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Module inSCIENCE, TECHNOLOGY,& SOCIETYThis module is a property of the Nueva Ecija University of Science and TechnologyDanny O. Alfonso Cristo Mark D. Ancheta Roel S. Ang Leonardo M. Aquino Bryan Joshua V. Bacani Joseph R. Del Carmen Jaynelle G. Domingo Angel Joyce C. Fajardo Gian Carlo S. Gaeto...

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NUEVA ECIJA UNIVERSITY OF SCIENCE AND TECHNOLOGY Cabanatuan City ISO 9001:2015 Certified

College of Arts and Sciences Mathematics and Science Department

Module in

SCIENCE, TECHNOLOGY, & SOCIETY UNIT XI.

GENE THERAPY Danny O. Alfonso Leonardo M. Aquino Jaynelle G. Domingo Alpha B. Gumayagay Olympia O. Riogelon Glenda R. Tandingan

Cristo Mark D. Ancheta Bryan Joshua V. Bacani Angel Joyce C. Fajardo Jewell Ann P. Manabat Julius Jay N. Rodriguez

Roel S. Ang Joseph R. Del Carmen Gian Carlo S. Gaetos Darwin U. Ong Janina C. Sercenia Diwata Y. Villaflor

This module is a property of the Nueva Ecija University of Science and Technology

UNIT XI. GENE THERAPY Overview In this unit, you will learn about Gene Therapy, a technique used to treat genetic diseases that otherwise do not have existing cures. We will also talk about its associated benefits and risks and the different ways it can be performed. The ethical considerations in performing gene therapy will also be covered.

Learning Objectives: At the end of the unit, I am able to: 1. describe gene therapy and its various forms; 2. identify ethical and moral issues that may arise from gene therapy; and 3. assess the potential benefits and detriments of gene therapy to global health and the society.

Lesson Proper What is Gene Therapy? A wide range of diseases such as cystic fibrosis, cancer, diabetes, heart disease, AIDS, and hemophilia are caused by genetic irregularities or deformities (Yazdani et al., 2018). Gene therapy is an experimental technique developed in order to treat these diseases. Gene therapy is the introduction, removal, or alteration of genetic material in order to prevent or treat a disease.

How Does Gene Therapy Work? Ideally, gene therapy may someday allow doctors to treat disorders by inserting or replacing genes into a patient’s cells instead of through surgery or drugs (U.S. National Library of Medicine, 2020). There are various approaches in performing gene therapy, including: a. Replacing a disease-causing mutated gene with a healthy copy of the gene b. Inactivating or “silencing” a mutated gene or a gene that is not functioning properly c. Introducing a new gene into the body to help counteract or fight the disease d. Correcting the sequence of a mutated gene

Replacing A Mutated Gene (GENE REPLACEMENT) In order to replace a problematic or mutated gene: • A functional and healthy gene will be inserted to a viral vector • The viral vector will carry and place the healthy gene on the site of mutation • The mutated non-functional gene will be “spliced” or cut and removed • The healthy gene will be attached and becomes a part of the final DNA strand.

Figure 20. Gene Replacement Source:https://slideplayer.com/slide/4318654/14/images/14/Gene+replacement.jpg

Gene Silencing or Gene Knockdown

Figure 21. Comparison between normal protein production and the protein production upon gene silencing Source:https://web.stanford.edu/group/hopes/cgi-bin/hopes_test/wp-content/uploads/2012/04/genesilencing.jpg

This method aims to repress or turn off the function of a mutated gene which prevents the cells from producing disease-causing proteins. Gene silencing reduces the expression of a disease-causing gene (Hood, 2004; Mocellin & Provenzano, 2004). It can be done by: a. inserting a repressor a.k.a silencer gene that reduces or prevents the expression of the mutated gene b. editing the gene to make it impossible for it to produce the protein it codes for

Although gene silencing is often considered as the same thing as gene knockdown, this is debatable because some say that when genes are knocked out, they are often completely removed or erased from the genome in order to stop their expression (Hood, 2004; Mocellin & Provenzano, 2004).

Introducing a New Gene (GENE ADDITION) In gene addition, new and functional genes are introduced or added into the genome to help fight or prevent a disease (Pharmaphorum, 2019).

