioTime has developed its PureStem pluripotent stem cell technology for generating cell therapies against a range of degenerative diseases. The firms clinical pipeline includes cell therapies for human immunodeficiency virus (HIV)-related lipoatrophy, macular degeneration, leukemia, and spinal cord injury. The lead program, against HIV-related lipatrophy, is undergoing pivotal clinical trials. Preclinical programs are in development against non-small-cell lung cancer and orthopedics. BioTime is separately developing its HyStem hydrogel technology for culturing and delivering therapeutic cells. Its majority-owned OncoCyte subsidiary is leveraging stem cell expertise to develop noninvasive gene expression-based cancer diagnostics.

At the start of 2017, BioTime and its majority-owned subsidiary Cell Cure Neurosciences established a 8600-ft2 cGMP cell therapy manufacturing facility in Jerusalem.

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BioTime Acquires Retinal Repair Cell Therapy from UPMC - Genetic Engineering & Biotechnology News

If reinstated, Donald Trumps order restricting travel to the US would hurt the cell therapy sector according to the International Society for Cellular Therapy (ISCT).

US President Donald Trump issued an executive order on January 27 that limited immigration from seven predominantly Muslim countries, halted refugee admission for 120 days, and barred all Syrian refugees.

Last Friday , a judge in Seattle suspended implementation of the order after lawyers representing Washington and Minnesota argued it was unconstitutional and discriminatory.

In response, Trump criticized the presiding judge and vowed to have the order reinstated. However, at the time of writing, nothing has been decided.

If reinstated, the travel restrictions will negatively impact the cell therapy sector according to the International Society for Cellular Therapy (ISCT) a Canada-based group representing doctors, regulators, researchers and industry which raised concerns in a statement today.

The US plays an essential part in cell therapy research as a leading country in the life science industry. It hosts the highest number of international conferences, critical for scientific collaboration and sharing of ideas.

The ISCT also highlighted the leading roles US investors and the FDA play in shaping the global cell therapy sector and warned against any regulations that restrict international collaboration.

ISCT views any policies that would prevent the free movement of properly credentialed scientists, patients, care givers and/or their families from entering the US, as significantly harmful to the sharing of key scientific findings and the ability to deliver cell therapy to all patients.

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Trump's travel restrictions will hurt cell therapy sector says ISCT - In-PharmaTechnologist.com

DUBLIN, Feb 3, 2017 /PRNewswire/ --

Research and Markets has announced the addition of Jain PharmaBiotech's new report "Cell Therapy - Technologies, Markets and Companies" to their offering.

Research and Markets Logo

This report describes and evaluates cell therapy technologies and methods, which have already started to play an important role in the practice of medicine. Hematopoietic stem cell transplantation is replacing the old fashioned bone marrow transplants. Role of cells in drug discovery is also described. Cell therapy is bound to become a part of medical practice.

Stem cells are discussed in detail in one chapter. Some light is thrown on the current controversy of embryonic sources of stem cells and comparison with adult sources. Other sources of stem cells such as the placenta, cord blood and fat removed by liposuction are also discussed. Stem cells can also be genetically modified prior to transplantation.

Cell therapy technologies overlap with those of gene therapy, cancer vaccines, drug delivery, tissue engineering and regenerative medicine. Pharmaceutical applications of stem cells including those in drug discovery are also described. Various types of cells used, methods of preparation and culture, encapsulation and genetic engineering of cells are discussed. Sources of cells, both human and animal (xenotransplantation) are discussed. Methods of delivery of cell therapy range from injections to surgical implantation using special devices.

Cell therapy has applications in a large number of disorders. The most important are diseases of the nervous system and cancer which are the topics for separate chapters. Other applications include cardiac disorders (myocardial infarction and heart failure), diabetes mellitus, diseases of bones and joints, genetic disorders, and wounds of the skin and soft tissues.

Regulatory and ethical issues involving cell therapy are important and are discussed. Current political debate on the use of stem cells from embryonic sources (hESCs) is also presented. Safety is an essential consideration of any new therapy and regulations for cell therapy are those for biological preparations.

The cell-based markets was analyzed for 2016, and projected to 2026.The markets are analyzed according to therapeutic categories, technologies and geographical areas. The largest expansion will be in diseases of the central nervous system, cancer and cardiovascular disorders. Skin and soft tissue repair as well as diabetes mellitus will be other major markets.

The number of companies involved in cell therapy has increased remarkably during the past few years. More than 500 companies have been identified to be involved in cell therapy and 303 of these are profiled in part II of the report along with tabulation of 292 alliances. Of these companies, 170 are involved in stem cells. Profiles of 72 academic institutions in the US involved in cell therapy are also included in part II along with their commercial collaborations. The text is supplemented with 64 Tables and 22 Figures. The bibliography contains 1,200 selected references, which are cited in the text.

