Dr. Michael M. Harpold prekursor badań nad trisomią 21 chromosomu nie żyje.

Chief Scientific Officer of LuMind Research Down Syndrome Foundation, osoba która dla LuMind fundacji zajmującej się poszukiwaniem metod terapeutycznych dla osób z zespołem Downa, znaczyła na polu medycznym bardzo dużo, zmarła…Los jak widać jest dramatyczny, bo łączy dobro jakie stworzył ten człowiek, w dniu gdy obchodzimy Światowy Dzień Zespołu Downa, z bólem jego śmierci. Chciałbym abyście pamiętali, że dr.Harpold pracował dla nas, choć go nie znaliście tak jak ja.

W 2014 roku dzięki Oli przygotowaliśmy wywiad z nim na temat badań. Chcieliśmy go opublikować w którejś z gazet, jednak żadna się nie zgodziła na to, gdyż dawała nadzieję na leczenie osób z zespołem Downa…ja to tak odbieram. Był to artykuł, który tylko mógł poruszyć Was, rodziców dzieci  z ZD i tylko Was, a to było za mało.

Poniżej prezentuję go w wersji oryginalnej i postaramy się z Olą, przetłumaczyć go na język polski.

 

1. Since ten years of existence LuMind foundation concentrates on funding scientific research, to improve intellectual and social condition of people with Down Syndrome. In Poland such approach is still seen as a sign of „lack of acceptance for what’s inevitable” meaning intellectual impairment of people with Ds. Was the decoding of human genome kind of initial event for starting the foundation? How was your experience during first years of work?

LuMind Foundation (under original name Down Syndrome Research and Treatment Foundation) was founded in 2004 with the mission: To stimulate biomedical research that will accelerate development of treatments to significantly improve cognition, including memory, learning and speech, for children and adults with Down syndrome, with the goals of creating new opportunities for all individuals with Down syndrome to lead more independent lives, participate more successfully in schools & employment, and prevent additional early cognitive decline with aging & Alzheimer’s disease.

Certainly, the international collaborative projects to sequence the complete human genome was helpful in helping to set a stage for accelerating new research on Down syndrome. This allowed researchers to identify and explore the function of genes on chromosome 21. The development of new animal models of Down syndrome, including new mouse models, was also a key development, and provided for more effective research into the functions of specific genes on chromosome 21 and how their over-expression contributed to the impairment of different functions. Additionally, over the previous 10-20 years there had also been major advances in neuroscience research and the understanding of cognitive processes, especially those involving learning and memory. An initial goal was to bring these into application to Down syndrome.

When the foundation was founded that relatively short 10 years ago, there really were few clues or research answers to the key questions that are essential to address to succeed in the discovery and development of effective and safe new therapies, including the requisite engagement with pharmaceutical companies. These key questions included: 1) Can research identify dysfunctional biological mechanisms that are associated with the developmental intellectual disability and/or the earlier onset Alzheimer’s disease in people with Down syndrome together with associated drug targets and drugs that overcome the dysfunction and improve cognition? 2) Can Down syndrome-specific cognitive assessment tests be developed to determine the efficacy of such drugs for clinical trials and approval? 3) Are there sufficient and effective clinical trial sites and sufficient patient participants to effectively undertake clinical trials? The research strategy and grants program developed by the LuMind Foundation, and importantly through the establishment and consultation with the highly distinguished and dedicated Scientific Advisory Board with uniquely diverse expertise and accomplishments (http://lumindfoundation.org/Scientific_Advisory_Board) has produced rapid and dramatic progress in addressing these questions and now led to 3 ongoing clinical trials, with a 4^th new clinical trial to be initiated shortly, for new medications to improve cognition and address both the developmental intellectual disability and prevent or halt the progression of the earlier onset Alzheimer’s disease in children and adults with Down syndrome.

