Down Syndrome: Towards A New Research Era And Effective Therapies

 In the midst of this month’s conversation about potential new treatments for people with Down syndrome and the possibilities, problems, and questions those treatments raise, I thought it was important to offer a summary of the research and its implications. To that end, I asked Dr. Faycal Guedj, a researcher at Tufts University who has been working on these new treatments, to provide an overview. Dr. Guedj also has a 25-year old sister with Down syndrome, so he approaches the subject from both a clinical and personal perspective.

My hope for this series is to collect an array of voices, and to start a civil conversation among people who disagree with one another so that we might all learn together. Yesterday we heard from Rachel Adams, who wrote about The Damaging Language of “Cure” and Down Syndrome. Although Dr. Guedj does not use the language of cure, he does offer a different perspective than Adams. In both cases, I hope you will read, reflect, comment, ask questions, and do so with respect even (especially) if you disagree. My questions to Dr. Guedj appear at the end of this essay. Now, Faycal Guedj writes:

Fifty years after the discovery of the chromosomal origin of Down syndrome (DS) as being the presence of three copies of chromosome 21 (HSA21), lots of mysteries around the pathophysiololgy of this disease have been uncovered. During this period, DS research went through three major steps: 1) The identification and sequencing of HSA21 genes; 2) The creation and characterization of mouse models to study these genes; 3) The development of therapeutic strategies mostly to improve cognition in young adults. 

In the year 2000, the sequencing of the HSA21 was completed and close to 250 genes were identified. Understanding the role of all these genes individually is a major challenge and hardly achievable, however, the presence of rare cases of partial trisomy 21 led to the discovery of candidate chromosomal regions containing a small number of genes strongly associated with some DS phenotypes. The first region called DS critical region (DSCR) contains 20 genes responsible for the cognitive delay and the craniofacial features of DS. The second region or the DS congenital heart defect region (DSCHD) contains 33 genes, and includes the DSCR.

At the same time, technical advances in genetic manipulation of mice have had a great impact on the achievements of the DS research community in the last two decades. We took advantage of the similarities between the human and mouse genomes to create several mouse models carrying a trisomy of either a single gene such as DYRK1A, SOD1, APP (monogenic models), or chromosomal regions  (partial trisomy models), including the Ts65Dn and Ts1Cje models. These models contributed enormously in increasing our knowledge of the cellular and molecular origins of different clinical traits of DS, and still offer the most reliable and effective systems to test therapeutic interventions before proceeding to human clinical trials.

To improve cognition in DS, researchers have chosen two major therapeutic strategies. The first strategy targets single candidate genes like Dyrk1A using specific a non-toxic inhibitor (Epigallocatechine gallate or EGCG, a green tea polyphenol). This approach gave very promising results in the mouse and led to a pilot clinical trial. The second therapeutic approach aims to normalize the imbalance observed in some networks affected in the brain of DS patients, including oxidative stress, GABA transmission, serotonine and acetylcholine networks as well as neuroinflammation. Around 20 molecules were tested on the Ts65Dn mice, and most of them were reported to significantly enhance learning and memory in this model.

Despite the positive effects in the mouse studies, a very limited number of human clinical trials were conducted mostly on young adults with DS. Piracetam, donepezil  and rivastigumine (three of them target acetyl choline pathway), memantine (targets neuroinflammation and NMDAR), vitamin E (targets oxidative stress), folinic acid and growth hormone failed to significantly improve cognitive performances in double-blinded clinical trials. More recently, a pilot clinical trial using EGCG-rich green tea extract (inhibitor of DYRK1A) demonstrated that treated individuals have higher accuracy in visual memory recognition and spatial working memory, suggesting a positive effect of this compound both on the hippocampal and prefrontal systems. A larger (130 affected young adults) and more sophisticated clinical trial is being conducted in France and Spain to confirm this therapeutic benefit of EGCG.

Now, what future for the DS research in the next 10 years?

The recent development and clinical use of non-invasive prenatal testing (NIPT) techniques will probably impose a huge shift in DS research towards a prenatal treatment approach. It is well established that DS is a developmental disease and most its clinical manifestations are emerging during fetal life and shortly after birth until childhood. An early diagnosis of trisomy 21 with NIPT (10 weeks of gestation) offers a tremendous opportunity to intervene in utero using safe and well-designed therapeutic strategies that will potentially lead to a very significant, which is not to say a complete, normalization of brain development and cognitive outcome in newborns and children affected with DS.

In such an approach, three major challenges emerge in identifying compounds that (1) are safe for pregnant women and their fetuses, (2) can cross the placenta to achieve therapeutic levels in the fetus, and (3) show evidence of clinical improvement after birth.

