Clinical trails of gene therapy are starting to show improvements for sickle cell anemia

    

 According to an article in the New York Times, there have been advancements in gene therapy for those suffering from sickle cell anemia. The article discusses the journey of a specific patient named Helen Obando who was the first Am6erican teenager to become sickle cell free from these clinical trails. The technique used as of late to treat sickle cell anemia is a bone marrow transplant from someone who does not have the disease and is a close enough match. However, there are cases in which a match cannot be found (like Obando's). 

    There are three types of clinical trials involving the treatment of the disease using gene therapy. The first, being the trial Obando underwent, used the technique to turn off her adult gene used to form hemoglobin and turn on her fetal one. The reason behind turning on the fetal gene is due to its inability to carry the sickle cell gene whereas the adult gene does. This allows perfectly formed red blood cells to be produced if the trial is successful. The second trial applied by Vortex used CRISPR in order to turn on and off those specific genes. CRISPR is used to target specific genes within the DNA and is a great technique when used to point out the hemoglobin producing gene. The third trial is being produced by Bluebird Bio which uses an inactive virus to give to the patients that held the appropriate hemoglobin gene. Unfortunately, Bluebird Bio had to pause its trial because two of its patients developed cancer.

    The unfortunate truth about sickle cell anemia is that the African American population are primarily born with the disease. Due to this commonality of the disease between African Americans, the progress for finding new methods for a cure have been happening slower than what may occur for non-minority groups. The reasoning behind this is up to opinion, but I think it is worth a conversation to have and that our heath care system may need to take a step back to reevaluate their focus. 

Sickle-cell Disease Cure May Be on the Horizon

An article from The New York Times discusses that success may have been made in "the first genetic cure of a common genetic disease". Sickle-cell disease affects the blood. It causes red blood cells to have a sickle or crescent shape as opposed to normal cells with a more smooth and circular shape. (NIH) The sickle shape of the cell causes issues with the ability of the cell to move through the circulatory system. It typically affects individuals of African descent. There is one specific gene that causes sickle-cell disease. It was believed that the disease could be cured if they could fix the problem on a genetic level. Stem cells are taken from a patient's bone marrow and then they are genetically modified and put back in to the individuals bloodstream, with hopes that they will form new and healthy blood cells.

I know that sickle-cell disease can be very painful and dangerous. The young man in the article that received the gene therapy treatment had suffered from four strokes by the time he was 18. Many people also die from complications of this disease. The fact that we are capable of making changes to someone on a genetic level is incredible. This could be a huge stepping stone in treatment for many other genetic disorders.

Early clinical trial data show gene therapy reversing sickle cell anemia

The Cincinnati Children's Cancer and Blood Diseases Institute has been researching and developing a new gene therapy to combat the horribly inherited disease, sickle-cell anemia. After finally being able to treat two patients, and now a year and six months after treatment, both patients are seeing "remarkable improvement in the quality of life due to remarkable reduction in disease symptoms."

This therapy developed in Cincinnati uses "modified gamma globin lentivirus vector to transfer healthy fetal hemoglobin (HbF) gene into a patient's blood stem cells." If sufficient amounts of HbF are present in the human body, the blood cells cannot "sickle" and therefore are able to properly transport oxygen through the blood. First, cells are collected from the sickle-cell patient and genetically modified with the lentivirus. Then after a low dose of chemotherapy to the patient's bone marrow, the newly corrected cells are placed back into the body. The goal of such gene therapy is to make it most accessible and affordable in Central Africa, where sickle-cell is rampant. However, some 90,000 people in the United States are still plagued with the disease.

As mentioned, the patients who received gene therapy have been experience a better life after their treatment. After only 15 and 12 months, patient one had only one acute sickle event and the second has had no issue with blood cells becoming stuck in the bloodstream. Cincinnati Children's hopes to be able to further their research and continue to treat more patients with less harmful treatments so the quality of life for genetically sickle-cell patients continues to improve.

The research done in Cincinnati seems to have been successful for the sickle-cell community. I am sure that those who suffer from or have family members that suffer from this horrible disease would be glad to see treatment option soon available, with little harm and to their health, and seemingly quick relief of past symptoms.
https://www.sciencedaily.com/releases/2018/12/181204095344.htm
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139383/
https://www.cincinnatichildrens.org/service/c/cancer-blood/cancer

How One Child's Sickle Cell Mutation Helped Protect the World from Malaria

Recently a study conducted by the Center of Research on Genomics and Global Health, a part of the National Institutes of Health looked into how humans obtained sickle cell anemia. This genetic mutation alters ones hemoglobin which is the molecule on the red blood cell that moves oxygen throughout the body. Roughly 7,300 years ago in Africa, scientists have found that if a person had two copies of a mutated hemoglobin gene led to the sickle cell shape attributed to the name, sickle cell anemia. However, researchers were left in a, "genetic mystery," onto why this mutation never died off. It was discovered that if a person had one mutated hemoglobin gene this allowed that individual to survive the mosquito transmitted disease, malaria, a wide spread disease in Africa at the time. Essentially, if an individual had only one copy of this allele they were safe however, if one was to have two copies of this allele, their blood cells would be defective and clog the blood vessels in the body. This discovery led researchers to believe that the development of sickle cell anemia is linked to human survival of malaria.

Article: https://www.nytimes.com/2018/03/08/health/sickle-cell-mutation.html
Original Study: http://www.cell.com/ajhg/fulltext/S0002-9297(18)30048-X

A Possible Cure for Sickle Cell Anemia

                Sickle Cell anemia is a blood disorder that affects 100,000 people in the United States alone. Sickle cell is an inherited genetic disease that results in an abnormal amount of hemoglobin causing blood cells to be  crescent shaped. While normal red blood cells live for about 120 days, sickle cells only live ten to twenty days max.

