Current Prospects on Genetic Engineering in the Health Sector

Considering the Example of CRISPR- and Car-T-driven Applications


Essay, 2018

17 Pages, Grade: 1,0


Excerpt


Regarding the current prospects on genetic engineering in the health sector, considering the example of CRISPR- and Car-T-driven applications

With the advance of genetic engineering (GE) new risks and opportunities have come under scientific focus, heralding in the prospect of treating many illnesses such as cancer and germ-line diseases both efficiently and effectively.Clustered Regularly Interspaced Short Palindromic Repeats(CRISPR) assisted approaches embody a new and improved method to perform GE in a very accurate and inexpensive manner when compared to other established methods. Proposed treatments include targeting specific mutated cell lines usingChimeric Antigen Receptor T-Lymphocytes(Car-T) as well as direct editing of the genome to eliminate harmfully mutated gene sequences. Furthermore, the application of CRISPR in the creation of self-propagating genes viaGene Drive(GD) may become an effective and possibly even necessary method to control the dissemination and prevalence of insect-borne diseases.

This essay aims to review foundational arguments in order to facilitate an educated judgement of the current trends in GE. As the field of GE encompasses many different approaches to handle multi-faceted problems and reach diverging goals, it is necessary to define the frameworks of my review. As such, I will put my main focus on presenting the circumstances surrounding applications associated with upholding or improving health standards across national borders. To do so, I will put forth the advantages and possible applications of prominent GE approaches while highlighting a few potential, associated risks that have already been demonstrated empirically. Even within this limited framework, neither does a generalised judgement applicable to health-associated GE exist, nor will over-arching reviews of GE be possible in the near future due to the fact that the use of GE depends heavily on the sub-field it is employed in as well as on the specific environmental and qualitative factors associated with its use. Those include (but are in no way limited to) global availability of research and derived treatments (in itself determined by financial, social and religious climate of the nation), amount of control and adjustment possible as well as the scale of potential failures (unique to method chosen). Nevertheless, it can be said that optimal utility of any approach can only be harnessed under strict and educated supervision. As they are now, a lot of GE procedures do not allow for suitably high levels of control. Certain areas - especially e.g. direct germ-line editing - demand necessary restrictions (such as administration to only specific patient profiles by professional staff etc.) to be agreed upon in order to increase treatment efficiency and prevent misuse. These are crucial to ensure sound morality and overall enrichment to mankind.

To show the empirical validity of my thesis I will adduce three exemplary cases in which GE has found implementation, directing attention specifically to theCRISPR/CRISPR-associated protein 9(CRISPR/Cas9) system, and thereupon discuss the prospects and contingent risks of these methods. Firstly, Car-T as a treatment for specific types of cancer (Kymriah) recently approved by the FDA in America embodies a new opportunity to handle cancer that has in some way evolved to resist tried and tested procedures (FDA News Release, 2017). In particular, it possesses the capability to combat cases of frequently relapsing types of cancer where traditional methods fail. Secondly, with an ever-growing need to increasequality-adjusted life yearsand decrease mortality associated with hereditary diseases non-causative treatment that focuses on simply alleviating the worst symptoms may become regarded as insufficient care. With the option of editing mutated sites in an individual’s genome via the CRISPR/Cas9 system a complete cure may be in sight. Finally, insect-borne diseases represent a substantial proportion of preventable casualties, particularly in nations with warmer climates and limited access to medical supplies. By employing CRISPR-assisted Gene Drive it becomes possible to greatly influence the genetic make-up of wild mosquito populations, even going as far as significantly reducing their population size. In all the above-mentioned cases, strict supervision and control is necessary in order to produce desirable effects. The methods are only to be regarded as tools that possess no intrinsic moral value of their own. However, their application may become morally questionable when misused.

Car-T utilises a CRISPR or retrovirally facilitated approach to induce expression of artificial, recombinant CAR on the patient’s (or a donor’s) T-Lymphocytes (TL). These are specially removed for this purpose - thereby treating cancer with the assistance of the patient’s own immune system and thus increasing treatment success (National Cancer Institute, 2017). Simplified, CAR functions similarly to conventionalT-cell receptors(TCR) in inducing immune responses. However, the treatment also poses risks in form of e.g. thecytokine-release syndrome(CRS) in which excessive TL activation may lead to severe systemic inflammation. As the modified TL continue to proliferate (as an integral part of the patient’s immune system) the modified naïve TL differentiate into cytotoxic effector cells, which act as a form ofliving drugsimulating immune responses via cytokines etc. and lowering treatment rejection. Car-T constitutes a very potent, self-renewing agent against certain types of responsive cancer, albeit this should be weighed up against overstimulation of the immune system as a potential risk.

Car-T treatments have undergone a variety of trials and have proven exceptionally effective when dealing with multiple forms of cancer. Clinical trials have shown the potency of Car-T treatment especially in cases of CD19-positive B-cell malignancies. A comprehensive review of studies involving CD19-targeting Car-T treatments shows that in about 250 patients more than 60% responded positively (Hartmann et al., 2017). This can be explained by the high degree of target specificity of CD19, which is only expressed on B-cell lineage cells and is lost upon maturation into plasma cells. However, a few of the available treatments have shown a correlation with neurological toxicity (Hartmann et al., 2017). Further toxicity due to recognition of similar, non-intended antigens (off-target) or non-cancerous tissue (on-target, off-cancer) as well as the aforementioned CRS have also been observed (Hartmann et al., 2017). A number of approaches to introduce a suicide switch (Zhang et al., 2017) or synthetic control devices in order to enhance control over active effector cells are currently being researched. As such, even though Car-T treatments are not without risks, both the responsiveness of patients as well as ongoing research to decrease Car-T associated side-effects show promise, especially for B-cell lineage cancer.