Key Topics Covered:

Part I: Technologies, Ethics & Regulations

Executive Summary

1. Introduction to Cell Therapy

2. Cell Therapy Technologies

3. Stem Cells

4. Clinical Applications of Cell Therapy

5. Cell Therapy for Cardiovascular Disorders

6. Cell Therapy for Cancer

7. Cell Therapy for Neurological Disorders

8. Ethical, Legal and Political Aspects of Cell therapy

9. Safety and Regulatory Aspects of Cell Therapy

Part II: Markets, Companies & Academic Institutions

10. Markets and Future Prospects for Cell Therapy

11. Companies Involved in Cell Therapy

12. Academic Institutions

13. References

For more information about this report visit http://www.researchandmarkets.com/research/4svftc/cell_therapy

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Cell Therapy - Technologies, Markets and Companies - Research and Markets - Yahoo Finance

The prognosis for people affected by multiple sclerosis (MS), a degenerative autoimmune disorder that decimates the central nervous system, is a bleak one. The disease oftenbegins with a sudden burst of neurological symptoms like muscle spasms, vision problems, and trouble walking, then progresses differently, depending on which form of MS someone has. But eventually, nearly everyone with the disease comesto the point of being unable to move, breathe, or live independently. And sufferers on average live anywhere from five to ten years less than the general public.

Currently, the best medications we have available do little more than slow MS down, or tamp down peoples symptoms. But an experimental therapy continues to provide the first glimmers of something ground-breaking an actual way to stop one form of the disease in its tracks, and maybe even reverse some of the damage already done.

In this months Neurology, researchers detailed the final five-year-old results of a small clinical trial called HALT-MS. Twenty-four volunteers with MS who hadnt responded to conventional drugs were first given a powerful form of chemotherapy, high-dose immunosuppressive therapy (HDIT), that wiped out their immune system. Then they were given a transplant of their own stem cells taken out earlier, known as autologous hematopoietic cell transplant (HCT). These purified cells, the researchers theorized, would seed a new generation of uncorrupted white blood cells and reset the immune system, freezing MS in its place.

For the most part thats exactly what the combination HDIT/HCT therapy did. Nearly 70 percent of patients, five years in, have experienced no signs of the disease progressing. They havent had a relapse of symptoms, become more disabled, or had new brain lesions show up in imaging exams. Some have actually improved physically in the years since the treatment. And even those not in complete remission appear to be suffering less than before. Importantly, though the treatment isnt free of side-effects, there havent been severe ones. There were three deaths seen during the trial, all of whom experienced worsening MS, but none were attributed to the treatment.

The volunteers all had relapsing-remitting MS, the most common form, in which symptoms come and go with little rhyme or reason.

The evidence at this time is encouraging, but it isnt definitive, study author Dr. Linda Griffith, a researcher at the National Institute of Allergy and Infectious Diseases (NIAID), which sponsored the study, told Vocativ.

As Vocativ has previously reported, this isnt the first trial to find similar success rates for HDIT/HCT, though it does come with its own dangers. Patients can die from it, and like all kinds of chemotherapy, the deliberate weakening of the immune system often leads to more infections. It also doesnt seem to be as effective for more advanced types of MS, when the disease has stopped causing active inflammation, said Griffith. And while it could be promising for people in the earliest stages of MS, the research needed to promote it as a first-line treatment isnt there yet either, she added.

For now, the only trials of HDIT/HCT have been small and isolated. And though the effects of it when successful seem to extend as far out as 13 years later, its too early to call it a full-on cure. We still dont have a clear grasp of why MS happens in the first place, but its thought that multiple triggers like infections and unlucky genetics combine to increase peoples risk. So even if resetting someones immune system does treat MS completely, its plausible that some percentage of patients could fall victim to it again down the road, Griffith explained. We just dont know enough right now.

But Griffith is hopeful that larger, randomized studies will be underway within the next year or so. And if those prove to be as successful as the HALT-MS trial and others, the therapy could someday soon lead to a light at the end of tunnel for the millions of MS sufferers alive today.

Excerpt from:
Experimental Stem Cell Therapy Stops Multiple Sclerosis In Its ... - Vocativ

Vascular disease Cell therapy lowers PAD amputation risk Nature.com Critical limb ischaemia (CLI) is a potentially fatal complication of peripheral artery disease (PAD). A meta-analysis of studies that evaluated the safety and efficacy of autologous cell therapy for intractable CLI/PAD now reports that cell therapy ...