                 The current treatment for sickle cell anemia is blood and marrow transplants. However many complications arise with these procedures. Some patient's body's simply cannot handle the transplant procedure, while others begin to develop an immune response to the foreign blood.

                In response to the problems regarding sickle cell treatments, researchers at John Hopkins University  are looking for new ways to cure the disease. By extracting stem cells from sickle cell patient, researchers have successfully corrected the genetic mutation that cause sickle cell. Linzhao Cheng, one of the researchers explained how the process occurs.  The patient's own blood cells are extracted and then  reprogrammed to act as stem cells. By making these stem cells and reproducing them, the researchers can cut out the sickle cell defect and replace it with a healthy gene. The last step of the procedure is to create an environment in which the stem cells would grow into healthy red blood cells.

                This is an amazing breakthrough in science however it is extremely time consuming. Before this treatment is available to sickle cell patients everywhere, the side effects of the lab grown blood cells must be tested and a much more efficient way to create these cells must be determined. Although this research is still in its early stages, the discoveries that comes from this could help people avoid other blood diseases such as malaria.

Original Article: http://www.medicalnewstoday.com/releases/290673.php

Second Article: http://www.nhlbi.nih.gov/health/healthtopics/topics/sca/treatment

Sickle Cell Trait Has Possible Link to Chronic Kidney Disease Among African Americans

A large multicohort study, conducted by a research team at John Hopkins University in Baltimore, found a possible association between sickle cell trait (SCT) and chronic kidney disease (CKD.) African Americans with a sickle cell trait do not develop sickle cell anemia but instead carry a single copy of the gene that is known to cause the disease. Sickle cell anemia is a disease that is characterized by misshaped red blood cells (sickle cells) that are sticky and stiff leaving the blood vessels more prone to obstruction. In contrast, SCT is less severe where only in very rare cases do people develop deformed red blood cells as a result of severe dehydration.

The researchers noted a gap in knowledge regarding possible conditions influenced by SCT. They highlight that African Americans have a disproportionately higher risk of developing chronic kidney disease and progression to end-stage renal disease (ERD.)  “SCT may be an important and unrecognized risk factor for renal disease in this population.” The study analyzed 5 US population based studies involving 2,233 African American participants 1,248 of which has SCT. 2,233 individuals had CKD, with 19.2% of individuals with SCT and 13.5 without the condition.

These findings imply that there is a higher risk for developing CKD in African Americans with SCT. In addition, researchers found that individuals with SCT have a faster decline in the rate at which fluids are filtered through the kidney. Further, 31.8% of people with SCT experienced albuminuria, a sign of a kidney disorder characterized by excessive protein in urine.

This study suggests the need for more research on kidney disease and other renal complications. Kidney failure is the 8th leading cause of deaths in the US. 90% of people with stage 3 CKD are unaware (Kidney Fund.Org, 2012.) This article is specifically significant to me because I have family members who have complications with their kidneys and who are on dialysis. If there is a better way to detect possible links between genes and the development of kidney disease perhaps possible interventions and medications can decrease the number of people affected in this vulnerable population.  

 Article: http://www.medicalnewstoday.com/articles/285322.php

Additional Link: Kidney Fund. Org. (2012, August 12). Kidney Disease Statistics. Retrieved from http://www.kidneyfund.org/about-us/assets/pdfs/akf-kidneydiseasestatistics-2012.pdf

DNA Favoritism Leads to the Continuation of Diseases

     There are many diseases that are passed down from generation to generation that are extremely harmful to those who are affected, while other disease are beneficial to the population. Some examples include Sickle Cell Anemia, six fingered dwarfism, and other genetic diseases. Typically individuals are supposed to acquire one-half of their genes from their mother and one-half from their father, but a recent study shows that this may not be the case.

Sickle Cell Anemia can be beneficial to those living in places with high rates of Malaria, giving the bacteria that cause Malaria a less livable environment than normal red blood cells. 

      Joseph Lachance and Sarah A. Tishkoff have studied gene conversion during meiosis and have found that certain forms of DNA are biased, potentially explaining why certain diseases are still very common throughout the population. One phenomenon believed to have lead to a small amount of bias is GC-bias, where a DNA mis-match causes one of the alleles from parent to be replaced, possibly by another allele from the same parent. This would result in the offspring having two alleles from the same parent instead of one allele from each.
 
       In order to see if this bias is the reason that so many diseases are persistent in their appearance in the population, Lachance and Tishkoff analyzed the genetic sequence of twenty-five individuals from five very diverse populations. Of the many polynucleotide sequences found, they grouped the mutations involving a single nucleotide into groups according to the type of change that occurred (either G and C to A and T, or the reverse). They discovered that GC-bias did play a role in deciding which genes underwent changes, but they also found that in areas where recombination occurred, were very popular spots for gene conversion.

      Although, the strength of their results was not incredibly strong, the results to do show that GC-bias is responsible for certain diseases still existing among certain populations. They also found that the reason GC-bias keeps diseases around is because often when the genes are converted, they are given another of the same allele, making the individual homozygous. If this allele is the recessive allele, and the disease is homozygous recessive, then the offspring will be affected with the disease and the chance of it being passed on becomes greater. If the GC-bias is occurring often, as Lachance and Tishkoff have shown, then if the conversions are equipping offspring with the genes for a disease, there is more of a chance that the disease will stay common in a population.

Orginal Article: DNA bias may keep some diseases in circulation, biologists show