About Sickle cell anemia

The sole treatment for sickle cell anemia, an inherited condition, is bone marrow transplantation with gene therapy. The beta GAG GTG point mutation, which causes glutamic acid to be replaced for valine at position 6 in the beta globin chain, is the cause of SCA. The sickle gene's pleiotropic character and other phenotypic manifestations of the mutation result in complicated genetic interactions that have not yet been fully explored. All of the body's organs and tissues are therefore affected by the SCA's various related problems. Bone marrow transplant or hematopeitci stem cell therapy has been the only potential treatment providng the quality of life for the suffering people with SCA. There have been evident reports with the effcetiveness of HSCT for SCA with lower relativemortality rates. However, there have been implciations associated with HSCT due to the limited number of avilabale HLA-ID donors and this limits the avilability of treatment to every idividula. Whereas gene therapy has no such limitaions, yet, has not been very successful in humans. Although it has been th only potentila cure for the SCA, however, there has bot been avilable any relaible research results in support of gene therapy. Also, it has been a costly apporach. Therefore, concluding from the research, bone marrow transplant has been a bette rtheraputic approach over gene therapy in th treatment of SCA.



Introduction

Sickle cell anemia (SCA) is a genetic disorder with no specically cure until today, except the bone marrow transplant (Ballas et al. 2012). Gene therapy as a potential cure for SCA has been proposed long ago where a targeted delivery of the antisickleling gene into the regenerating hematopoietic stem cells (HSCs) for a permanent purpose could lead the production of corrected RBCs in patients (Ballas et al. 2012).

Although being the ultimate cure for SCA, gene therapy has still not achieved the feasible scores in treatment conditions. However, there have been made some significant modifications at achieving the basic level of hemoglobinopathic genetic corrections (Ballas et al. 2012). While, recently there have been suggested some advancements in genetic manipulation using non viral methods of editing of genes with therapeutic relevance (Hoban, Orkin, and Bauer, 2016).

SCA is a cause due to a point mutation in exon 1 of beta glogin GAG → GTG causing the subsitituion of glutamic acid by valine at the 6th position of the peptide chain of beta globin. The mutation has multiple phenotypic expressions incuding the pleiotropic nature of the sickle gene, causing complex genetic interactions which have not been understood so far. Therefore, the SCA has numerous associated complications affecting all the body organs and tissues (Ballas et al. 2012).

Since the SCA has multiple complicated effects and has still not found any spefic cure through any theraputic means except gene therapies and bone marrow transplant, where their effects and efficiency has been debatable, it provides an immense scope for the future research. Therefore, notably seeing the demand for the indepth research in the SCA the current work has been chosen with a purpose of throuogly analysing the review research studies regarding the treatment options for sicikle cell anemia and self evaluates the order and process of the study (Ballas et al. 2012).

The study is being conducted to understand the currect status of the treatment therapies, their effectiveness, and long term benefits in the patient. Since there is a personal interest in selecting the topic, the work has been structured in order to find a scope for future growth in the similar filed by gowing a better understanding through previously done reserach studies. Therefore, the purpose of the study is to find the treatament therapies for SCA and their associated benefits and risk. The study will be able to answer the reseach question i.e. Which is a more effective treatment for Sickle Cell Anaemia – Gene Therapy or Bone Marrow Transplant?

The answer to the research question will be followed by a qualitative process of evaluation and analysis from the selected studies for literature review and an end conclusion will be made accordingly.

Literature Review

This section of the paper is focused on discussing the various research studies that have been carried in previous years in order to understand the relationship among Sickle cell anemia and the treatment outcome sof gene therapy and bone marrow transplant. This part provides an insight into the recent research and the selected topic with the with the further scope in future.

In a research of Hoban, Orkin, and Bauer (2016), they have reviewd the work of several groups within the past few decades, who have been working in order to achieve the methods which are safe and efficient for gene transfer in HSCs among SCA patients. Based on their research they proposed must achieve two main objectives in order to have gene theray as a reality for the SCA. The objectives included (1) “safe and efficient gene transfer or correction of long-term repopulating HSCs” and (2) “high-level, appropriately regulated, stable gene expression” (p.3). As per the recent clinicl progress status, the goals have reached an achievable point. Theorugh the achieved discoveries and the insight into the development of beta globin gene clustures the the path has been marked for the gene therapy in SCA (p. 3).

Lucarelli, Isgro`, Sodani, and Gaziev, (2012) mentioned in their research the severe organ damage in the SCa patinets due to the polymerization of HbS sequence, microemboli formation, intima vessal adhesions and infraction of organs. However, it can be cured through gene tehrpay and hematopoietic stem cell transplantation (bone marrow transplant) due to its genetic origin.

There has been an association of morbity with SCA and HSCT has bene the only therapeutic cure where its outcomes have been excellent from the matched donor siblings; however, its applicability ahs been limited due to the lack of a donor sibling math and have bene raising concerns in relation to regimen related toxicity (Lucarelli, Isgro`, Sodani, and Gaziev, 2012).