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Vascular disease Cell therapy lowers PAD amputation risk - Nature.com

A North Texas teenager who battled severe asthma for years is breathing free and clear again after doctors used stem cell therapy to temporarily treat his condition. (Published Monday, Jan. 30, 2017)

A North Texas teenager who battled severe asthma for years is breathing free and clear again after doctors used stem cell therapy to temporarily treat his condition.

Kenton Crenshaw, 18, of Crowley, never knew when his asthma would strike.

"Like 2, 3, 4 in the morning and it just hits me and I freak out," Crenshaw said.

"My asthma stopped me from doing lots of stuff that I wanted to do," he added.

Activity, even as light as walking outside, came with risk.

"I spent eight Christmases in the hospital because of asthma days or weeks long, birthdays it's just controlled my life," he said.

Crenshaw took countless medications but nothing seemed to help, so his family brought him to Dr. Bill Johnson at Innovations Medical in Dallas.

Johnson is one of a growing group of doctors using stem cell therapy to treat various diseases.

"The stem cells have the ability to reproduce and become other types of tissue, and that's what makes them so special," Johnson said.

Johnson took a small amount of fat from the Crenshaw through liposuction and separated the stem cells in a centrifuge.

He then mixes the stem cells with a solution, which is given back to patients, like Crenshaw, through intravenous therapy or breathing treatments.

"He has an overactive immune system with his lungs and airways, and what the stem cells can do is turn that down, decrease inflammation, and he's had a remarkable course," Johnson said, of Crenshaw.

It's been a few months since the treatments, and Crenshaw says he hasn't needed many of his medications.

"I felt like I never had asthma, like I feel perfect. I didn't do one breathing treatment in almost three months and I used to do four to six breathing treatments a day," he said.

The treatment isn't said to cure his asthma, but the results can last a year possible longer.

"I hope I never have an asthma attack the rest of my life," Crenshaw said.

Stem cell therapy treatments cost upwards of $7,000 and are not covered by insurance.

Published at 10:03 PM CST on Jan 30, 2017 | Updated at 10:41 PM CST on Jan 30, 2017

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Stem Cell Therapy Helps North Texas Teen Beat Asthma | NBC 5 ... - NBC 5 Dallas-Fort Worth

ByEthan Weston February 2, 2017

Stem cell research is making medical breakthroughs, and now, it could offer hope to people who have multiple sclerosis.

A newNational Institutes of Healthstudy suggests one-time stem cell transplants might be more effective than long-term medicinal treatment at treating relapsing-remitting MS.

Multiple sclerosis is an autoimmune disease that causes a person's immune system to attack their central nervous system. Common symptoms are impaired motor function, weakness and chronic pain. Relapsing-remitting MS is the most common form of the disease.

Stem cells are cells that haven't decided what they want to be when they grow up. That means they can develop into different types of cells. Because of that, they can be used to heal older damaged cells, like those attacked by the immune system.

The study followed 24 people who weren't having success with the typical MS medications. The experimental treatment suppressed participants' immune systems with chemotherapy. Then, their own stem cells were transplanted back into their bodies to rebuild their immune systems.

Related StoryPart-Pig, Part-Human Embryos Could Give Us Replacement Human Organs

Five years after treatment, most participants' symptoms were in remission. Some of them even showed some improvements.

Larger studies will be needed to confirm these findings. But the head of the study said it's a good first step toward more effective treatment for an incredibly debilitating and deadly disease.

See more here:
Stem Cell Therapy Offers Hope to Multiple Sclerosis Patients (VIDEO) - Newsy

Sickle-cell disease (SCD) is a group of blood disorders typically inherited from a person's parents.[1] The most common type is known as sickle-cell anaemia (SCA). It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells. This leads to a rigid, sickle-like shape under certain circumstances.[1] Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain ("sickle-cell crisis"), anemia, bacterial infections, and stroke.[2]Long term pain may develop as people get older. The average life expectancy in the developed world is 40 to 60 years.[1]

Sickle-cell disease occurs when a person inherits two abnormal copies of the haemoglobin gene, one from each parent.[3] Several subtypes exist, depending on the exact mutation in each haemoglobin gene.[1] An attack can be set off by temperature changes, stress, dehydration, and high altitude.[2] A person with a single abnormal copy does not usually have symptoms and is said to have sickle-cell trait.[3] Such people are also referred to as carriers.[4] Diagnosis is by a blood test and some countries test all babies at birth for the disease. Diagnosis is also possible during pregnancy.[5]

The care of people with sickle-cell disease may include infection prevention with vaccination and antibiotics, high fluid intake, folic acid supplementation, and pain medication.[4][6] Other measures may include blood transfusion, and the medication hydroxycarbamide (hydroxyurea).[6] A small proportion of people can be cured by a transplant of bone marrow cells.[1]

