Gene therapy for sickle cell disease steps closer

Researchers have found a way to repair the faulty gene that causes sickle cell disease, which they suggest is a significant step forward in the search for a viable gene therapy.

 In a study,  they report how - using the CRISPR gene-editing tool - they corrected the gene in stem cells from diseased patients and showed they could make red blood cells capable of making functioning hemoglobin. They also transplanted the stem cells into mice and found them thriving in their bone marrow months later.

Sickle cell disease is a group of inherited disorders where red blood cells form abnormal, hard and sticky, crescent, or sickle shapes instead of normal, flexible, disc-like shapes.

The sickle red blood cells stick to vessel walls and cause blockages, slowing the flow of blood and stopping oxygen reaching nearby tissues. This can cause pain and damage to tissue and organs. Also, sickle cells die faster than normal red blood cells, raising risk of anemia, which can also damage organs.

The disease is caused by a single mutation in a gene that codes for a protein chain in hemoglobin - the molecule in red blood cells that carries oxygen. The faulty hemoglobin forms stiff rods within the red cell, making it crescent-shaped.

Sickle cell disease affects millions of people around the world. The number of Americans living with it is not known, but estimates suggest it is around 100,000.

Children born with sickle cell disease in high-income countries typically survive and can go on to live full lives and enjoy most of the activities that other people do. However, in low-income countries, children born with the disease typically die before they reach their fifth birthday.

Gene therapy and the promise of CRISPR

Since its early beginnings in the 1980s, gene therapy has been a holy grail among researchers looking for ways to cure or treat genetic disorders.

CRISPR is a relatively new gene-editing tool that is said to have "triggered a revolution in genome engineering within living systems." Researchers prefer CRISPR to older methods because it is easier and faster.

The technique is a type of molecular scissors that snip out faulty strips of DNA so they can be replaced with corrected versions using other tools.

The senior author of the new study, has been trying ways to target sickle cell genes with gene-editing technology for several years.

He says with the new CRISPR technology, they can work much faster and more effectively, significantly cutting the time of experiments.

"We spent half a dozen years trying to target the beta globin gene using the old technology," he remarks, adding that within a week of trying CRISPR, they had a gene-editing tool that was much better.

For their new study, Prof. Porteus and his team took hematopoietic stem cells from the blood of patients with sickle cell disease and corrected the faulty gene using CRISPR to remove a strip of DNA and a virus to insert the correct version. Hematopoietic stem cells are stem cells that make blood cells.

They concentrated the human hematopoietic stem cells so that 90 percent carried the corrected sickle cell gene and then injected them into young mice.

Proof of concept that gene-editing can repair sickle cell

Prof. Porteus says that the hematopoietic stem cells have the ability to travel from the bloodstream into the bone marrow, where they then "set up shop and start making other blood cells."

Sixteen weeks after the transplant, the researchers found the stem cells were thriving in the mice's bone marrow.

A gene therapy for sickle cell disease would not have to replace all of a patient's sickle cells Prof.  explains. You just need a sufficient amount of normal cells. Patients whose sickle cells are below 30 percent show no symptoms of disease.

The researchers now need to take their discovery through a series of tests so they can investigate the safety aspects of the new gene editing tool.

This is going to be no mean feat - no CRISPR-edited genes have yet been tested for safety or efficacy in human clinical trials. A particular challenge is how to overcome potential so-called "off-target" effects, where the molecular scissors accidentally cut out the wrong piece of DNA.

Prof. Porteus says Stanford is building the infrastructure so they can start to take their findings out of the lab and scale them up into the types of systems that will be needed to create gene therapy for patients.

For now, he and his team can say that their gene-edited human hematopoietic stem cells appear to behave like normal, healthy human hematopoietic stem cells.

They suggest their findings are proof of concept that using gene-editing can repair sickle cell and other blood-borne genetic diseases, such as thalassemia.

    "What we've finally shown is that we can do it. It's not just on the chalkboard. We can take stem cells from a patient and correct the mutation and show that those stem cells turn into red blood cells that no longer make sickled hemoglobin."


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Novel device measures stiffness and stickiness of red blood cells

Researchers have created a versatile device that measures two important properties of red blood cells that are relevant for sickle cell and other diseases: deformation and adhesion.

The team, from Case Western Reserve University (CWRU) in Cleveland, OH, describes the innovative device - a microfluidic platform with a computer algorithm that does the math - in a paper published in the journal Technology.