A very prominent case has been demonstrated in the successful treatment of relapsingChildhood Acute Lymphoblastic Leukaemia(ALL) - one of the most common types of childhood onset cancer - of Emily Whitehead. She did not respond well to chemotherapy but to date has been able to live for upwards of five years in remission. Whitehead was part of a trial led by Stephan Grupp, M.D., Ph.D., of the Children’s Hospital of Philadelphia, where twenty-three of the thirty participants with ALL showed a complete response to the procedure with no signs of recurrence when examined a month after beginning of treatment (Maude et al., 2014). Nevertheless, the treatment is not risk-free, as the increased number of proliferating TL are associated with mild to severe CRS. This syndrome is characterised by systemic inflammation caused by the high release of pro-inflammatory cytokines and acute phase agents (such as IL-6 or CRP) due to the excessive activation of TL. In eight of the reported cases severe CRS led to (non-infective) fever, hypotension and coagulopathy as well as dependency on respiratory support (Maude et al., 2014). Therefore, while moderate to severe side-effects appear common in association with Car-T treatment, it has nonetheless proven itself very effective when dealing with relapsing cancer on the basis of several long-term observed cases.

Car-T has many disadvantages and associated side-effects as it is still in its early stages of development. However, that does not minimise the fact that it is likely to continue saving lives as its development is furthered, where other treatments fail, offering an additional therapeutic option. Already, there are scientists seeking to decrease the risks that come with gene therapy. As an example, inhibition of IL-6 has been proposed to limit the severity of CRS (National Cancer Institute, 2017). Extrapolating from the cases where Car-T has already shown itself to function well, it is likely that furthering research in these areas will prove worthwhile. Although Car-T may never be effective against types of cancer that do not express specific cell markers, helping patients who may have experienced multiple remissions is nonetheless a worthwhile goal. Moreover, furthering understanding and control of Car-T may provide us with the means to combat even later-stage cancer, where surgical measures have been exhausted due to metastatic propagation of the cancerous cells. By utilising the patient’s own immune system, liquid tumours (which rely mainly on chemotherapy etc.) and metastasising cancer can potentially be effectively treated. Expansion into treatment of solid cancer appears difficult but is also in discussion, constituting another important field of research (National Cancer Institute, 2017). Due to the fact that TL can be selectively modified, some also see it as a future possibility to successfully engage AIDS/HIV. However, as Car-T treatment has been shown to frequently induce moderate to severe side-effects even with strictly controlled dosage and involves accurate modification of the patient’s TL, the procedure should only be carried out by professional teams while implementing new results derived from research. Otherwise, they may cause symptoms (such as CRS) which may be difficult to treat. All in all, Car-T can be seen as a therapeutic alternative to established procedures that appears promising despite many difficult to control side-effects encountered during clinical trials. These may be further reduced in future development and treatment adjustments derived from continued research.

Another area of significant potential that can be seen in the advent of CRISPR/Cas9 is the treatment of germ-line diseases, which were not curable until recently. Treatment of hereditary diseases nowadays mostly centre on alleviating the most harmful symptoms but cannot directly target the root cause, as the disease stems from genetic defects. As such the harmful effects of the mutation accumulate and eventually severely impact the patient’s quality of life. Many established concepts of GE employed in agriculture or with bacterial cultures are not suitably safe for use in live humans (e.g. injection of genetic data into cells, inducing random and unreliable gene incorporation). CRISPR, which is derived from what can be seen as essentially the bacterial counterpart of a multi-cellular adapted immune system, allows for far more specific control over e.g. the site of insertion or knock-out. As an enzyme/guideRNA(gRNA) complex that can be either inserted into the genome to be replicated by the target cell or injected into the target cell as a dead complex, it targets specific short gene sequences encoded in the gRNA and functions as an endonuclease. The ensuingdouble strand break(DSB) can then be repaired byNon-homologous End-Joining(NHEJ) leading to knock-out of the target gene or byHomologous Directed Recombination(HDR) resulting in reparation of the targeted gene via a correspondent chromosome or simultaneously injected gene sequence. As a consequence, although other existing methods (zinc-finger nucleases; retroviral) should not be disregarded as methods to edit the genome, CRISPR/Cas9 provides a unique procedure to purposefully and efficiently modify specific gene sites to possibly causatively treat hereditary diseases.

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Details

Title
Current Prospects on Genetic Engineering in the Health Sector
Subtitle
Considering the Example of CRISPR- and Car-T-driven Applications
College
University of Heidelberg
Grade
1,0
Author
Year
2018
Pages
17
Catalog Number
V448486
ISBN (eBook)
9783668833494
ISBN (Book)
9783668833500
Language
English
Keywords
CRISPR, genetic entineering, Car-T, review, Gene Drive
Quote paper
Jia xiang Jin (Author), 2018, Current Prospects on Genetic Engineering in the Health Sector, Munich, GRIN Verlag, https://www.grin.com/document/448486

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