As of 2013 about 3.2 million people have sickle-cell disease while an additional 43 million have sickle-cell trait.[7] About 80% of sickle-cell disease cases are believed to occur in sub-Saharan Africa.[8] It also occurs relatively frequently in parts of India, the Arabian peninsula, and among people of African origin living in other parts of the world.[9] In 2013, it resulted in 176,000 deaths, up from 113,000 deaths in 1990.[10] The condition was first described in the medical literature by the American physician James B. Herrick in 1910.[11][12] In 1949 the genetic transmission was determined by E. A. Beet and J. V. Neel. In 1954 the protective effect against malaria of sickle-cell trait was described.[12]

Sickle-cell disease may lead to various acute and chronic complications, several of which have a high mortality rate.[13]

The terms "sickle-cell crisis" or "sickling crisis" may be used to describe several independent acute conditions occurring in patients with SCD. SCD results in anemia and crises that could be of many types including the vaso-occlusive crisis, aplastic crisis, sequestration crisis, haemolytic crisis, and others. Most episodes of sickle-cell crises last between five and seven days.[14] "Although infection, dehydration, and acidosis (all of which favor sickling) can act as triggers, in most instances, no predisposing cause is identified."[15]

The vaso-occlusive crisis is caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ resulting in ischaemia, pain, necrosis, and often organ damage. The frequency, severity, and duration of these crises vary considerably. Painful crises are treated with hydration, analgesics, and blood transfusion; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac or naproxen. For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia devices are commonly used in this setting. Vaso-occlusive crisis involving organs such as the penis[16] or lungs are considered an emergency and treated with red-blood cell transfusions. Incentive spirometry, a technique to encourage deep breathing to minimise the development of atelectasis, is recommended.[17]

Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected.[18] It is usually infarcted before the end of childhood in individuals suffering from sickle-cell anemia. This spleen damage increases the risk of infection from encapsulated organisms;[19][20] preventive antibiotics and vaccinations are recommended for those lacking proper spleen function.

Splenic sequestration crises are acute, painful enlargements of the spleen, caused by intrasplenic trapping of red cells and resulting in a precipitous fall in haemoglobin levels with the potential for hypovolemic shock. Sequestration crises are considered an emergency. If not treated, patients may die within 12 hours due to circulatory failure. Management is supportive, sometimes with blood transfusion. These crises are transient, they continue for 34 hours and may last for one day.[21]

Acute chest syndrome (ACS) is defined by at least two of the following signs or symptoms: chest pain, fever, pulmonary infiltrate or focal abnormality, respiratory symptoms, or hypoxemia.[22] It is the second-most common complication and it accounts for about 25% of deaths in patients with SCD, majority of cases present with vaso-occlusive crises then they develop ACS.[23][24] Nevertheless, about 80% of patients have vaso-occlusive crises during ACS.

Aplastic crises are acute worsenings of the patient's baseline anaemia, producing pale appearance, fast heart rate, and fatigue. This crisis is normally triggered by parvovirus B19, which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them.[25] Parvovirus infection almost completely prevents red blood cell production for two to three days. In normal individuals, this is of little consequence, but the shortened red cell life of SCD patients results in an abrupt, life-threatening situation. Reticulocyte counts drop dramatically during the disease (causing reticulocytopenia), and the rapid turnover of red cells leads to the drop in haemoglobin. This crisis takes 4 days to one week to disappear. Most patients can be managed supportively; some need blood transfusion.[26]

Haemolytic crises are acute accelerated drops in haemoglobin level. The red blood cells break down at a faster rate. This is particularly common in patients with coexistent G6PD deficiency.[27] Management is supportive, sometimes with blood transfusions.[17]

One of the earliest clinical manifestations is dactylitis, presenting as early as six months of age, and may occur in children with sickle-cell trait.[28] The crisis can last up to a month.[29] Another recognised type of sickle crisis, acute chest syndrome, is characterised by fever, chest pain, difficulty breathing, and pulmonary infiltrate on a chest X-ray. Given that pneumonia and sickling in the lung can both produce these symptoms, the patient is treated for both conditions.[30] It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery.[citation needed]Hematopoietic ulcers may also occur.[31]

Normally, humans have haemoglobin A, which consists of two alpha and two beta chains, haemoglobin A2, which consists of two alpha and two delta chains, and haemoglobin F, consisting of two alpha and two gamma chains in their bodies. Of these, haemoglobin F dominates until about 6 weeks of age. Afterwards, haemoglobin A dominates throughout life.[citation needed]