Sickle cell disease is a group of inherited red blood cell disorders. People with the disease have abnormal hemoglobin - the protein that carries oxygen - in their red blood cells. The abnormal hemoglobin is called sickle hemoglobin.

Red blood cells containing normal hemoglobin are flexible and shaped like a doughnut with a thin flat area in the middle instead of a hole. This allows them to squeeze round bends in blood vessels and through smaller ones to deliver vital oxygen to tissues and organs.

However, sickle hemoglobin has a tendency to form stiff rods inside the red blood cell - changing it into the crescent or sickle shape that gives the disease its name.

Red blood cells containing sickle hemoglobin are less flexible than normal red blood cells and also tend to be stickier. These two features increase the risk that they will cause a blockage in a blood vessel and impede the delivery of oxygen to nearby tissues and organs.

When such a blockage occurs, it causes a sudden and severe attack of pain - called a pain crisis - that is typical of sickle cell disease. Pain crises occur without warning and often require hospitalization for effective treatment.

In extreme cases, the blockage of blood vessels in sickle cell disease can lead to widespread organ damage and early death.

Currently, the only way to cure sickle cell disease is with a stem cell transplant. But unfortunately, most patients are either too old for a transplant or do not have a relative with a good enough genetic match to receive transplantable stem cells from.

Effective treatments exist and these can reduce symptoms and prolong life. Early diagnosis and regular monitoring to prevent complications also helps.
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Potential monitor of disease progression

By assessing the extent of stiffness and stickiness, or the "dynamic deformability and adhesion," of red blood cells, the new microfluidic device offers great potential as a way to monitor progression of sickle cell disease, note the researchers.

They say the device could also help with research and developing new treatments for sickle cell disease.

Other ways to measure stiffness and stickiness in red blood cells - such as atomic force microscopy and optical tweezers - do exist, but they do not lend themselves to working with whole blood in a clinical setting, say the researchers.

They note their device can assess the stiffness of a single red blood cell, and also, by mimicking blood vessel properties, assess the stickiness of red blood cells from whole blood of sickle cell patients.

Lead investigator Umut Gurkan, an assistant professor in CWRU's Department of Mechanical and Aerospace Engineering, says:

"The microfluidic system developed here has the potential to be used in a high-throughput manner with an integrated automated image processing algorithm for measurement of RBC [red blood cell] deformability and adhesion in patients' blood."

The authors explain that healthy red blood cells undergo reversible deformation when they circulate around the body in blood vessels. They respond to "fluid shear stresses" extremely fast - they can bend and regain their shape in the space of 100 milliseconds.
'Interplay between dynamic deformability and increased adhesion'

To assess dynamic deformability of red blood cells, the researchers used what they call a dynamic deformability index (DDI), which they define as "the time-dependent change of the cell's aspect ratio." Essentially, a cell's DDI is a measure of how quickly it springs back to its normal shape after experiencing flow shear stress.

In their paper, the team describes a range of tests where they measured the DDI of deformable and non-deformable red blood cells.

The researchers also compared adhesion of deformable and non-deformable red blood cells from blood samples taken from sickle cell patients. They tested the stickiness of the cells under different flow shear stresses - both within and outside ranges experienced in normal blood vessels.

They found that at flow shear stresses "well above the physiological range," non-deformable sickle red blood cells were much stickier than deformable sickle red blood cells, "suggesting an interplay between dynamic deformability and increased adhesion" of red blood cells when blood vessel blockage occurs.

The team suggests the device may also be useful for studying the deformation of cells that could be relevant in other diseases - such as diabetes, malaria and the bone marrow disorder polycythemia vera.

The researchers plan to study red blood cell stiffness and stickiness in more sickle cell disease patients so they can link the two properties with other disease and patient characteristics.

As the technology for making them becomes cheaper and more widely available, more and more researchers are using microfluidic devices in all kinds of ways to investigate, diagnose and perhaps even treat disease.

For example, Medical News Today recently learned how an "IVF chip" incorporating microfluidics with imaging techniques enabled researchers to film a single sperm fusing with an egg cell.

And in May 2015, another article described how scientists are using microfluidic technology to develop new immunotherapy vaccines. Using microfluidic technology, they can squeeze immune system B cells so their membranes develop temporary holes through which antigens that program specific immune responses can be inserted.

