Step 10: Individualized Treatment Plan

The ultimate goal for all of our research is to reach this 10th and final step: the creation of an individualized treatment plan! 

With all the information we will have gained over the years, the experience for future families diagnosed with a chromosome 18 condition will be very different from those who came before them. 

Because we will know which genes are responsible for which features of each of the conditions, we will be able to offer predictive information to a family based on the deletion or duplication.  We can start screening for the specific health problems that the child is at risk for.  We can start offering targeted therapies for the developmental challenges that are associated with the condition.  For those conditions that have approved drug treatments, we can start treatment.

It will take a lot of work, patience, and dedication on the part of both the researchers and the families.  However, it is definitely possible to make chromosome 18 conditions “treatable”, and we will continue to work to make that a reality for the families of the Chromosome 18 Registry!

Step 9: Clinical Trials

If our mouse experiments have shown that a candidate drug is safe and effective, it is time to move on to the final stage: clinical trials!

Ultimately, the clinical trials will tell us whether people get the same benefits from the treatment as the mice did.  These trials are very heavily monitored and regulated by the government to ensure that researchers gain the most information while ensuring the safety of the people participating in the research. 

Clinical trials have multiple phases, including phases to determine dosages, efficacy, and side effects of the treatment.  These trials frequently last several years and involve children and adults with the condition we are working to treat.

Once a treatment has made it through the clinical trials and has been approved by the FDA, it is finally available for treatment!

Step 8: Animal Models

Once we have identified a treatment that seems to work in test tubes and petri dishes, it is time to see whether it works in living things.  The most common animal used in these types of experiments is the mouse.  We would use a mouse that has been specifically genetically engineered to have a missing or extra copy of the gene that we were evaluating in the lab.  These mice would have similar medical problems to the ones seen in individuals missing that particular gene.  The mice experiments will tell us many things. 

First, we want to know whether this treatment is effective in a living organism.  Experiments in a test tube can be rigidly controlled.  We can control which reactions go on inside the test tube.  We can also control the amount of different substances and proteins we put into the experiment.  However, a living organism is much more complex, and no test tube experiment can fully replicate the full range of reactions and variables that are present in an animal.  We want to know whether, in the complex environment of a living organism, the drug either reduce or enhance gene expression.

Another goal of these experiments will be to see whether the drug actually makes the problems better.  Does compensation for the extra or missing gene actually cure the problem, or, at the very least, improve it?  For example, if we know that a gene is linked to dysmyelination, does treatment with this drug candidate improve myelination in these mice?

Third, we want to get an idea about the potential side effects of this drug in living organisms.  If the drug successfully treats the underlying problem but the side effects are worse than the original problem, it is probably not a good drug candidate.

Once we have determined that a particular drug is effective and safe in mice, we can move on to the next stage: clinical trials!

Step 7: Treatment Development

This step marks the beginning of our ultimate goal: the development of a treatment for chromosome 18 conditions!  Up to this point, we have…

1.  Learned all that has already been written about the condition (Literature Review)

2.  Fully investigated individuals with these conditions, both from a clinical and a molecular standpoint (Clinical and Molecular Assessments)

3.  Fully described the various medical and developmental concerns associated with the condition (Syndrome Description)

4.  Identified the genes directly responsible for the various features of the condition (Gene Identification)

5.  Created personalized management plans based on the genes involved (Syndrome Management Plan)

6.  Figured out how a change in the number of genes leads to the features of the condition. (Gene Function Studies)

We’ve come a long way from where we started, when precious little was known about each of these conditions.  At this point of the path, we will be able to predict which children are likely to have which complication, and we will be able to make up a plan specific to that person’s genetic situation.

Of course, there is still much work to be done.  We still want to develop a treatment that addresses the root cause of the issue: the deletion or duplication.  We are looking for a molecular “fix”, so to speak.