2. Why have you decided to devote your scientific career to Down Syndrome research?

Prior to my becoming involved with the LuMind Foundation and Down syndrome research, I was involved in biomedical research both in academia and as an executive in the biotechnology and pharmaceutical industries. My focus included involved diverse problems in molecular biology, biotechnology, and biomedical science, including significant contributions to research in molecular signaling in the nervous system as well as drug discovery primarily focused on disorders of the nervous system. When I was contacted almost 10 years ago by a former colleague of mine, now a physician, who is the mother of a child with Down syndrome, it became quite clear from or discussion and additional review that there was a real need to bring the tremendous research advances (some of which is described above in answer to question #1) to application to and catalyzing new Down syndrome research, especially cognition research. As with all people I strongly believe individuals with Down syndrome deserve the very best, cutting-edge biomedical research to address their health-related issues, and I believed my expertise and experience could be helpful in making this happen. At its core this is a social justice issue to which we should all be committed. (also see bio http://lumindfoundation.org/page.aspx?pid=656)

3. To what extend has the understanding of DS as biological, neurological and genetic disorder changed during last years ?

As briefly described in the answer to question #1 above, there have been many major advances in biomedical research in the past couple of decades or so, and these advances have made possible a much deeper exploration of all aspects of Down syndrome, including at the biological levels of genetics, molecular biology and neurological/neuro-scientific levels. This is evidenced by the acceleration in the applications of these advances to Down syndrome research in the past 10 years has contributed to very rapid and dramatic progress. In particular, neuroscience research has provided a much deeper understanding of cognitive function, including learning, memory and speech, and demonstrated that cognitive dysfunction can be changed, even across the lifespan, and lead to significant improvements. This deeper evidence-based understanding, and especially together with the initiation of major clinical trials with potential new therapeutic drugs has led to an unprecedented shift, both among biomedical researchers and people in the Down syndrome community, in thinking that the developmental intellectual disability, as well as the earlier onset of Alzheimer’s disease, in people with Down syndrome could be treated with medications…This is no longer unimaginable or intractable.

4. How do you raise funds for financing scientific research? Data shows, that the government does not designate appropriate amount of money for the research. Might it be caused by common belief, that DS is incurable and one can’t change it’s symptoms because of it’s genetical grounds? Did it change during last ten years?

As with virtually all non-profit organizations, LuMind is dependent upon raising funds from gracious and generous donors at all levels, individuals within and beyond the Down syndrome community. Historically, financial support, both governmental and non-governmental, for Down syndrome research has been disproportionately low. That has been due to many reasons, however, rather than dwell on past discrepancies, LuMind has focused more on what can be done to change that and effectively increase both non-governmental and governmental funding for Down syndrome biomedical research. Among the most important ways that is being accomplished is making possible and demonstrating the dramatic progress in Down syndrome cognition research that has been made over the past 7 or so years with, as yet, even relatively modest increases in funding support for the research. LuMind also works with governmental agencies and representatives, researchers, Down syndrome advocacy organizations and the wider public to raise awareness about these advances and promote research support and progress…The results and accomplishments bring increased and rapidly changing attention to Down syndrome research and what may be possible which can help further drive greater increases in funding and support.

5. You collaborate now with most prominent labs and research center in United States. How does this cooperation look like?

There are many important components to successfully encouraging and promoting collaborations and cooperation among researchers. In today’s biomedical research, and especially with a goal of not only more deeply understanding a disorder at basic research levels but advancing that forward to availability of safe and effective therapies, many disciplines are required, i.e. so-called interdisciplinary research. In general, no one researcher or institution will have all of the diverse expertise required for the entire process. LuMind aims to identify and engage the best and brightest researchers with this needed diversity of expertise to solve problems and answer the most pressing questions to accelerate research progress. As a part of that process and fundamental to the LuMind strategy and grants program, a key component is facilitating and requiring communications among and between researchers. In the LuMind Grants Program, the foundation aims to provide input and sufficiently meaningful funding levels to the selected projects and researchers which encourages and provides for engagement with and incorporating needed new talent, expertise and technologies to solve problems and advance the research. Sharing of research results as well as materials is not only encouraged but required as one of the criteria for research support. Additionally, LuMind recognizes the importance of Down syndrome research conferences and attendance and participation by international researchers which will further encourage and support needed collaborations, and has been providing collaborative co-sponsorships and funding for a number of such research conferences both on the developmental intellectual disability and Alzheimer’s disease in Down syndrome. For additional information see www.lumindfoundation.org, including the various information under “Research” and “News” tabs.