While they performed the first transplant in 1993 on a 16 old girl suffering form SCA, however, ever since there has been seen only slow progession in transplantation of stem cells and about 250 transplants performed till date. The reason for the conservative approach for transplant for SCa has been the absence of indictaions that have bene universally accepted for the transplant.

The bone marrow transplant has encountered a lack of identical HLA donor as a frequent barrier for SCA treatment with the linmited current approach which has been stopped HSCT for patients older tha 16 years of having advanced organ damage due to the reasons of high regimen related gimen- related toxicity. The attempts have been made for reducing the preparative level of regimens for patinets with SCD focused on two approaches. First is the myeloblationproduction, requiring the infusion of donor’s marrow for the recovery of hematopoeitic cells. Second, includes the recovery of hematopeitic cells without donor cell infusion by non eradicating hematopoeis of the host. There have been reported the sustained engraftment along with the reduction in the regimen intesnity (Lucarelli, Isgro`, Sodani, and Gaziev, 2012).

As per their study, there have aslso been achived a higher rate of cure by following current protocols of myoblative conditioning and perfomring the HSCT on SCA children. Whereas the investigators think all memebrs of a family of an SCA child should undergo HLA typing because HSCT can be perfomed on all the SCA patients above 17 years, therefore, if the matched identifie for a sibling or a parent, the major complications can be prevented before it affects the child (Lucarelli, Isgro`, Sodani, and Gaziev, 2012).

There has been a reduced quality of life of life associated with substantial morbidity and short expenctany with SCA. Within the past two decades, the survival has been significantly improved due to better surviellence with a rate of 94% under 18 years of age. However, the case of mortality has been still significant among adult pateints due to unpreventable complications of hypertension, strike, chronic pulmonary necrosis, recurrent venoocclusive crises, and priapism. Thereore, according to Angelucci et al. (2014), HSCT has been the only approach for the cure of SCA.

According to Angelucci et al. (2014) research study, HSCT indication in SCa has been based mainly on the mobidty associated withSCA, there will be a strong indication of the severity of sickness of the child. With a transplantation related mortality reduction along with the elevated knowledge of complication and severity in untreated patients within the past years, the indications for accepting HSCT has become less restrictive. Also, according to their research, HSCT has been the only available treatment cure for current hemoglobinopathies.

The outcomes of transplantation have been improved in comparison to past five decades, with transplant survival rates of more than 90% and disease free as more than 80%. Therefore, the research stated if there can be a future cure in terms of gene therapy for SCA, there would be a requirement for the equivalent results regarding benefits and cost ratio with HSCT, which has been widely applied as a cure in standard therapeutic treatments of hemoglobinopathies (Angelucci et al. 2014).

According to studies there have been made some observed regarding the SCA cure for the suffering children using HLA- indentical (HLA-ID) boe marrow transplant form siblings. Suseqntly the investigators have also reported form the past studies there have been an associated cessation of clinical complications, prgan injuries in SCA due to graft establishment (Walters, 2015).

During the encouragement of successful outomoes of the observed investigations, there have been illustrtated the important and borader ways of utilizing the HSCT. In an “Evidence-Based Management of Sickle Cell Disease treatise published in 2014 by the National Heart, Lung, and Blood Institute” there has been proposed and concluded a requirement ofr additional reasech in order to sddress the potential theraoutic risks like graft failure in Graft versus host disease (GVHD), before using HSCT as a widely used therapeutic study (Walters, 2015).

Walters (2015) mentione din their study, there have been fewindividuals with suitable doners at the first place with an estimated rate of 14% SCa individuals will be having the suitable HLA-ID doner sibling while 19% with a volunteer unrelated marrow donor suitable match. Secondly, there has been a risk of treatment related morbitidy due to GVHD along with higher infertility risk. Therefore, a reluctance has been caused among affectd person and the families due to this consideration which has also been followed by the SCA experts in regard to recommend and persue the therapy (Walters, 2015).

. As mentioned in the above discussed sections, HSCT for SCA has been facing major barriers due to lack of donors and requires a feasible otion of expanding the avilabilty of unrelatated HLA compatible donors for the therapy. The donors matching the six “(HLA-A, B, and DRB1 loci) to 10 HLA antigens (including HLA-C and DQB1 loci) can be identified via the National Marrow Donor Program” (Walters, 2015); however, the chances of finding HLA matched unrelated similar donors have been less likely among ethnic groups due to HLA diversity and under representation among volunteer donor pool. Therefore, there have been lesser chances of finding a suiabel donor for all SCA indviduals at the current situation.

While discussing the bone marrow thearaputic approach for SCA, there has been a successful case published in a recebt article regarding gene therapy for SCA as indicated in the journal of New England Medicine.

SCA has been mainly affecting people from Africa, Caribbea, Middle East, and Asin and East Mediterranean and has been approximately to be affected around 5mn in the entire wolrd. The victims usually are affected by anaemia at first, feeling weak and tired, appears to have a higher risk of infections, stroke alon with the experiences of severe body pain.