Figure 24. Gene Addition Therapy Source:https://cdn1.byjus.com/wp-content/uploads/2016/07/Gene-Therapy.png

The introduction of a new gene can also be used to kill specific diseased cells. This is useful for diseases like cancer. There are two ways to do this: 1. by inserting a gene called the suicide gene into the diseased cells that will cause the cells to die 2. by inserting a gene that will cause the cells to produce a protein that will mark them as a target for the body’s natural immune system response.

Figure 25. Killing Specific Cells Source: https://genetherapyscience.weebly.com/uploads/9/1/4/6/91468512/gene-therapy-targeting-yourgenome.png?453

Correcting the sequence of a mutated gene (GENE EDITING) In gene editing, instead of replacing the whole gene, the specific error is located and edited.

Figure 26. Gene Editing Source:https://images.theconversation.com/files/142832/original/image-20161024-15958-8t6r6g.png?ixlib=rb1.1.0&q=45&auto=format&w=1000&fit=clip

Two types of Gene Therapy There are two distinct types of gene therapy, depending on the nature of the target cells: Somatic and Germline Gene Therapy. If the target cells are anybody cells except the sperm and egg cell and the cells that produce them, this is Somatic Gene Therapy. When the cells targeted are either sperm or egg cells, this is Germline Gene Therapy (Chatterjee, Singh, & Saluja, 2013).

Figure 27. Two types of cells Source:https://i2.wp.com/sitn.hms.harvard.edu/wp-content/uploads/2019/03/Final-Figure-03.png

Somatic Gene Therapy This type of gene therapy is effective in treating diseases like muscular dystrophy, cystic fibrosis, cancer, and some infectious diseases. The effects of this method are short-lived and will not be passed on to the next generation. So, the children of a patient treated using somatic gene therapy are still at risk of contracting the diseases.

Figure 29. The Process for Somatic Gene Therapy Source:https://images.app.goo.gl/ZZcWuERSmJmfZFG1A

Somatic Gene Therapy can be done ex vivo (outside the body) or in vivo (inside the body)

Figure 30. In vivo and Ex vivo Somatic Gene Therapy Source:https://www.mdpi.com/cancers/cancers-11-01265/article_deploy/html/images/cancers-11-01265-g001.png

Germline Gene Therapy In Germline Gene Therapy, on the other hand, the cells that produce the reproductive cells or sex cells (the egg or sperm) are modified, and all the cells of the resulting embryo will possess the edited gene. The effect of removing or correcting the disease will be passed on to the patient’s children as well as the generations after them. Therefore, there is a possibility of permanently removing an inherited disorder or disease from a family line. As of 2014, about 40 countries have discouraged or banned research on Germline Gene Therapy (Araki & Ishii, 2014). It is currently not allowed to be done on humans because of ethical and safety concerns and issues regarding possible permanent changes in human genes.

Figure 31. The Process of Germline Gene Therapy Source:https://image.slidesharecdn.com/genetherapy-exvivomethod-190603094856/95/gene-therapy-ex-vivo-method-10638.jpg?cb=1559555393

Challenges Associated with Gene Therapy While Gene Therapy is no doubt a breakthrough in science and medicine, there are several challenges to its success and problems that can be associated with it. A. Gene Delivery and Activation In most cases, a therapeutic gene needs to be delivered not just to a single cell but to groups of cells or tissues. This requires an accurate and specific gene delivery. Otherwise, gene therapy may be useless. After arriving at the correct target cells, the genes must also be “turned on” and have to remain “on”. However, cells can have the tendency to “turn off” certain genes when there are already too many active genes. In some cases, delivered genes may also be overactivated, causing their overexpression. The overproduction of enzymes or proteins due to this overactivation may lead to other health issues and problems. B. The Body’s Immune Response Our immune system is naturally inclined to attack any foreign intruders like viruses and bacteria. Because gene therapy uses viral vectors to transport genes, they need to be able to avoid the body’s immune system to prevent it from attacking them. This is often challenging to do. Additionally, the treatment effects are often short-lived, so patients will need to undergo multiple rounds of gene therapy. However, if the patient’s immunity is low due to gene therapy, there is a risk for the disease to progress or get worse. This makes it even more difficult to repeat gene therapy.