6. You write that the aim of LuMind Foundation is not finding a cure for DS. Why not? Do you see no possibility to „cure” the genome or prevent mutations?

Given the current and nearer-term capabilities of science as well as available resources, there can be real progress toward developing safe and effective therapies for the various biomedical issues affecting people with Down syndrome. As all individuals with Down syndrome are affected by the developmental intellectual disability and earlier onset of Alzheimer’s disease, this represents the current realistic LuMind focus and goal.

7. Could one say, that your aim is change DS from „incurable disease” to a „chronic disease”, that could be controlled with medicines and supplements? If so, how advanced are you on this way?

From a formal medical perspective, Down syndrome is defined as a disorder, not a disease. Through the progress and advancement of the LuMind research strategy and program and Down syndrome cognition research major goal is to change beliefs that treatments and improvements in cognition associated with the developmental intellectual disability and Alzheimer’s disease in people with Down syndrome are intractable or unimaginable, and that real progress is being made…To underscore how far this has advanced, as described above, over the past three years 3 new major clinical trials have been initiated and are progressing…Even as recently as 5 years ago these are accomplishments that were widely considered unimaginable.

8. If not a cure than what? You write, that even 10 -15 % improvement of intellectual potential would help in leading more self -sufficient and satisfactory life for people with DS. Could you describe it more precisely? What kind of education or other activities would be available then for people with DS?

With the improvements in the types of cognitive function related to learning and memory that have been demonstrated through the results of laboratory preclinical research it could be anticipated that people with Down syndrome could make more associations and greater connections in their knowledge; improvements in attention (focus) and better “task-juggling” so they could be faster at processing information with improvements in initiating activities which would contribute to improved progress in school and employment; and, greater ability and willingness to try new strategies and ways of doing tasks. With respect to the earlier onset Alzheimer’s disease in people with Down syndrome new medications would be anticipated to halt or prevent the progression of Alzheimer’s disease minimizing the associated further loss of cognitive, learning and memory function and neurodegeneration.

9. What areas of disability are in the centre of your attention ?

Staying true to the mission, and based on the breadth of impact on people with Down syndrome and current resources, LuMind Foundation is focused on biomedical research that will accelerate development of treatments to significantly improve cognition, including memory, learning and speech, associated with the developmental intellectual disability and earlier aging and prevent or halt the progression of the onset of Alzheimer’s disease children and adults with Down syndrome. As there are more than 4 million people with Down syndrome around the world, this research and its potential impact can be hugely significant.

10. What kind of research is in in progress right now?

LuMind Foundation recently announced the award of more than $1.1 million for its new 2014-15 Research Grants (for more detailed information see http://lumindfoundation.org/Research–LuMind-2014-2015-grant-award-details). These grants continue an aggressive, high priority and wide-ranging set of Down syndrome cognition research problems including, but not limited to:

· Further exploration of how a single dose treatment of SAG (an SHH growth factor-like drug) given to a mouse model of Down syndrome early in life completely restores cerebellar development and improves hippocampal function involving learning and memory associated with the developmental intellectual disability in Down syndrome. A second study is investigating the role of altered regulation of a gene involved in synaptic plasticity related to cognition and brain network dysfunction in Alzheimer’s disease and Down syndrome and the identification of potential new therapeutic targets. A third study concerns the development and application of a new method for real-time analysis of brain signaling that correlate with cognitive function, learning and memory which could accelerate the evaluation of the effectiveness of new drug in mouse models of Down syndrome.

· Research focused on identification and investigation of potential new drugs that can regulate the proteins produced by the over-expressed APP gene and overcome effects of Alzheimer’s disease in Down syndrome. Research is also directed at identification of additional over-expressed chromosome 21 genes involved in the age-dependent development of Alzheimer’s disease related to endosomal signaling dysfunction in nerve cells and their role in neurodegeneration and cognitive dysfunction in mouse DS models which may lead to the identification of new drug targets, potential drugs, and therapeutic strategies to improve cognition.

