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I am often asked why we just don’t try to put back that missing piece of chromosome or remove the extra chromosome. There are a whole host of reasons why this is not technically possible. Even if it were possible, it is not the optimal approach to treatment for the chromosome 18 conditions.
There are no strategies for removing chromosomes or even single genes as a clinical treatment for any condition. But there are strategies for adding genes. The problems regarding doing this, for even just a section of a chromosome, is that it would include many genes. This creates several issues.
Packaging: Gene therapy typically uses virus capsules to deliver a single new gene to the cells of the body. The size of the genetic material that a virus capsid can contain is too small to include more than a single gene. Therefore, replacing a section of a chromosome containing several to dozens of genes is just too big to fit and therefore not feasible.
Delivery: Using gene therapy to restore the missing chromosome piece would require integration into every cell of the body. Since a chromosome section with many genes will have genes that need to work on many different types of cells the replacement would have to be delivered to all cells of the body. There are no strategies for doing this. The current gene therapy treatments are for single gene conditions where the target organ is accessible such as blood.
Instead of trying to deliver a section of a chromosome, an alternative would be to try to add back only the key genes that are responsible for the main issues. This might get around the packaging issue since a single gene might be small enough to be delivered by a vial capsule. But there are issues with that strategy as well.
Target: The tissue being treated would have to be accessible to a gene delivery method. Blood is readily accessible but other tissues such as the brain are more difficult.
Efficiency: The newly delivered gene would have to be present in enough cells to be able to make a meaningful change in the organ that is made up of those cells. And the infected cells would need to have that gene working at a normal level at the right time of life.
Longevity: There is little ability to control how long the inserted gene will remain active as the infected cells divide. The introduced gene can be lost during cell division so in rapidly dividing cells the newly inserted gene and its effects may be rapidly lost.
Regulation: - There is limited ability to control the magnitude of the resulting effect from the introduced gene. The problems resulting from a chromosome abnormality are due to too many or too few copies of perfectly normal genes. For these genes there is a Goldilocks effect. Both too little and too much can cause problems. Therefore, the ability to control the level of gene activity in the treated cells means there could easily be too little or too much gene expression and hence inadequate levels to be helpful or too much and be problematic.
Immune reactions: Because gene therapy is most commonly delivered using a gene packaged in a virus capsule, the body could mount an immune reaction to the virus and destroy it, making the recipient quite sick. Even if that rare event does not happen, performing a second round of gene therapy will most assuredly result in an immune reaction and clearance of the virus before it can insert the gene into host cells. This makes current viral vector gene therapy a “one and done” therapy. There is no possibility for a second dose if the first one did not result in a strong enough effect. There is also no possibility for a second gene therapy to treat with a second key gene for multigene disorders like a chromosome abnormality. Fortunately, there are other gene therapy approaches under development that may overcome this hurdle.
There are many single gene disorders for which gene therapy is a good choice as a therapy. These are primarily life threatening or significantly life shortening single gene disorders caused by a part of the body that is accessible by a virus such as bone marrow. But, for a chromosome abnormality it makes much less sense.
What does make sense? How do we approach the treatment goal? Next month we will explore those possibilities.
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