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Genetic Engineering
Genetic engineering shows impeccable promise as a future modality of curing various diseases from their root. Genetic therapies have been studied for the last few years by researchers within the medical field and the results are promising to revolutionize the healthcare sector. Attempts have been made over the last few centuries to understand the disease given the knowledge that it arises from a mutation. Studies investigate the possibility of gene therapies as interventions (Brody, 2021). There have been trials for various gene editing mechanisms and there is reason to remain optimistic because a cure is within sight.
Sickle Cell Disease Cause and Effect
Understanding the use of genetic therapies in Sickle cell disease (SCD) requires an understanding of the mechanism of occurrence of this disease and its effects. SCD arises from a mutation in one gene which encodes for the protein beta-globulin, a component of hemoglobin. Patients with SCD, therefore, have abnormal red blood cells with inadequate oxygen-carrying capacity (Brody, 2021). This means that the ability of these people to perform various activities is impaired. The oxygen carried by the sickle cells is not adequate to meet their needs, while the normal red blood cells are not capable of compensating for the inadequacies of the sickle cells. The shape of sickle cells is like that of a sickle, contrasted to the normal shape of red blood cells which is round biconcave. This shape is not ideal for the various vessels such as capillaries where the cells pass to deliver oxygen to the various destinations (Brody, 2021). The inability of sickle cells to pass such barriers is associated with a feature of SCD known as painful crises where the patients suffer massive pain from the blocked sickle-shaped cells in the capillaries.
Gene Therapy Focus and the Use of Lentiviruses
Gene therapy is, therefore, required to focus on changing the genes producing the beta-gene in the body. This is likely to ensure that the produced red blood cells have the necessary protein which bears the normal shape of the red blood cells. They can therefore carry oxygen as originally intended and pass the capillaries without much difficulty. Approaches for gene therapies for sickle cell disease have been underway and the studies show massive promise with negligible side effects when compared to the benefits. Gene therapies for SCD have included the introduction of lentiviruses into the genome of various patients to attempt editing specific genes (Eisenstein, 2021). The editing of these genes is intended to ensure that the beta-globin gene is repaired and that they produce proteins as originally intended in the biconcave shape. The viruses are introduced with retroviruses that produce the normal beta-globin protein as intended. A modification to this mechanism has been the introduction of a virus that additionally inhibits the production of the impaired gene.
The introduced retroviruses operate like viral infections which rely on host mechanisms to replicate. The viruses are added to the host genome, transcribed alongside host genes, and translated as proteins in the human cytoplasm. The translation yields the intended protein for the red blood cells which is normal in shape and can be relied upon to meet oxygen demands. An additional approach using the retrovirus mechanism has been the restoration of fetal hemoglobin (Eisenstein, 2021). During the antenatal period, gamma-globulins are relied upon to meet fetal oxygen demands. The globulins are contained within fetal red blood cells and their oxygen-carrying capacity is impeccable to ensure they compensate for the scarcity within the uterine environment. Shortly after birth, the production of gamma globulins is gradually phased out and replaced with the less efficient beta globulins, stimulated by the beta globulin gene in the genome. This approach using viruses seeks to restore the efficient gamma globulins for patients with SCD to compensate for the inadequacies presented by mutations within the beta globulins genes.
Trials using the viruses have gained momentum over the last few years with various companies making attempts. Three people were treated by Cavazzana’s group using this approach, and this has achieved a massive reduction in sickle-cell symptoms (Eisenstein, 2021). Kohn is another institution that has conducted small trials and they currently have a second patient undergoing trials (Eisenstein, 2021). Bluebird Bio’s current trial cohort consists of 25 patients who have undergone the therapy using lentivirus and is the most reliable guide to the efficacy of this mechanism (Eisenstein, 2021). Preliminary results indicate that the participants have benefited from the production of functional hemoglobin and reduced symptoms such as pain, hence minimal visits to the hospital for pain relief. The risk with the virus insertion technology is the possibility of evoking unintended consequences for the recipients.
Hematopoietic Stem Cells Transplantation Technology
The hematopoietic stem cell transplantation technology is an additional mechanism for curing SCD. This mechanism involves the stimulation of the production of hematopoietic stem cells from a patient and their isolation outside the body. The isolated cells are thereafter analyzed and their genome is isolated for manipulation. These are injected back into the host’s body and the production of abnormal sickle-shaped red blood cells is inhibited through the use of chemotherapeutic agents (Eisenstein, 2021). The reduction in the production of abnormal cells by chemotherapy and the injection of the modified genes and cells ensures that the new red blood cells produced are normal. The mechanism does not necessarily require the destruction of the host’s existing abnormal cells, but instead, a 20% reduction is adequate to allow the modified cells to thrive. The injection of these newly modified stem cells and the subsequent production of normal red blood cells improves the oxygenation capacity of the patient’s blood.
The CRISPR-Cas9 Gene Editing Technology
The CRISPR-Cas9 gene editing technology is a safer alternative for managing SCD which averts the risks posed by using the virus. The use of viruses presents the possibility of unintentional damage to other genes within the body. The CRISPR-Cas9 technology uses a guide RNA which allows the injected genetic material to settle at a specific site within the recipient genome (Eisenstein, 2021). The Cas9 enzyme splits the double-stranded human genome, allowing a series of deletions and insertions at the site. These changes alter the gene sequence and cause the production of a different RNA during transcription and a different protein during translation (O’Leary, 2022). These combine to produce red blood cells without sickle cell deficiencies, and improved oxygenation for the patients. More specifically, the CRISPR-Cas9 gene technology alters the production of gamma globulins, increasing their quantity in the recipients who need them (Eisenstein, 2021). This change follows a modification of the BCL11A gene within the DNA, enabling targeted changes, and averting the risks of generalized insertions.
The Challenge of Cancers
The field of gene therapies is a slippery trial with the possibility of causing unprecedented catastrophes. These arise from the level of manipulation of the human being at the basic level, the genome. The risks associated with these attempts include the possibility of multiple cancers occurring within the patients. The lack of adequate specificity with the modification technologies means that there is a possibility that an unintended gene could be affected. The cancers likely to arise from these trials include acute myeloid leukemia which has been reported in multiple trials. Bluebird Bio was among the firms that halted its modification attempts when acute myeloid leukemia was reported in its two participants (Eisenstein, 2021). The suspected causes of these mutations and cancers include activation of cancer-promoting genes by the viruses and uncontrolled growth of bone marrow hematopoietic stem cells.
The challenge of cancers is a big roadblock for gene therapies for SCD and the use of the approach in curing other diseases whose root cause is abnormalities within the DNA. This challenge has to be weighed by professionals within the field, and the general public to assess whether the benefits outweigh the risk. On one spectrum of this study is the ability to combat a disease that has plagued the human species since the start of time and the other is to abandon the endeavor due to the challenge of cancer. The fruitful undertaking is to devise a mechanism for overcoming the problem of cancers while keeping the studies alive.
References
Brody, H. (2021). Sickle-cell disease. Nature, 596(7873), S1. Web.
Eisenstein, M. (2021). Gene therapies close in on a cure for sickle-cell disease. Nature, 596(7873), S2–S4. Web.
O’Leary, K. (2022). A new frontier in CRISPR technology. Nature Medicine. Web.
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