C. Impact to Non-Target Genes and Cells While very small, there is also a risk of attaching or inserting modified genes into the wrong part of the genome or the wrong cell, which can lead to a series of reactions that can cause cell death. This may also negatively affect the function of surrounding healthy cells. Viral vectors also tend to disrupt vital genes, possibly leading to another disease or predisposition to other diseases like cancer. This can also trigger inflammatory, toxicity, or immune responses. Other cells may also be targeted aside from the target cells. D. Limited Access and Commercial Availability Many genetic diseases are not common. For rare diseases, gene therapy should be individualized and customized to every patient to ensure effectiveness. This makes developing and administering gene therapy very expensive. Even for more common genetic disorders and related diseases like cancer, gene therapy is still more costly than other treatment options. Because of this, many people cannot afford and do not have access to gene therapy. E. Multi-gene Disorders Multiple genes with different functions control genetic disorders like high blood pressure, heart disease, arthritis, diabetes, and Alzheimer’s disease. So, to treat these diseases, many genes may have to be corrected, deleted, or replaced. Doing so may lead to complicated reactions in the body or possibly even more dangerous diseases.

Ethical Questions in Gene Therapy Because it involves changing the body’s genetic information, the use of Gene Therapy, especially germline gene therapy, is a widely debated topic due to its ethical issues (US National Library of Medicine, 2020). Some of the ethical questions about gene therapy that we should address are: 1. How can we distinguish “good” from “bad” gene therapy? 2. Who gets to decide which traits and genes constitute a disability or disorder? 3. Because of the expensive costs of gene therapy, will it only be available for rich people? 4. Is there a possibility that a widespread use of gene therapy can make society less accepting of people who are different? 5. Aside from medical applications, should we be allowed to use gene therapy for enhancements of basic human traits such as athletic ability, height, intelligence, and hair or eye color?

Online Video Watching: If you are interested to learn more about Gene Therapy and other related topics, you may watch the following videos that you can find online (optional):

1. TED Talk: Juan Enriquez on “The Next Species of Human” https://www.ted.com/talks/juan_enriquez_the_next_species_of_human/up-next?language=en 2. TED Talk: Susan Lim on “Transplant Cells Not Organs” https://www.ted.com/talks/susan_lim_transplant_cells_not_organs?language=en 3. Science Fiction: Stem Cell Research (Youtube) https://www.youtube.com/watch?v=mPy7NFkJ-TQ References Araki, M., & Ishii, T. (2014). International regulatory landscape and integration of corrective genome editing into in vitro fertilization. Reprod Biol Endocrinol, 12, 108. doi:10.1186/1477-7827-12-108 Chatterjee, A., Singh, N., and Saluja, M. (2013) Gene Therapy in periodontics. Journal of Indian Society Periodontology. 17(2):156-161 Hood E (March 2004). "RNAi: What's all the noise about gene silencing?". Environmental Health Perspectives. 112 (4): A224–9. doi:10.1289/ehp.112-a224. PMC 1241909. PMID 15033605. Mocellin S, Provenzano M (November 2004). "RNA interference: learning gene knock-down from cell physiology". Journal of Translational Medicine. 2 (1): 39. doi:10.1186/1479-5876-2-39. PMC 534783. PMID 15555080. Pharmaphorum (2019). Gene addition - a new chapter in treating rare diseases. Retrieved from https://pharmaphorum.com/views-andanalysis/gene-addition-a-new-chapter-in-treating-rarediseases/#:~:text=A%20technique%20called%20'gene%20addition,to%20fight%20or%20prevent%20disease on July 20, 2020 U.S. National Library of Medicine (2020). Your Guide to Understanding Genetic Conditions: What is Gene Therapy? Retrieved from https://ghr.nlm.nih.gov/primer/therapy/genetherapy on July 20, 2020 U.S. National Library of Medicine (2020). Your Guide to Understanding Genetic Conditions: What is Gene Therapy? Retrieved from https://ghr.nlm.nih.gov/primer/therapy/ethics on July 20, 2020 Yazdani, A., Alirezaie, Z.,Motamedi, M.J., & Amani, J. (2018) Gene Therapy: A New Approach in Modern Medicine. Int J Med Rev 2018 Sep;5(3):106-117....