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Last month we discussed the challenges with gene therapy. If gene replacement or gene removal therapy is not a viable approach for new treatments for the chromosome 18 conditions, then what is a viable approach?
In the case of chromosome abnormalities, the most important fact is that it is not necessary to delete a whole extra chromosome or insert a missing chromosome arm. This is because only a few of the many genes in these large multi-gene pieces of chromosome are in actual need of correction. In fact only a very small proportion of the genes cause problems when there are too few or too many copies. We call these rare genes “dosage sensitive genes” because their functions are sensitive to the “dose” or the number of copies of the gene. In the case of the chromosome 18 deletions (18p-, 18q- and Ring 18), 90% of the 263 genes on chromosome 18 code for sufficient protein to sustain normal function when present in one copy (i.e. a half dose). This majority of genes are dosage insensitive. There is no need to correct 90% of the genes! Only 10% of the genes on the entire chromosome are dosage sensitive.
In the case of duplications, it is not yet clear exactly how many genes are responsible and in need of some dosage correction, but it is likely to be a similarly small number. It might even be that the same genes in need of down regulation when duplicated are the same ones in need of up upregulation when one of them is deleted. The fact that only a few genes are in need of re-regulation means that there is no need to replace a whole chromosome arm or remove an extra copy of the entire chromosome. What we need to do is to identify the dosage sensitive genes, learn which cells, tissues and organs they are active in and essential and then determine how to upregulate or down regulate their activity. This is hardly a trivial task, but it is most definitely a doable task using established scientific methods.
The task before us therefore is to get one gene to be upregulated to produce the same amount of protein as two genes (18q-, 18p- and Ring 18). Or, to get 3 (Trisomy 18) or 4 (Tetrasomy 18p) copies of the genes to be downregulated so they only produce the amount of protein typically made by two genes. We need to be able to entice perfectly normal genes to either do more or do less. There are no defective genes that must be replaced or repaired which is the most common approach for gene therapy. Instead, for the chromosome 18 conditions there are merely too few or too many copies of perfectly normal genes. The gene therapy task therefore is to be able to change gene activity by changing their regulation.
Upregulating and downregulating genes is not a completely unnatural process. In fact, you do it to some degree every day in the foods you eat and the activities you participate in. This is an underlying basis for how your body responds and adjusts to daily life. But it is not just foods that impacts your metabolism, it is anything you ingest. This includes drinks, dietary supplements and drugs.
Drug therapy has important advantages over genes therapy. A drug therapy for re-regulating specific genes is that the resulting level of gene activity can be fine-tuned to get the optimal effect. If the effect is suboptimal, the dose can be increased. If there are unwanted side effects a drug therapy can be stopped. This makes it a reasonable approach to therapy when there is a Goldilocks level of effectiveness, not too little or too much but just the right amount.
At this point we don’t know what all the treatment modalities for the chromosome 18 conditions will be. Some aspects currently have standard treatments available, and we will continue to identify and perfect those approaches. But many other challenges do not have current therapies. The role of the Chromosome 18 Clinical Research Center is to identify the exiting effective treatments and when there is no treatment, develop novel treatments. Every single day we are working toward the goal of making the chromosome 18 conditions treatable.
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