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New Tech Helps At-Risk Couples Ensure Their Kids Don't Inherit Their Illnesses

To be born with the right genes used to be a blessing. But thanks to technological advances, it is possible today for at-risk couples undergoing in-vitro fertilisation (IVF) to have their embryos subjected to genetic screening before being implanted in the womb. This way, the couple will know the child doesn’t have any genetic or chromosomal defects.

A Dr. shared a case study. Two partners – both carrying the genes for thalassemia, a life-limiting blood disorder – had tried to have a baby thrice but failed. The first two pregnancies had to be medically terminated after doctors diagnosed the foetuses with thalassemia and the third was a miscarriage.

Doctors then advised the couple to undergo IVF followed by pre-implantation genetic diagnosis (PGD). Two IVF cycles later, they had six embryos at the day-5 stage. An embryologist performed biopsies and sent the cell samples to a genetic lab to be analysed; the embryos were kept frozen. When the results arrived, they showed three embryos were ‘normal’ and three had inherited the genes for thalassemia. So doctors transferred the ‘normal’ embryos to the womb. Later, an amniocentesis confirmed that the child did not have thalassemia, and the mother delivered a healthy baby.


A diagram illustrating how IVF works: After ovulation, the egg is collected from the woman’s reproductive organs, fused with sperm and the resulting fertilised ovum is reinserted into the uterus. 

“Any additional embryos that are free of genetic problems are kept frozen for possible use later while embryos with problematic genes are destroyed,” the Dr.  said.

“PGD enables identification of genetic defects in the early embryo before the embryo is transferred to the uterus in an IVF program,” the head of the department of reproductive medicine explained.

The founder and scientific director  said that, “according to the Human Fertilisation and Embryology Authority, UK, PGD has been approved for testing over 600 genetic conditions.”

There are “numerous tests,” in Dr.’s words, that enable PGD. For example, scientists developed PGT-M – pre-implantation genetic testing for monogenic defects – to prevent the birth of a baby with genetic defects “when the previous baby was affected” or when the parents have “a history of inheritable disease in the family.”

Another kind is PGT-A, where the ‘A’ stands for aneuploidy, a condition where the body’s cells don’t have the normal number of chromosomes, 46. This gives rise to chromosomal disorders like Down syndrome. In PGT-A, embryos from parents presumed to be ‘chromosomally normal’ are screened to check whether the cells in each embryo contain 46 chromosomes. Such screening is called pre-genetic screening (PGS).

“At present, PGS and PGD are the only options available to parents trying to avoid the risk of having a child affected with a genetic disease, prior to implantation,” Dr. added.

PGD has been gaining traction of late. “Screening the embryo for possible life-threatening and debilitating genetic diseases before transfer changes reproductive options for families at risk,” the Dr.  told. “In some cases, further testing is needed during pregnancy to ascertain if a genetic factor is still possible.”

But “overall, PGD has been able to diagnose genetic defects with approximately 98% accuracy,” she added.

This is the result of major advancements in the last three decades, such as being able to visualise specific chromosomes using fluorescence in situ hybridisation, to produce thousands of copies of a DNA fragment using the polymerase chain reaction, and to profile genomes rapidly using next-gen sequencing (NGS).

This isn’t to say the procedure is entirely free of issues. For example, according to a review published by the American Society for Reproductive Medicine (ASRM) in 2017, IVF embryos sometimes have a condition called mosaicism – where all cells in the embryos don’t have identical sets of chromosomes. When these abnormal cells proliferate, it could result in a miscarriage or severe birth defects.

However, Dr. said, “Techniques like NGS have allowed for very high-fold coverage,” allowing scientists to detect “even low levels of mosaic mutations” and ensure only the healthiest embryos are transferred. In general, according to the review, NGS can eliminate mosaic cells when they make up fewer than a fifth of all cells in the embryo but fail when the extent of mosaicism crosses 50%. In the latter case, the embryo is deemed aneuploid and discarded.

According to Dr., the most frequently diagnosed disorders include those of blood and muscles, and other rare conditions such as cystic fibrosis, beta thalassemia, sickle-cell disease, spinal muscular atrophy, myotonic dystrophy, haemophilia A and Duchenne muscular dystrophy.

Since the requisite testing facilities aren’t widely available in India, results can take up to three weeks to arrive. But this hasn’t put people off from opting for it, especially since the procedure seems safe. According to the Centre for Advanced Reproductive Services, Connecticut, there has thus far been no increase in the rate of congenital abnormalities or pregnancy complications due to embryo biopsies.
Nonetheless, Dr Natarajamani hopes that non-invasive techniques will replace biopsies soon, given the inescapable risk the latter procedure carries in some cases.

