Gene therapy makes sense. And antisense, too!

Genes code proteins. When a gene carries a defective mutation, it will either stop coding the protein or it will code a defective one. This is, unfortunately, the basis of many genetic diseases. In principle, if we could substitute the defective gene with a healthy one, the problem would be solved. That's what gene therapy boils down to. In fact, there are ways to deliver the genes to the affected cells. For example, you can take a virus that targets the cells where the defective gene is expressed, keep the virus's ability to inject its genome into the target cell, but modify its genetic content so that now it contains the healthy genes. The virus will "attack" the target cell in its usual manner and inject its genetic content inside. But now, because the virus has been artificially modified, the new genetic content won't be the usual viral genes that cause infections. Instead, they will be the new, healthy genes, which will be integrated in the cell's DNA and start coding the healthy protein.

Gene therapy has been used successfully to treat various genetic diseases (see the studies listed here) and there have been very encouraging results when used to treat cancer in mouse models (see, for example, [1]) as well as in humans [2].

However, there are situations where the "simple" scenario I described above will not work. 

We are diploid organisms, which means we carry two copies of each chromosome, and hence two copies of each gene. The two copies may or may not be identical. When they differ, we say that the individual is heterozygous at that particular locus. Now, it so happens that in some heterozygous individuals one of the two copies of the gene is dominant negative. What that means is that even if the other copy is healthy, and it codes a healthy protein, the defective protein (produced by the defective gene) interacts with it and alters its function. Basically, the mutated protein dominates over the non-mutated one and overrides its ability to function properly.

When this happens, "delivering" the healthy gene will not solve the problem because the defective gene will continue to produce the defective protein, which, in turn, will override the effect of the healthy one. Does this mean we can't use gene therapy to fix the defective gene? Of course we can! We just have to use a different kind of gene therapy, namely antisense gene therapy.

This is how it works.

I've used the expression "genes produce proteins." Well, it's a little more complicated than that. Each strand of DNA gets first transcribed in RNA and then the RNA (which is single stranded) is translated into the protein. The idea behind antisense gene therapy is to prevent the defective RNA strand to be translated into the defective protein. How? By binding the defective RNA before it can be used by the cell to make the defective protein.

DNA is made of two strands that are complementary to each other. The same principle works for RNA, even if RNA is usually found in single strands. So, if you make its complementary (the antisense strand), it will bind to it like opposite magnets do. And that's exactly what antisense gene therapy does: instead of delivering pieces of DNA, it delivers pieces of antisense RNA made to complement exactly the defective RNA.

The figure below is from this website:

As you can see from the figure, the defective RNA is "plugged" by its antisense complement and at that point is no longer able to make the defective protein. The healthy protein, produced by the unmutated copy of the gene, completely takes over thus eliminating the source of the disease.

References [3] and [4] below show examples of antisense gene therapy used in treating brain and cervical cancers. 

[1]  Suto, R., Tominaga, K., Mizuguchi, H., Sasaki, E., Higuchi, K., Kim, S., Iwao, H., & Arakawa, T. (2004). Dominant-negative mutant of c-Jun gene transfer: a novel therapeutic strategy for colorectal cancer Gene Therapy, 11 (2), 187-193 DOI: 10.1038/sj.gt.3302158

[2] Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, & Rosenberg SA (2006). Cancer regression in patients after transfer of genetically engineered lymphocytes. Science (New York, N.Y.), 314 (5796), 126-9 PMID: 16946036

[3] Zhang Y, Zhu C, & Pardridge WM (2002). Antisense gene therapy of brain cancer with an artificial virus gene delivery system. Molecular therapy : the journal of the American Society of Gene Therapy, 6 (1), 67-72 PMID: 12095305

[4] Yatabe, N., Kyo, S., Kondo, S., Kanaya, T., Wang, Z., Maida, Y., Takakura, M., Nakamura, M., Tanaka, M., & Inoue, M. (2002). 2-5A antisense therapy directed against human telomerase RNA inhibits telomerase activity and induces apoptosis without telomere impairment in cervical cancer cells Cancer Gene Therapy, 9 (7), 624-630 DOI: 10.1038/sj.cgt.7700479