According to Gulf times article (2017), “a team from the AP-HP university hospital group in Paris, the Imagine Institute of Genetic Diseases and gene therapy company bluebird bio said they managed to get a French teenager off transfusions”. The child has been the first victim to receive treatement for SCA, in October 2014 in Paris, in a gene therapy in trials in the clinical trials. Although others clients have also been tested, however, no official publications have been published.

The team invoved in treatment has gathered the haematopoietic stem cells, from then aged 13 years old boy’s bone marrow. The immature cells have been treated with a therapeutic gene, which has been carried in a deactivated virus in order to recod the DNA in order to gather the production of blood cells. According to the data related to health of the kid after 15 months of treatment revealed he has been doing well so far while the officially oublished result on the peer journals ahave been still pending. As per the report, study leader Maria Cavazzana has mentioned: “He is well, he no longer needs monthly (blood) transfusions, anti-pain medication, or hospitalization” (2017).

A medicine professor Philippe Leboulch in Paris University, has told the BBC News program about the requirement to perfom the same therapy in many other patinets in order to feel confindent about the robust successful approach and proposing it as the mainstream therapy. While Prof Leboulch has been still nervous regarding the use of the word “cure” due to the results being proven only on the first person during clinical trials. The aspect is due to the fact that this is just the first client to heal through trials in the clinical stages. While the research does have shown the underlying capability in the therapy of the gene regarding transformation of the lives of victims with SCA. However, the has been expensive and can only be done in cutting-edge healthcare facilities and labs, while most SCA victims have been living in African continent. Therefore the upcoming issue will be the transformation of the initila science into things that really can help a lot of people (2017).

Methods and Analysis

This section of the chapter has been focused on briefing the process and protocls applied while carring the research. This section will help in sorting out the technqiues being used while performing the work and the techniques and approaches that will be used for evaluation of the work.

The current work has been based on qualitative approach. The reseach articles have been searched using system based approach using the database. NCBI, PMC has been used for finding the article withs specific key words as “sickle cell anemia”, “ gene therapy, and “ bone marrow transplan.” The articles have been selected using filters for the search within 5 years for human species. The most relevant articles were seleted for the literature review and analysis. The analysis has been done using a qualitative approach. Each article was reviewd crtically and analysed through by studing the aim objectives, implications, relevance to the study, outcomes, and limitatios with respect to the current study topic.

Conclusion

The Hematopoietic stem cell transplantation for SCA has evolved to become from initially reported cases inorder to become an important therapeutic option with a curative potential. There have been successful results of the use of HSCT as being the only successful therapy in SCA with the successive future outcomes in the proceeding years. However, the furture of this treatment approach has been hinging upon the broad availability of donors and To achieve the success rate of HSCT after the HLA-ID. The future of HSCT has also been relying on the communication of the natural SCD history among families and their providers, and by discussing HSCT as an important treatment option, even if not preferred, for the ones who have severe SCD (Walters, 2015).

Along with HSCT, there have been successful cases of gene therapy treatment approaches in SCA which appears more promising with a better future in terms of curing the SCA. However, there has been observed consequences with gene therapy in SCA. As it has been a costly procedure, it can not be available by every person. There have been risks associated with the viral vector inflammation during the viral vector methods of gene transfer. Also, there have not been seen very much potentially successful cases of gene therapy in humans, making it an unstable approach so far. Although it has a potential to cure the to the SCA and many genetic disroders, gene therapy has its implications and limitations rendering it less successful in the current scenario, while bone marrow transplant has been in recent practice and there have been seen positive outcomes. It might not be the complete cure, however, it has a potentially better scope in terms of life quality inSCA patients. Therefore, it has been evident from the studty that amomg gene therapy and bone marrow transpalnt (HSCT), bone marrow transplabt has been a better approach so far.



References

Angelucci, E., Matthes-Martin,S., Baronciani, D., Bernaudin, F., Bonanomi, S., and Cappellini, M.,D. et al. (2014). Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Hematologica, 99(5), 811-820.

Ballas, S.K., Kesen, M.R., Goldberg, F.M., Lutty, G.A., Dampier, C., Osunkwo, I., and Wang, W.C. et al. (2012). Beyond the Definitions of the Phenotypic Complications of Sickle Cell Disease: An Update onMan agement. The ScientificWorld Journal, 1-55. doi:10.1100/2012/949535.

Gulf Times. (2015). Gene therapy hope for patients with sickle cell disease[online] (updated 2015) Available at: http://www.gulf-times.com/story/535292/Gene-therapy-hope-for-patients-with-sickle-cell-di

Hoban, M.D., Orkin, S.H., and Bauer, D.E. (2016). Genetic treatment of a molecular disorder: gene therapy approaches to sickle cell disease. Blood,127(7),839-848.

Lucarelli, G., Isgro`, A., Sodani, P., and Gaziev, J. (2012). Hematopoietic Stem Cell Transplantation in Thalassemia and Sickle Cell Anemia. Cold Spring Harb Perspect Med,2:a011825. doi: 10.1101/cshperspect.a011825

Walters, M.C. (2015). Update of hematopoietic cell transplantation for sickle cell disease. Curr Opin Hematol, 22(3), 227-233. doi:10.1097/MOH.0000000000000136.