On March 17, in a ceremony at the Jerome Lejeune Foundation offices in Paris, Dr. Alberto Costa received the 2016 Sisley-Jerome Lejeune Prize* for excellence in research.
Dr. Costa is a professor in the Departments of Pediatrics and Psychiatry at Case Western Reserve School of Medicine in Cleveland, OH and Director of their Intellectual Disability Program. He has been a pioneer of research and treatments of Down syndrome and was featured in a New York Times Magazine article in July 2011 about his odyssey as the father of a new baby with Down syndrome and his pathway into the DS research community.
We are grateful to Dr. Costa for taking time to respond to a few questions about the status of Down syndrome research, and what he anticipates for the future.
Dr. Costa, I had the privilege of interviewing you in Paris in March 2011 during an international research conference organized by the Jerome Lejeune Foundation. At that time you were about to conclude your clinical trial using Memantine to assess its efficacy in improving cognition in individuals with Down syndrome. Can you give us a brief overview of that trial and where it has led your research to the present?
AC: Our pilot trial of the effects of the drug memantine in young adults with Down syndrome (just search “NCT01112683” at http://www.clinicaltrials.gov), was published in the journal Translational Psychiatry (2:e141, 2012. doi:10.1038/tp.2012.66). This was a small-scale, randomized, placebo controlled clinical trial of memantine in young adults with Down syndrome of both genders and with ages varying from 18 to 32 years. The aim of the pilot study was to test whether a 16-week treatment with memantine could be efficacious in producing performance improvements in memory tasks thought to be dependent on structures deep in the brain’s temporal lobe (such as the hippocampus), as well as to test if this drug was safe and well tolerated in the study participants. Although no significant differences were observed between the memantine and placebo groups on the two predetermined primary efficacy measures, we were able to detect a small but significant improvement on one of the neuropsychological measures of long-term memory that we used. More important than that, however, was the fact that analysis of the pilot trial data indicated the possibility that this drug may positively affect performance in up to five different neuropsychological measures. The numbers told us that a clinical trial three times larger than our original pilot trial should be able to detect such positive effect if it really exists. This is why we decided to design and organize the current Phase II, follow-up clinical trial of memantine in adolescents and young adults with Down syndrome (see “NCT02304302” at http://www.clinicaltrials.gov). Interestingly, three of the five measures for which we expect to detect significant performance improvements in the Phase II trial are known to be highly correlated with general intelligence, which is definitely a hopeful sign that the drug memantine might one day become part of standard medical treatment for individuals with Down syndrome. However, we will only have a better idea if this truly will be the case once the current trial is finished in approximately two years from now.
When we spoke in 2011 you mentioned that several clinical trials were just about to begin. You were prophetic! Now we have several trials underway and more in planning, how would you characterize the status of Down syndrome research today?
AC: I would not quite say prophetic, as, at the time I was helping a couple of the groups running some of these clinical trials by directly providing them with critical information for them to setup their studies. But yes, there are several trials underway currently. I would definitely characterize the status of Down syndrome research today as more hopeful than it has ever been. However, one cannot lose sight of the fact that we are still in the very early stages of this research and that no single trial has yet demonstrated efficacy in an unequivocal way.
Do you think advancements in research have had any positive impact on funding for research?
AC: Yes, they have. But most of the positive impact on funding for research has come from private foundations, such as the Alana Foundation, the Global Down syndrome Foundation, Lumind, and the Lejeune foundation. Although there has been some opportunities in the UK and the EU, there has been very little progress in the availability of funds, or the opening of new, specific requests of application, from the National Institutes of Health in the United States.
It seems the more we learn about Down syndrome the more we have to appreciate its complexity. For example, a paper was published in Feb 2016 in Neuron showing brains of people with Down syndrome have an overall reduction in the “density of myelinated fibers” suggesting a possible pathway to treatment. But the paper also verified that an extra 21st chromosome has an impact on gene expression on other chromosomes as well. What impact does this understanding have on potential therapeutic treatments? Are we looking at the right targets and taking the right approach by isolating single genes like DRYK1A, CBS, or APP? Do we know enough about protein interactions to know if we’re striking the right targets, or do we need to be looking more holistically?
AC: Historically, the targeting of specific chromosome 21 genes as a potential approach to a rational pharmacotherapy for Down syndrome was a first logical line of attack. However, as the field matures, the notion of antagonizing the actions of a single chromosome 21 gene, or a small subset of such genes, as a means to counteract the negative effects of the overexpression of such genes in persons with Down syndrome is proving to be both naïve and impractical. Therefore, many of us are focusing on targeting molecular pathways or complex cellular processes (e.g., adult neurogenesis or myelination), which researchers in the area are finding to be altered in either mouse models or cell models of Down syndrome. There is no doubt that this is a more holistic approach to the problem and one that is more likely to bear fruit in the near to midterm future. Complexity is an inherent fact of biology and it should not deter anyone from moving forward in the search for therapeutics. Regulation of gene expression and its impact for health and disease is not well understood at present. For example, when a healthy person takes a single pill of acetaminophen or aspirin, it can have a significant impact on the expression level of many gene products, but the actual consequence of this on the level of the person’s everyday experience is typically negligible. Therefore, one should not panic when they see lab data showing levels of gene products going up and down because of a biological insult or genetic disorder.
Your daughter, Tyche must be 20 or 21 years old now. Are you optimistic that there will be targeted treatments available for her within another decade or so?
AC: Tyche is 20 years old now. She is taking remedial classes at a local community college and is a generally happy young woman. Because many developmental windows are now closed to her, I do not necessarily believe that she will directly benefit from pharmacological treatments to enhance cognition that may become available within the next 10 years. However, what keeps me motivated to come to work every day is the hope that she may still benefit from potential therapies that may slow down or halt the development of the Alzheimer-type pathology that affects virtually all persons with Down syndrome by their late thirties to early forties. What also motivates me is the hope that therapies may become available for much younger individuals with Down syndrome in this same timeframe, so I can dare to dream of a new generation of persons with Down syndrome who will be significantly more productive, happy, and engaged in the community than most individuals with Down syndrome who are living today.
*Note: The Sisley Foundation generously provides funding each year so that the Jerome Lejeune Foundation can recognize an outstanding researcher for their contributions to research on Down syndrome or other genetic intellectual disabilities. The Jerome Lejeune Foundation in immensely grateful to the Sisley Foundation for their collaboration and support of this important research and those who have commited their lives to improving the lives of others through medical research.