Then there are the potential ethical issues. However, the Dr. is quick to defend PGD and draws a line between PGD and PGS as well as other, more morally fraught practices.

“PGD is clearly and absolutely indicated in certain circumstances, like in couples with a previous child with abnormalities, with a family history of abnormalities, etc.,” he said. “The debate is only about routine screening of all embryos, as in PGS, before embryo transfer or when [the technique] is used to identify the sex of the embryo.”

In his telling, the doctors’ decisions aren’t arbitrary but are guided by the recommendations of bodies like the ethics committee of the ASRM. For example, in an opinion published last year, entitled ‘Disclosure of sex when incidentally revealed as part of … PGT’, this committee reached the following conclusion:

“When patients undergo [assisted reproductive therapy] and PGT for medical reasons, embryo sex could be a common secondary finding. Patients should be informed of this possibility before undergoing PGT. Patients have the right to information about an embryo’s sex, as well as the right to request not to be given this information. Clinics may have policies not to take an embryo’s sex into account in making transfer decisions. Clinics must have nondiscrimination policies regarding embryo transfer when the sex of the embryo is known. Patients should be informed about these policies.”

Indeed, all genetic labs in India are required to follow guidelines set by the Pre-Conception and Pre-Natal Diagnostic Techniques (Prohibition Of Sex Selection) Act 2003.

The Dr. has no doubts: “PGD is an amazing technology and the application of next-gen sequencing [has been] a game-changer. It will reduce the incidence of genetic diseases and complications [associated with] multiple births.” She added that many IVF centres around the world have also been able to achieve “fantastic birth rates” after transferring “only one genetically normal embryo” into the womb.

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World Sickle Cell Day - Everything That You Should Know

World Sickle Cell Day is observed each year on June 19th to raise the public awareness regarding this disease and its treatment methods. Sickle Cell disease is an inherited transmitted deformity/abnormality of haemoglobin. It is an inherited form of anaemia. This abnormality generates changes in the shape of red blood cells from round to crescent, which reduces the oxygen carrying capacity and slows down the flow of blood to various parts of the body.

Generally, red blood vessels are round and flexible, passing easily through the blood vessels. The red blood cells become sticky and rigid in sickle cell anaemia. Sickle cells last 10 to 20 days, which causes anaemia because of the disorder of red blood cells, while healthy red blood cells could live up to 120 days.

Millions of people around the world are affected by Sickle Cell Anemia. There is no specific cure for this disease as Sickle cell anaemia is not contagious, it is hereditary. Sickle cell anaemia is named so for the reason that red blood cells are crescent-shaped or sickle-shaped, and anaemia signifies lack of blood. There is a difference between iron-deficiency anaemia and sickle cell anaemia.

Symptoms
Sickle Cell Disease (SCD) has many symptoms which includes: serious anemia, episodes of suffering, additionally a range of complications, heart failure, dizziness,  chronic kidney disease (CKD), acute chest syndrome (ACS), chest pain, gallstones, pulmonary hypertension, immune deficiency, paralysis or stroke, splenomegaly, joint damage mainly in the hip joint, foot ulcers, delayed puberty, retinopathy, and endocrine disorders.

Diagnosis
Sickle Cell Disease is diagnosed by blood tests.

Treatment
Bone marrow transplant or stem cell transplant in patients usually below the age of sixteen is the only available cure for the disease.

Aim of the World Sickle Cell Day
The aim of the World Sickle Cell Day is to support and promote research for the patients in order to help them upgrade their overall quality of life to the maximum possible extent. It also aspires to increase awareness for sickle cell disease disorder in the general public so that they know how to deal with patients suffering from the disease. Moreover, the World Sickle Cell Day has the objective of raising awareness of the importance among generations of pre-marital screening to lessen the transmission of Sickle Cell Disease.

Target Groups for Awareness Programs
Though it is desirable that everybody knows about Sickle Cell Disease, the target groups for the awareness programs include health decision-makers, sickle cell anaemia sufferers and their families, health organizations and associations, people who are planning to get married, and the health workers including health educators, physicians, and nurses.

On the World Sickle Cell Day, different societies provide advocacy, information, and advice for raising awareness. They also provide educational and welfare grants, support services, annual children’s holiday, home help, hospital visits, mentoring and befriending through holding talks, assisting into research and training, lobbying for better service provision, patient education seminars, and campaigning.

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