Sickle-cell conditions have an autosomal recessive pattern of inheritance from parents. The types of haemoglobin a person makes in the red blood cells depend on what haemoglobin genes are inherited from her or his parents. If one parent has sickle-cell anaemia and the other has sickle-cell trait, then the child has a 50% chance of having sickle-cell disease and a 50% chance of having sickle-cell trait. When both parents have sickle-cell trait, a child has a 25% chance of sickle-cell disease, 25% do not carry any sickle-cell alleles, and 50% have the heterozygous condition.[32]

Sickle-cell gene mutation probably arose spontaneously in different geographic areas, as suggested by restriction endonuclease analysis. These variants are known as Cameroon, Senegal, Benin, Bantu, and Saudi-Asian. Their clinical importance is because some are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease.[33]

In people heterozygous for HgbS (carriers of sickling haemoglobin), the polymerisation problems are minor, because the normal allele is able to produce over 50% of the haemoglobin. In people homozygous for HgbS, the presence of long-chain polymers of HbS distort the shape of the red blood cell from a smooth doughnut-like shape to ragged and full of spikes, making it fragile and susceptible to breaking within capillaries. Carriers have symptoms only if they are deprived of oxygen (for example, while climbing a mountain) or while severely dehydrated. The sickle-cell disease occurs when the sixth amino acid, glutamic acid, is replaced by valine to change its structure and function; as such, sickle-cell anemia is also known as E6V. Valine is hydrophobic, causing the haemoglobin to collapse on itself occasionally. The structure is not changed otherwise. When enough haemoglobin collapses on itself the red blood cells become sickle-shaped.[citation needed]

The gene defect is a known mutation of a single nucleotide (see single-nucleotide polymorphism - SNP) (A to T) of the -globin gene, which results in glutamic acid (E/Glu) being substituted by valine (V/Val) at position 6. Note, historic numbering put this glutamic acid residue at position 6 due to skipping the methionine (M/Met) start codon in protein amino acid position numbering. Current nomenclature calls for counting the methionine as the first amino acid, resulting in the glutamic acid residue falling at position 7. Many references still refer to position 6 and both should likely be referenced for clarity. Haemoglobin S with this mutation is referred to as HbS, as opposed to the normal adult HbA. The genetic disorder is due to the mutation of a single nucleotide, from a GAG to GTG codon on the coding strand, which is transcribed from the template strand into a GUG codon. Based on genetic code, GAG codon translates to glutamic acid (E/Glu) while GUG codon translates to valine (V/Val) amino acid at position 6. This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structures of haemoglobin in conditions of normal oxygen concentration. What it does allow for, under conditions of low oxygen concentration, is the polymerization of the HbS itself. The deoxy form of haemoglobin exposes a hydrophobic patch on the protein between the E and F helices. The hydrophobic side chain of the valine residue at position 6 of the beta chain in haemoglobin is able to associate with the hydrophobic patch, causing haemoglobin S molecules to aggregate and form fibrous precipitates.

The allele responsible for sickle-cell anaemia can be found on the short arm of chromosome 11, more specifically 11p15.5. A person who receives the defective gene from both father and mother develops the disease; a person who receives one defective and one healthy allele remains healthy, but can pass on the disease and is known as a carrier or heterozygote. Heterozygotes are still able to contract malaria, but their symptoms are generally less severe.[34]

Due to the adaptive advantage of the heterozygote, the disease is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such as Africa, the Mediterranean, India, and the Middle East.[35] Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases.[36]

The malaria parasite has a complex lifecycle and spends part of it in red blood cells. In a carrier, the presence of the malaria parasite causes the red blood cells with defective haemoglobin to rupture prematurely, making the Plasmodium parasite unable to reproduce. Further, the polymerization of Hb affects the ability of the parasite to digest Hb in the first place. Therefore, in areas where malaria is a problem, people's chances of survival actually increase if they carry sickle-cell trait (selection for the heterozygote).

In the USA, with no endemic malaria, the prevalence of sickle-cell anaemia among African Americans is lower (about 0.25%) than in West Africa (about 4.0%) and is falling. Without endemic malaria, the sickle-cell mutation is purely disadvantageous and tends to decline in the affected population by natural selection, and now artificially through prenatal genetic screening. However, the African American community descends from a significant admixture of several African and non-African ethnic groups and also represents the descendants of survivors of slavery and the slave trade. Thus, a lower degree of endogamy and, particularly, abnormally high health-selective pressure through slavery may be the most plausible explanations for the lower prevalence of sickle-cell anaemia (and, possibly, other genetic diseases) among African Americans compared to West Africans. Another factor that limits the spread of sickle-cell genes in North America is the absence of cultural proclivities to polygamy, which allows affected males to continue to seek unaffected children with multiple partners.[37]

The loss of red blood cell elasticity is central to the pathophysiology of sickle-cell disease. Normal red blood cells are quite elastic, which allows the cells to deform to pass through capillaries. In sickle-cell disease, low oxygen tension promotes red blood cell sickling and repeated episodes of sickling damage the cell membrane and decrease the cell's elasticity. These cells fail to return to normal shape when normal oxygen tension is restored. As a consequence, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion and ischaemia.