To do this, we must look for treatments that “make up” for the missing or extra pieces of chromosome.  In order to understand how we approach this challenge, it is important to have a basic understanding of genetic concepts.  Humans have two copies of each chromosome.  Genes are located on the chromosomes.  These genes code for proteins that play different roles throughout the body.  There are proteins that carry oxygen, proteins that help digest food; proteins that tell our body when to start producing certain hormones, and more!  Proteins play an important role in all of the body’s functions. 

So, what happens when there are missing or extra copies of a gene?  There may be too little or too much of the protein that the gene codes for.  This is likely the mechanism by which missing or extra copies of a gene lead to the various concerns associated with chromosome 18 conditions.  So, we want to find drugs that will either (1) increase the expression of a gene in a person with a deletion or (2) decrease the expression of a gene in a person with a duplication.

We start our search for a treatment in the laboratory.  We look at the effects of different drugs on gene expression.  At this point, we are just looking at the effects of the drug in vitro.  This means that we are looking at how the drug works outside of a living organism (for example, in test tubes or petri dishes).  When we find one that seems to affect gene expression, we have found a potential treatment!  It is then time to move on to our next step: Animal Models!

Step 6: Gene Function Studies

Happy Thanksgiving, everyone! In celebration, I'm finally getting around to posting the next step in our "Path to Treatment" for chromosome 18 conditions.

So far, we've talked about:

Step 1: Literature Review
Step 2: Clinical and Molecular Assessments
Step 3: Syndrome Description
Step 4: Gene Identification
Step 5: Syndrome Management Plan

Even after we have linked specific genes with specific features of the conditions involving chromosome 18, we still don’t necessarily have a good idea of HOW those genes cause medical and developmental problems. For example, we might wonder why it is that missing a specific gene causes severe language delays. Is it because the gene plays a role in how the way the brain develops? Or is it because it causes some problems with the way that the brain communicates with the muscles that control the muscles necessary for speech?

It is at this point that we really start relying on the experiences and knowledge of scientists in other disciplines. Many genes on chromosome 18 already have already had extensive information published in the scientific literature. Scientific papers might give us information about what happens when a single base pair in a gene is changed. Or it might tell us a little bit about the protein product that the gene is responsible for creating. Or perhaps where in the body those proteins are localized.

Unfortunately, there are also many genes on chromosome 18 that have very little information available. In this case, we can turn to an increasingly large variety of technologies that have been developed to understand gene function.

Once we understand how gene deletions and duplications lead to the various health and developmental concerns, we can start working to fix those problems at the molecular level. Basically, we want to find a treatment that can address the underlying changes in the genes and therefore the proteins that they code for.

Step 5: Syndrome Management Plan

We're continuing the "Path to Treatment" series today! As you may already know, the ultimate goal of the Chromosome 18 Clinical Research Center is to not to "manage" the chromosome 18 conditions, but to find treatments specifically designed for the chromosome changes. This is a long process, with many steps along the way. On this page, we have already discussed the first four steps towards meeting our goal...

Step 1: Literature Review
Step 2: Clinical and Molecular Assessments
Step 3: Syndrome Description
Step 4: Gene Identification

I also just realized that I have not posted a link that may help with the visualization of the whole process! Here's a diagram that shows the steps, in order, as well as where we are with the various chromosome 18 conditions. I'll also post a copy of the image below.

You might want to click on the image to enlarge. Or, visit this link, which will take you to a PDF that has brief descriptions of each step.

And with that introduction, I will start discussing the next step in the process: a "Syndrome Management Plan"!

Once we have identified the genes that are responsible for different features, we can start to create a management plan that is tailored to an individual’s specific chromosome change.

Right now, most chromosome 18 changes are diagnosed by a routine chromosome analysis. You can read more about how chromosome 18 changes are diagnosed here. The chromosome analysis can identify the chromosome change and the general location of that change, but it cannot determine exactly which genes were involved. So, even though we know that different genes are involved in different people’s deletions or duplications, the chromosome analysis does not give us enough information to know exactly which genes are different. Therefore, we cannot give people specific information about what to expect based on the results of the chromosome analysis. Instead, we must rely on a general description of the chromosome change to give families an idea of what types of things to expect.

