The Long Road for Developing Novel Treatments for People with Chromosome 18 Conditions - Part 1
If you are trying to understand the research, what we do and why we are doing it, here are the major steps from a 10,000 foot, or maybe even a mile high view – all to make life better for people with chromosome 18 conditions.
1. Define standards of care and identify areas of need.
Describing the conditions is and has been our primary area of work. When we began, the issues faced by people with chromosome 18 conditions were described using very broad terms such as failure to thrive and absent speech. More importantly, low expectations for improvement led may individuals to receive less than aggressive care. To remedy that, we performed many clinical evaluations at UT Health San Antonio and gathered what must seem to our participant families as unending survey and questionnaire data. All of this information is collected in an effort to more precisely define the issues, and in order to determine if there are standard therapies that might be applicable.
Notable examples of how this research data has been beneficial includes the diagnosis of, “failure to thrive” in some of our children was determined to be growth hormone deficiency, which is treatable. “Absent speech” in others turned out to be in part due to a hearing impairment, which is also treatable. Because we performed this research, expectations for achieving a quality life have been greatly increased.
As a case in point, our research center was recently contacted by a healthcare provider who had a new patient with 18p- who has spent more than a decade in challenging foster care situations, and consequently has many unmet needs and challenges. After explaining what our young adult participants with similar deletions have achieved, this provider will most certainly have higher expectations and be more aggressive with goals for improvement for this young person. I was able to provide this information thanks to the behavioral questionaries filled out by so many participating families over the years. This information will in turn surely improve this young person’s life because the expectations for him were increased.
These are just a few examples of the power of research to improve people’s lives. The summation of this work has been compiled into Management Guides for each of the chromosome 18 conditions. The work continues as we devise new ways to investigate the underlying causes of problems in hopes there are standard treatments, or at least ways to minimize the problems.
This descriptive research has not solved all the issues, but it has more precisely defined many of them. Some of the aspects of the chromosome 18 conditions don’t have standard or optimal treatments and will require the development of novel therapies. To accomplish this, we must embark on a longer road to treatment. However, in anticipation that we would need to develop novel therapies, we began the first steps on the road to treatment development at the very beginning of this research in parallel with this descriptive work. Those first steps involve identifying the key genes that are responsible for the specific aspects of the conditions in need of treatment.
2. Identify the gene responsible
Identifying the genes that cause specific aspects of the chromosome 18 conditions
has been very successful. These data are summarized in the Gene Dosage Maps on our website (https://wp.uthscsa.edu/chrome-18/). The name of these maps comes from the fact that the information focuses on the effects of the chromosome 18 genes when they are present in some number other than the normal two copies. In other words, the genes are present in an abnormal “dose”.
Identifying the genes that cause specific aspects of the chromosome 18 conditions is important because the development of new drugs requires extensive knowledge of the underlying biology of the condition. Because we know that the chromosome 18 conditions are caused by deletions or duplications of genes on chromosome 18, we have an advantage for two reasons.
First, we know the causative gene(s) are one of the 263 genes on chromosome 18. This narrows the list of causative genes down significantly from the 20,000 in the entire human genome. Second, we know the basic mechanism of disease is either too many or too few copies of those perfectly normal genes. This means we don’t need to replace genes with harmful mutations or repair damage done by those mutated genes. We just need to upregulate or down-regulate the perfectly normal genes.
At this point we know that about 90% of the genes play little or no role is the medical or behavioral issues of someone with a chromosome 18 condition when present in an abnormal number of copies (dose). We are working to understand the role of the remaining 10%. This is progress.
3. Define the defect in individual cells of the body
Once we have identified an important gene to focus on because we think it is the cause of a significant medical or behavioral problem, we need to gain an understanding of what too few or too many copies of that gene does within the cells and tissues of the body. We need to understand which cells of the body are affected, and how those abnormal cells affect which tissues. There are multiple approaches for doing this, but they all basically use cells grown in a dish to determine how they are look and behave differently from normal cells. These could be mouse cells that have the specific gene in question deleted or prevented from working. Or, they could be blood cells from someone with a chromosome 18 condition which have been induced to become a different type of cell in which that gene is important.
Additionally, these cells can be induced to form specific organoids that resemble the tissue that the cells typically are a part of. For example, cells from someone with a chromosome 18 condition grown in a dish could be induced over many months to form brain organoids to then determine their abnormal functioning within the context of the cell types that they normally interact with. This is a very powerful strategy for learning the basic biology on the effect of a gene copy number change.
4. Create a mouse with the same genetic defect.
At the same time as the cellular work described above is happening, mouse models of deletions or duplications of the single gene of interest can be occurring. Creating a mouse with a deletion of a specific gene is an established procedure and is useful on many levels. A mouse can be evaluated for any abnormality in development, behavior, and general health. Additionally, a mouse can be dissected to observe changes in anatomy or physiology. This is particularly important for genes that affect brain function or behavior since human brain biopsies are definitely not feasible.
The previous steps describe ongoing research by the Chromosome 18 Clinical Research Center. The following steps are in our future – stay tuned for the rest of the story next month.