The actual anaemia of the illness is caused by haemolysis, the destruction of the red cells, because of their shape. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction.[38] Healthy red blood cells typically function for 90120 days, but sickled cells only last 1020 days.[39]

In HbSS, the complete blood count reveals haemoglobin levels in the range of 68g/dl with a high reticulocyte count (as the bone marrow compensates for the destruction of sickled cells by producing more red blood cells). In other forms of sickle-cell disease, Hb levels tend to be higher. A blood film may show features of hyposplenism (target cells and Howell-Jolly bodies).

Sickling of the red blood cells, on a blood film, can be induced by the addition of sodium metabisulfite. The presence of sickle haemoglobin can also be demonstrated with the "sickle solubility test". A mixture of haemoglobin S (Hb S) in a reducing solution (such as sodium dithionite) gives a turbid appearance, whereas normal Hb gives a clear solution.

Abnormal haemoglobin forms can be detected on haemoglobin electrophoresis, a form of gel electrophoresis on which the various types of haemoglobin move at varying speeds. Sickle-cell haemoglobin (HgbS) and haemoglobin C with sickling (HgbSC)the two most common formscan be identified from there. The diagnosis can be confirmed with high-performance liquid chromatography. Genetic testing is rarely performed, as other investigations are highly specific for HbS and HbC.[40]

An acute sickle-cell crisis is often precipitated by infection. Therefore, a urinalysis to detect an occult urinary tract infection, and chest X-ray to look for occult pneumonia should be routinely performed.[41]

People who are known carriers of the disease often undergo genetic counseling before they have a child. A test to see if an unborn child has the disease takes either a blood sample from the fetus or a sample of amniotic fluid. Since taking a blood sample from a fetus has greater risks, the latter test is usually used. Neonatal screening provides not only a method of early detection for individuals with sickle-cell disease, but also allows for identification of the groups of people that carry the sickle cell trait.[42]

Folic acid daily for life is recommended. From birth to five years of age, penicillin daily due to the immature immune system that makes them more prone to early childhood illnesses is also recommended.

The protective effect of sickle-cell trait does not apply to people with sickle cell disease; in fact, they are more vulnerable to malaria, since the most common cause of painful crises in malarial countries is infection with malaria. It has therefore been recommended that people with sickle-cell disease living in malarial countries should receive anti-malarial chemoprophylaxis for life.[43]

Most people with sickle-cell disease have intensely painful episodes called vaso-occlusive crises. However, the frequency, severity, and duration of these crises vary tremendously. Painful crises are treated symptomatically with pain medications; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) devices are commonly used in this setting. Diphenhydramine is also an effective agent that doctors frequently prescribe to help control itching associated with the use of opioids.[citation needed]

Management is similar to vaso-occlusive crisis, with the addition of antibiotics (usually a quinolone or macrolide, since cell wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome),[44] oxygen supplementation for hypoxia, and close observation. Should the pulmonary infiltrate worsen or the oxygen requirements increase, simple blood transfusion or exchange transfusion is indicated. The latter involves the exchange of a significant portion of the person's red cell mass for normal red cells, which decreases the percent of haemoglobin S in the patient's blood. The patient with suspected acute chest syndrome should be admitted to the hospital with worsening A-a gradient an indication for ICU admission.[22]

The first approved drug for the causative treatment of sickle-cell anaemia, hydroxyurea, was shown to decrease the number and severity of attacks in a study in 1995 (Charache et al.)[45] and shown to possibly increase survival time in a study in 2003 (Steinberg et al.).[46] This is achieved, in part, by reactivating fetal haemoglobin production in place of the haemoglobin S that causes sickle-cell anaemia. Hydroxyurea had previously been used as a chemotherapy agent, and there is some concern that long-term use may be harmful, but this risk has been shown to be either absent or very small and it is likely that the benefits outweigh the risks.[13][47]

Blood transfusions are often used in the management of sickle-cell disease in acute cases and to prevent complications by decreasing the number of red blood cells (RBC) that can sickle by adding normal red blood cells.[48] In children preventative red blood cell (RBC) transfusion therapy has been shown to reduce the risk of first stroke or silent stroke when transcranial Doppler (TCD) ultrasonography shows abnormal cerebral blood flow.[6] In those who have sustained a prior stroke event it also reduces the risk of recurrent stroke and additional silent strokes.[49][50]

Bone marrow transplants have proven effective in children. Bone marrow transplants are the only known cure for SCD.[51] However, bone marrow transplants are difficult to obtain because of the specific HLA typing necessary. Ideally, a close relative (allogeneic) would donate the bone marrow necessary for transplantation.

