What Would We Do if We Had All the Research Funding We Needed?
I am often asked this question and I presume when people ask, they expect the answer will yield the single most important thing that we need to do. However, our mandate at the Clinical Research Center involves five different chromosome 18 conditions that encompass 263 genes. Therefore, the answer is not as simple as it would be for a single condition caused by a single gene. Multiple multi-gene conditions require multiple parallel strategies and priorities to achieve the goal of making these conditions treatable so that those affected may have healthy and independent lives.
This mandate is therefore not a single path to an endpoint but rather a network of paths, strategies and priorities that will combine to lead us to the goal. One of the overall strategies is to understand the medical, developmental, and age-related consequences more deeply and specifically for each of the chromosome 18 conditions (18p-, Tetrasomy 18p, 18q-, Ring 18 and Trisomy 18). This involves enrolling individuals in a lifelong study to learn as much as we can about every aspect related to their chromosome 18 condition. There are currently over 700 participants enrolled in the Chromosome 18 Clinical Research Center study, however, most have not been evaluated in person by our team at UT Health. While much can be learned from the questionnaires and video interviews that are currently performed, the most important aspects can only be evaluated on-site by our team of investigators. On-site evaluations are particularly critical as we move toward trying to develop specific therapies for these conditions. The development and testing of new therapies requires clinical trials. The success or failure of those clinical trials will be determined by measuring very specific outcomes called “clinical endpoints.” Such endpoints often rely on changes in something in the blood, or some specific performance measure such as reaction time or changes detectable by an MRI scan. All these measures first need to be discovered and then monitored though evaluations done in person at UT Health. To set ourselves up to be ready to do the clinical trials for any newly developed therapies in the future, we need precise assessments of the issues we hope to correct. These assessments, will, in turn, generate data that could be used as clinical trial endpoints. The cost of bringing families to San Antonio and performing these evaluations is very high, but this is really a priority need.
Another overall strategy that requires significant effort focuses on the underlying genetic causes of the chromosome 18 conditions. We must remember that these conditions are caused by too many or too few copies of perfectly normal genes. Most of these genes, about 90%, do not disrupt any normal bodily processes when there are too few or too many copies. We made significant progress in learning which genes are, and which genes are not responsible for adverse effects. We are narrowing down the list of 263 genes on chromosome 18 to a handful of potential genes that we believe are the key driver genes of the adverse effects. The path from identifying a suspected genetic cause of an abnormality to then learning how to correct that defect is multi-faceted. It involves creating stem cells and mice with deletions or duplication of these key genes and evaluation their abnormalities. Ultimately, both the cells and mice can be used to screen different drugs as potential treatments.
Although these two strategies may look like two distinct areas of research; actually, one continually informs the other in the quest to make these conditions treatable. For example, the clinical evaluations may more narrowly define and characterize some of the global diagnoses, like autism or intellectual disability. This knowledge can then help to point to a particular gene as the cause. Inversely, sometimes the knowledge of the function of the genes informs the clinical evaluations that we should be doing and could even point to potential treatments. These illustrate that the clinical and molecular information each inform the other and together these data lead to understanding, answers, and treatment. Thus, it is vital that we learn about the underlying genetic causes of the chromosome 18 conditions and perform clinical evaluations with participants.
Within that overall strategy, there are multiple individual projects that are current priorities:
- Clinical evaluations and molecular characterization of participants with small deletions or duplications of chromosome 18. This information helps us to more narrowly correlate certain characteristics with small regions of the chromosome and ultimately specific genes.
- Clinical evaluations of additional participants with 18p- and Tetrasomy 18p. To date we have only performed in-person evaluations of 10 relatively young participants with each of these conditions. This is not a sufficient number of individuals on which to draw strong conclusions.
- Clinical evaluations of participants with distal 18q deletions specifically involving characteristics related to myelination of the brain.
- Characterization of patient derived stem cells that have been differentiated into the type of brain cells that make myelin. These cells can be used to determine the effectiveness of different drugs to correct the myelination problem.
- Generation and characterization of mice with a deletion of the dysmyelination region of chromosome 18 to better understand the cellular basis of the myelin defects and to test potential drugs identified above.
- Items 3, 4 and 5 above can be repeated for any of the other chromosome 18 conditions after we are able to characterize the effects of specific gene deletions or duplications.
These are just a few specific examples, however, there is much that we can do and need to do to make the chromosome 18 conditions treatable. Our goal remains to help people with these conditions lead productive and independent lives. None of the research above requires the invention of new methodologies. Everything that we need to do has been done for other single gene conditions involving other chromosomes. Now, we just need to do these things for people with the chromosome 18 conditions.
So, what would we do if we had all the research funding we needed? We would not do one thing; we would do a lot of things that would all work together to make life better for people with chromosome 18 conditions.