However, microarray analysis has changed all this. Microarray analysis is a new technology that can give us precise information about the location of a breakpoint, as well as the specific genes that are involved in a chromosome change. It can also detect much smaller chromosome changes. Now, when the diagnosis of a chromosome 18 change is made on a chromosome analysis, clinicians can perform a microarray analysis and learn which of genes are involved in the deletion or duplication. That information, combined with our knowledge of the roles that various genes play in causing medical and developmental concerns, will one day allow us to create personalized medical management guides for individuals with a chromosome 18 change.

This is probably best explained with an example. In the future, we will be able to say something like this: “Gene A is responsible for foot abnormalities, Gene B causes growth hormone deficiency, and Gene C leads to kidney problems.” Then, when a routine chromosome analysis identifies a deletion of the tip of chromosome 18, we will perform microarray analysis to get additional information about exactly which genes are involved in the deletion. Microarray results for this newly diagnosed individual may tell us that Gene A and Gene B are deleted, but Gene C is not deleted. Using this information, we can be sure that the family has a thorough orthopedic evaluation to detect any problems and start necessary treatments as soon as possible. We will also be able to tell the family that there is a high probability the child will develop growth hormone deficiency. We therefore will need to closely monitor growth and refer to endocrinology at the first sign of a problem. We can also tell them that a renal ultrasound is not necessary, because the gene for kidney abnormalities is not deleted, and therefore they are at no greater risk for kidney problems than any other children.

In this way, we can create individualized management guides that are specifically tailored to a person’s chromosome change.

While this is a step in the right direction, an individualized management guide is not the same thing as a treatment. From this point onwards, our efforts will be focused on identifying treatments that are specific to each chromosome change.

Step 4: Gene Identification

Today, we're continuing the "Path to Treatment" series here on this blog! The aim of these posts is to talk about the various steps that researchers go through in the question for treatments of the chromosome 18 conditions. You can read the previous installments here:

Step 1: Literature Review
Step 2: Clinical and Molecular Assessments
Step 3: Syndrome Description

The fourth step, gene identification, pulls together information from the clinical and molecular assessments. In essence, this step involves trying to link different features of the condition with specific genes on chromosome 18. We take a group of people with distal 18q- (or other chromosome 18 condition) that have the same feature, for example, growth hormone deficiency. We look at the data that we gathered during the clinical assessments and identify all individuals that did not respond to the growth hormone stimulation test, and are therefore growth hormone deficient. Because there is no common breakpoint on 18q, everyone has a different deletion involving different genes. We compare the deletions of the patients with growth hormone failure and determine which area of chromosome 18 is deleted in all those particular patients. This area is called the “critical region”. We would assume that the gene responsible for growth hormone failure is located within this region.

Usually, the critical region will contain several different genes. The trick is to determine which one is most likely to cause a problem when deleted or duplicated! We expect that only 5-10% of the genes on chromosome 18 will actually be responsible for the features of the chromosome 18 conditions. Considering that there are just over 300 genes on chromosome 18, we expect to identify about 15-30 genes that actually play a role in causing the medical and developmental concerns associated with the chromosome 18 conditions.

We have a number of different ways to determine whether a gene is in fact the one that we are searching for.

(1) We research the genes in the critical region. This usually involves several visits to the medical school library! We look at what has been reported in the scientific literature to determine where the gene is usually expressed, what its function is, and whether it makes sense that a deletion or duplication of the gene could lead to the feature we’re examining.

(2) We look at animal models. These are animals (usually mice) that have been bred to be missing a particular gene. We then look at the animal to see what problems it has. If it has the same issue that we are examining, such as growth hormone deficiency or a heart defect, then this is evidence that we have the right gene!

(3) We search for people with gene deletions of or single base pair changes in the gene of interest. For example, if we think that a particular gene is the cause for growth hormone deficiency, we might look at that gene in people with isolated growth hormone deficiency. If we can find changes in the gene in any of those people, that is even more evidence that we’ve found the right gene!

Once we have found the genes that cause the features of the chromosome 18 conditions, we can progress to the next step: the creation of an individualized management plan!