About 90% of people survive to age 20, and close to 50% survive beyond the fifth decade.[52] In 2001, according to one study performed in Jamaica, the estimated mean survival for people with sickle-cell was 53 years old for men and 58 years old for women with homozygous SCD.[53] The specific life expectancy in much of the developing world is unknown.[54]

Sickle-cell anaemia can lead to various complications, including:

The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, tribal regions of India and the Middle-East.[67] Migration of substantial populations from these high prevalence areas to low prevalence countries in Europe has dramatically increased in recent decades and in some European countries sickle-cell disease has now overtaken more familiar genetic conditions such as haemophilia and cystic fibrosis.[68] In 2013 it resulted in 176,000 deaths due to SCD up from 113,000 deaths in 1990.[10]

Sickle-cell disease occurs more commonly among people whose ancestors lived in tropical and sub-tropical sub-Saharan regions where malaria is or was common. Where malaria is common, carrying a single sickle-cell allele (trait) confers a selective advantagein other words, being a heterozygote is advantageous. Specifically, humans with one of the two alleles of sickle-cell disease show less severe symptoms when infected with malaria.[69]

Three-quarters of sickle-cell cases occur in Africa. A recent WHO report estimated that around 2% of newborns in Nigeria were affected by sickle cell anaemia, giving a total of 150,000 affected children born every year in Nigeria alone. The carrier frequency ranges between 10% and 40% across equatorial Africa, decreasing to 12% on the north African coast and <1% in South Africa.[70] There have been studies in Africa that show a significant decrease in infant mortality rate, ages 216 months, because of the sickle-cell trait. This happened in predominant areas of malarial cases.[71]

The number of people with the disease in the United States is approximately 1 in 5,000, mostly affecting Americans of Sub-Saharan African descent, according to the National Institutes of Health.[72] In the United States, about one out of 500 African-American children and one in every 36,000 Hispanic-American children have sickle-cell anaemia.[73] It is estimated that sickle-cell disease affects 90,000 Americans.[74] Most infants with SCD born in the United States are now identified by routine neonatal screening. As of 2016 all 50 states include screening for sickle cell disease as part of their newborn screen.[75]

As a result of population growth in African-Caribbean regions of overseas France and immigration from North and sub-Saharan Africa to mainland France, sickle-cell disease has become a major health problem in France.[76] SCD has become the most common genetic disease in the country, with an overall birth prevalence of 1/2,415 in mainland France, ahead of phenylketonuria (1/10,862), congenital hypothyroidism (1/3,132), congenital adrenal hyperplasia (1/19,008) and cystic fibrosis (1/5,014) for the same reference period. In 2010, 31.5% of all newborns in mainland France (253,466 out of 805,958) were screened for SCD (this percentage was 19% in 2000). 341 newborns with SCD and 8,744 heterozygous carriers were found representing 1.1% of all newborns in mainland France. The Paris metropolitan district (le-de-France) is the region that accounts for the largest number of newborns screened for SCD (60% in 2010). The second largest number of at-risk is in Provence-Alpes-Cte d'Azur at nearly 43.2% and the lowest number is in Brittany at 5.5%.[77][78]

In the United Kingdom (UK) it is thought that between 12,000 and 15,000 people have sickle cell disease [79] with an estimate of 250,000 carriers of the condition in England alone. As the number of carriers is only estimated, all newborn babies in the UK receive a routine blood test to screen for the condition.[80] Due to many adults in high-risk groups not knowing if they are carriers, pregnant women and both partners in a couple are offered screening so they can get counselling if they have the sickle cell trait.[81] In addition blood donors from those in high-risk groups are also screened to confirm whether they are carriers and whether their blood filters properly.[82] Donors who are found to be carriers are then informed and their blood, while often used for those of the same ethnic group, is not used for those with sickle cell disease who require a blood transfusion.[83]

In Saudi Arabia about 4.2% of the population carry the sickle-cell trait and 0.26% have sickle-cell disease. The highest prevalence is in the Eastern province where approximately 17% of the population carry the gene and 1.2% have sickle-cell disease.[84] In 2005 in Saudi Arabia a mandatory pre-marital test including HB electrophoresis was launched and aimed to decrease the incidence of SCD and thalassemia.[85]

In Bahrain a study published in 1998 that covered about 56,000 people in hospitals in Bahrain found that 2% of newborns have sickle cell disease, 18% of the surveyed people have the sickle cell trait, and 24% were carriers of the gene mutation causing the disease.[86] The country began screening of all pregnant women in 1992 and newborns started being tested if the mother was a carrier. In 2004, a law was passed requiring couples planning to get married to undergo free premarital counseling. These programs were accompanied by public education campaigns.[87]