A new era has started in DS research: Multidisciplinary teams need to be formed with a combination of geneticists, neuroscientists, clinicians, pharmacologist, toxicologist, families and parents advocate groups to resolve these challenges, and get the necessary expertise and support in order to provide effective treatments and guidelines to the national and international DS community.

In the Mother Infant Research Institute (Tufts Medical Center, Boston), we started, with Drs. Diana Bianchi and Tomo Tarui, a multidisciplinary collaborative effort that brings together the word-known expertise of Dr. Tarik Haydar (Boston University, Boston), Dr. Jeroen Pennings (National Institute for Public Health and the Environment, The Netherlands) and Dr. Donna Slonim (Tufts University, Boston) to develop effective prenatal treatments using a rigorous approach. We combine the study of human amniotic fluid and amniocytes obtained from DS pregnancies and the brains of several mouse models, including Ts65Dn and Ts1Cje to identify several candidate and FDA-approved drugs that will be extensively tested during the next 3-5 years in vitro and in vivo with potential clinical trials during this period.

This collaborative effort will need an important financial support by the DS community, foundations and public health funding agencies, and could be translated to develop therapies for other conditions, including other neurodevelopmental diseases (trisomy 18, autism, fragile-X) and neurodegenerative conditions (Alzheimer and Parkinson disease).

I strongly believe, now more than ever, that the lives of these kids will change for the best, and that humanity will benefit from their high social skills to improve our world.

My final thought goes to my sister, Imene, affected with DS and who is 25 years old: “I wish that you were born just now, your life would have been so different!!! I LOVE YOU MORE THAN ANYTHING ON EARTH”.

Faycal Guedj, a brother of a sister with DS.

Upon reading, I asked Dr. Guedj to answer a few further questions: 

Would you expect these therapeutic interventions to change the physical effects of DS in addition to the cognitive? For instance, would you expect fewer instances of heart defects and/or less severe defects?

Answer: I didn’’t want to dive into complicated details for your readers, but I suspect that a well-designed prenatal treatment will positively impact not only the brain development but also the heart and the thymus. In DS patients, the development of these organs is perturbed by the expression increase of some chromosome 21 genes, which induce imbalance in some pathways (NFAT pathway is an example). This pathway is very active in the brain, heart and thymus during fetal development and we can imagine that targeting it with a particular drug will improve cognition but also decrease the severity of heart and thymus defects.  An effective treatment will need to be associated with extensive learning programs, speech and physical therapies to potentiate its effect.

On the more philosophical level, I think many of my readers do not assume that higher IQ is necessarily good. You imply that improved cognition is of course a good thing, and I wonder if you can explain why researchers see such positive gains as a result of  improved cognition.

Answer: Cognition stands for a set of intellectual performances including IQ, learning, memory, speech development, reading, writing, behavior… The bottom line is that improving cognition will help individual with DS to live an autonomous life. I think that it will be a huge achievement for families. As you know, we are always asking ourselves this big question: ”How my kid will be living when I am gone?”. Every parent of a kid with Down syndrome thinks about this all the time, and probably improving the independent life skills of these kids is one part of the answer.

One final point of clarification– do you think Imene would live a better life now due to this type of research or due to advances we have made as a culture or both?

Answer: I believe that my sister will benefit from these advances and that her life quality will improve dramatically. However, it is well known that the brain of the fetus, the baby and the child are still actively developing, and that the earlier we treat, the more efficiently will we improve the cognitive outcome in our kids.

Dr. Faycal Guedj received his Ph.D. in neuroscience and human genetics from the University of Paris. He did his postdoctoral research at Tufts University where he continues to work on questions related to treatments for individuals with Down syndrome. 


About Amy Julia Becker

Amy Julia Becker writes and speaks about family, faith, disability, and culture. A graduate of Princeton University and Princeton Theological Seminary, she is the author of Penelope Ayers: A Memoir, A Good and Perfect Gift (Bethany House), and Why I Am Both Spiritual and Religious (Patheos Press).


