Injection of double-stranded RNA can lead to gene silencing by degradation of RNA molecules complementary to either strand of the dsRNA. Could RNAi be used in gene therapy for a defect caused by a recessive allele? A dominant allele? If so, what might be the major obstacle to using RNAi as a therapeutic agent?

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Hi, everyone. Welcome back. Here's our next question. What is the major challenge in gene therapy for diseases caused by recessive alleys? Choice. A risk of the immune response against the therapeutic genes. B difficulty in delivering therapeutic genes to target cells. C high cost of gene therapy or d difficulty in identifying carriers of the recessive allele. Well, we can go ahead and cross out difficulty in identifying carriers of the recessive allele because you wouldn't be doing gene therapy on carriers. They don't have the disease since it's a recessive condition. So not doing gene therapy on carriers, you would be looking to do gene therapy to help people who have the disease and relieve them of their symptoms and the disease. You don't need to identify them. They have the condition. In addition, we can eliminate choice. A risk of the immune response against the therapeutic genes. A risk of an immune response is a very real risk of gene therapy, but that immune response isn't against the therapeutic genes in general. It's usually against the vector used to deliver the genes, which is often a viral vector. And indeed very famously in 1999 a young man named Jesse Gelsinger died of a massive immune response to the identi viral vector used to deliver the gene therapy in the trial. He was in. So choice a correctly identifies a risk but to the wrong thing. So we're down to difficulty in delivering therapeutic genes to target cells or the high cost of gene therapy. Well, the high cost definitely is a challenge but given the cost of treatment over a lifetime of many of these conditions in general, you consider the high cost worthwhile. Given the money that in the end would be saved in treating all of these conditions. So choice C you probably wouldn't call the major challenge in gene therapy. So we are left now with choice B difficulty in delivering therapeutic genes to target cells. And indeed, this is the major challenge. DNA is a large and charged molecule and therefore not easily taken up by human cells. So you have to have a means by which to deliver it. And there are various different things uh viral vectors as we discussed and depending on the type of cells. So for instance, there have been promising trials with various conditions involving blood cells because you can remove blood from the body, treat the cells and reintroduce it to the body. After killing off the blood cells that are there. You can use stem cell therapy in that way, we already have uh use of bone marrow with its stem cells. So something involving the blood will be a lot less challenging than, for instance, conditions involving the brain, lot more difficult to deliver something to brain cells get across that blood brain barrier. So, depending on the location of cells being targeted, that can be very difficult. Um, we discussed the possibility of immune response. If the vector you're using to deliver the genes causes an immune, uh you know, an overactive immune response that can cause problems. Mhm. And in addition, you can risk deleterious insertion of the genes. So, in one trial, uh for gene therapy, the patients ended up suffering from leukemia because the gene, the corrected gene disrupted a gene was inserted in a place where it ended up causing leukemia. So depending on where your gene inserts, you can have risks compared to that. So those are just some of the problems and challenges when you're considering how to deliver these therapeutic genes. So that would definitely come under the category of the major challenge in gene therapy choice B difficulty in delivering therapeutic genes to target cells. See you in the next video.

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Key Concepts

RNA Interference (RNAi) Mechanism

Genetic Basis of Recessive and Dominant Alleles

Challenges of RNAi in Gene Therapy