Sickle-cell disease is common in ethnic groups of central India who share a genetic linkage with African communities,[citation needed] where the prevalence has ranged from 9.4 to 22.2% in endemic areas of Madhya Pradesh, Rajasthan and Chhattisgarh.[88] It is also endemic among Tharu people of Nepal and India; however, they have a sevenfold lower incidence of malaria despite living in a malaria infested zone.[89]

In Jamaica, 10% of the population carries the sickle-cell gene, making it the most prevalent genetic disorder in the country.[90]

The first modern report of sickle-cell disease may have been in 1846, where the autopsy of an executed runaway slave was discussed; the key findings was the absence of the spleen.[91][92] There were also reports amongst African slaves in the United States exhibiting resistance to malaria but being prone to leg ulcers.[92] The abnormal characteristics of the red blood cells, which later lent their name to the condition, was first described by Ernest E. Irons (18771959), intern to the Chicago cardiologist and professor of medicine James B. Herrick (18611954), in 1910. Irons saw "peculiar elongated and sickle-shaped" cells in the blood of a man named Walter Clement Noel, a 20-year-old first-year dental student from Grenada. Noel had been admitted to the Chicago Presbyterian Hospital in December 1904 suffering from anaemia.[11][93] Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks" but completed his studies and returned to the capital of Grenada (St. George's) to practice dentistry. He died of pneumonia in 1916 and is buried in the Catholic cemetery at Sauteurs in the north of Grenada.[11][12] Shortly after the report by Herrick, another case appeared in the Virginia Medical Semi-Monthly with the same title, "Peculiar Elongated and Sickle-Shaped Red Blood Corpuscles in a Case of Severe Anemia."[94] This article is based on a patient admitted to the University of Virginia Hospital on November 15, 1910.[95] In the later description by Verne Mason in 1922, the name "sickle cell anemia" is first used.[12][96] Childhood problems related to sickle cells disease were not reported until the 1930s, despite the fact that this cannot have been uncommon in African-American populations.[92]

The Memphis physician Lemuel Diggs, a prolific researcher into sickle cell disease, first introduced the distinction between sickle cell disease and trait in 1933, although it took until 1949 until the genetic characteristics were elucidated by James V. Neel and E.A. Beet.[12] 1949 was the year when Linus Pauling described the unusual chemical behaviour of haemoglobin S, and attributed this to an abnormality in the molecule itself.[12][97] The actual molecular change in HbS was described in the late 1950s BY Vernon Ingram.[12] The late 1940s and early 1950s saw further understanding in the link between malaria and sickle cell disease. In 1954, the introduction of haemoglobin electrophoresis allowed the discovery of particular subtypes, such as HbSC disease.[12]

Large scale natural history studies and further intervention studies were introduced in the 1970s and 1980s, leading to widespread use of prophylaxis against pneumococcal infections amongst other interventions. Bill Cosby's Emmy-winning 1972 TV movie, To All My Friends on Shore, depicted the story of the parents of a child suffering from sickle-cell disease.[98] The 1990s saw the development of hydroxycarbamide, and reports of cure through bone marrow transplantation appeared in 2007.[12]

Some old texts refer to it as drepanocytosis.[citation needed]

In December 1998, researchers from Emory University conducted an experimental bone marrow transplant procedure on a group of 22 children under 16 years old.[99] One of those patients, 12-year-old Keone Penn, was apparently the first person to be cured of sickle-cell disease through this method.[100] The stem cells were sourced from a donor unrelated to Penn. A 2007 Georgia Senate bill proposing the collection and donation of stem cell material, the "Saving the Cure Act", was nicknamed "Keone's Law" in his honor.[101]

By mid-2007 a similar set of clinical trials in Baltimore had also cured several adults.[102]

In 2001 it was reported that sickle-cell disease had been successfully treated in mice using gene therapy.[103][104] The researchers used a viral vector to make the micewhich have essentially the same defect that causes human sickle cell diseaseexpress production of fetal haemoglobin (HbF), which an individual normally ceases to produce shortly after birth. In humans, using hydroxyurea to stimulate the production of HbF has been known to temporarily alleviate sickle cell disease symptoms. The researchers demonstrated that this gene therapy method is a more permanent way to increase therapeutic HbF production.[105]

Phase 1 clinical trials of gene therapy for sickle cell disease in humans were started in 2014. The clinical trials will assess the safety and initial evidence for efficacy of an autologous transplant of lentiviral vector-modified bone marrow for adults with severe sickle cell disease.[106][107] As of 2014, however, no randomized controlled trials have been reported.[108]

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Sickle-cell disease - Wikipedia