  1. Louise Kinross says:

    Thank you for sharing this overview of research, which is more advanced than I imagined. With 20 genes involved in cognition of people with Ds, coming up with a therapeutic prenatal intervention sounds HIGHLY challenging.
    I was sad when I read Dr. Guedj’s wish that his adult sister had been born now, so that her life could have been different.
    I would like to hear more about his sister, what her life looks like, and how he feels her life would have been different if she was born now. Is it really that he wishes his sister’s life was different, or is it that he wishes our culture was different so that she could be accepted as a valuable human being?
    It reminds me of an interview I did with Jean Vanier, the humanist/philosopher/theologian, who said the greatest gift I could give my own son with intellectual disability is to make it clear to him that I love him AS HE IS, NOT BECAUSE HE CAN CHANGE.
    I also wanted to make a comment about the assumption that high IQ = better quality of life. One of the researchers in our autism centre here at Holland Bloorview shared that she finds youth with autism and higher IQs tend to have more significant mental health problems because they are much more aware of their differences and of others’ reactions to them (leading to higher rates of depression/anxiety). She noted that many youth with autism and lower IQs had very rich lives and were very happy with themselves.
    As noted in my comment on Rachel Adams’ piece in this series, physicians tend to rate QOL of people with intellectual disabilities as very low, whereas the people themselves rate it as good or excellent. So who is right? QOL is very subjective and I think it’s arrogant to make presumptions that someone whose thought process is different than ours is necessarily leading a less fulfilling life. That said, I am well aware of all of the challenges of intellectual disability — and also of the stigma it carries in our world. I wish more research was being done in how to remove deeply embedded stigmas about people with intellectual disability (particularly in light of French research this year showing that most adults carry a negative bias against children with Ds at the automatic level, as shown on implicit association tests).
    Thanks very much for sharing this!

  2. I am a single Mom to a wonderful 22-year-old son with Down Syndrome. I also work in research. This whole field is literally exploding the past couple of years or so, as it is so interlaced with other things such as Alzheimer’s, etc. It is just so exciting and fascinating to watch from my perspective. I look forward to what might actually come of it all and possibly how my own son, just by existing, might help in some small way, as I have just this month registered him in the new clinical trial registry that has been started by the NIH.

    As for the comment below from Louise Kinross, I understand what she’s saying here… “youth with autism and higher IQs tend to have more significant mental health problems because they are much more aware of their differences and of others’ reactions to them.” I note pretty much this same thing to people when I speak of my own son, as he would probably be classified a “lower-functioning” young man with Down Syndrome. It is indeed somewhat of a “double-edged sword.” On one hand, I think it would be nicer/easier/better if he were higher-functioning and able to do more on his own. However, because he is not, he is pretty much oblivious to what others around him might think of him. Those who are higher functioning can sometimes be more aware of this; and I think it can sometimes be quite damaging to them, as they understand more and therefore can be hurt easier by other people’s actions/feeling towards them.

  3. Mike Sullivan says:

    I stopped reading at the first sentence “the pathophysiololgy of this disease”. I thought this was about people with Down syndrome, so I lost interest at that point.

  4. Mike Sullivan says:

    Will you be running an article on this from a faith perspective Julia? Along the lines of human life being an expression of God through co-creation, the spiritual nature of people with Down syndrome and why people are trying to stop them being born, or feel the need to change them. I think for a patheos perspective a theological discussion on this would be valuable.

    • LeticiaVelasquez says:

      Dr Jerome Lejeune, the French geneticist who discovered trisomy 21 the cause of Down syndrome in 1959 was inspired by his deep faith and love for his patients with Down syndrome. His conviction to find a treatment for Down syndrome was galvanized by this incident which his daughter and biographer Clara Lejeune Gaymard described to me in this interview.

      “I remember it so clearly. I was 10 years old, and, one day, he came home for lunch. The day before, on television, there was a movie about a family where a woman had a child with Down syndrome, and she wanted to abort, and she couldn’t do it then.

      “After, there was a debate about abortion of the diseased children, and a boy came to his consultation with his mom, and he was crying, and my father said, “Why are you crying?” And his mother said, “He saw the movie, and I couldn’t stop him crying,” and then he jumped in my father’s arms, and he was only 10 with Down syndrome. He said, “You know, they want to kill us. And you have to save us, because we are too weak, and we can’t do anything.” And [my father] came back home for lunch, and he was white, and he said, “If I don’t protect them, I am nothing.” That’s how it started.

      “And then his career came down. He didn’t have money for his research. He was like a pariah, and so on, but he accepted that because he thought he was doing that which was his duty.”

      Dr Lejeune certainly loved those with Down syndrome but he knew as that 10 year old boy with Down syndrome knew, “. I see only one way left to save them, and that is to cure them. The task is immense—but so is Hope.”.

      Most expectant parents cannot comprehend how wonderful our kids are because they don’t know them, so a ‘cure’ is pivotal to making sure more babies are accepted and make it to birth.

      • Mike Sullivan says:

        Yes. So sad that we can’t accept people as they are, so we have to change them to confirm with our own needs. The demise of our culture means we have to cure them to save them.