· Further development and refinement of the first set of Down syndrome-specific battery of cognition tests (Arizona Cognitive Test Battery or ACTB, and Arizona Memory Assessment for Preschoolers and Special Populations or AMAP) that measure cognitive function involving both the developmental intellectual disability and Alzheimer’s disease in various areas of the brain affected in Down syndrome across the lifespan. These tests also provide a way to more specifically evaluate the efficacy of potential drug treatments and other interventions to improve cognition in individuals with Down syndrome. An additional research study is exploring the development of EEG-based methodologies as potential biomarker assessments of cognitive function in individuals with Down syndrome that can provide critical support for fundamental cognition research and clinical trials. Another research study is further extending sleep studies with the ACTB to define the relationship between sleep disturbances, including sleep apnea, and impairment of cognitive development which can provide new insights to address sleep disorders to improve cognitive function in children and adults with Down syndrome.

· The Down syndrome Cognition Project (DSCP) continues to focus on deeper understanding of the genetic contributions to the substantial variation in cognitive ability among individuals with Down syndrome using the Arizona Cognitive Test Battery (ACTB), identify targets for therapeutic interventions and establish a network of collaborating clinical sites as an initial scaffold for a clinical trials network.

· Further research on the GABA -A receptor, a protein that plays a major part in over-inhibition which leads to cognitive dysfunction in Down syndrome, extending research in mouse models of Ds about how the over-inhibition may impair circadian rhythms and sleep in Ds, how this may contribute to cognitive impairment, and whether drugs that overcome the inhibition ameliorate these impairments. Follow up research is also continuing on a recent discovery of another over-expressed chromosome 21 gene, Usp16, and its potential role in deficient brain development, loss of brain cells, and early aging in Ds. (jest to już projekt nieaktualny przyp. JP)

· Research investigating the potential for an additional existing FDA-approved drug, fomoterol, which acts as a norepinephrine mimic, to restore contextual learning in the mouse DS model and also overcome the effects of the Alzheimer’s disease neuropathology in Ds on cognition. The results could provide further evidence and a rationale for accelerated clinical evaluation of this drug in individuals with Ds.

11. Some of the research is still in the stage, where scientists are experimenting with mice with modified genome. To what extent are the results appropriate also for human beings?

In virtually all research on disorders and diseases to identify dysfunctional mechanisms and associated potential drug targets and to development drug treatments, animal models for the disorders have been key in the initial steps in the process. This is true in Down syndrome research where researchers have developed a series of animal, primarily mouse, models that contain 3 copies of genes which are found on human chromosome 21 and these models develop many of the same characteristics found in people with Down syndrome, including the cognitive, learning and memory dysfunction. Using these mouse models for Down syndrome researchers have identified at least 9 new potential therapeutic drug targets have been discovered and, with associated experimental drugs, have been shown to overcome specific impairments to improve cognition and/or neurodegeneration associated with Alzheimer’s disease in these mouse models. These studies provided essential results necessary to advance the evaluation of potential therapeutic drugs into clinical trials (as described above and see http://lumindfoundation.org/clinical_trials).

12. Some pharmaceuticals, important for people with DS, are undergoing clinical trials ( Roche). What kind of research preceded those clinical trials? How do they look like? How have you recruited people with Ds to take part in this research? When can we expect them to be available on the market? How can people with DS benefit form this medicine ?

Information concerning the current clinical trials, together with additional links for more information can be found at http://lumindfoundation.org/clinical_trials. The fundamental research supported by LuMind that provided basis of support for advancing to the clinical trials is in part described at http://lumindfoundation.org/page.aspx?pid=684 and associated descriptions of LuMind Research grants.

LuMind works directly with the Down syndrome community and organizations to encourage consideration of patient recruitment. LuMind also works with clinical researchers and their institutions as well as the sponsoring biopharmaceutical companies on patient recruitment.

The various ongoing clinical trials remain in progress and at this stage it is difficult to generalize how rapidly any given trial might progress, and, if successful, exactly when a specific new drug and therapy would be available. With respect to time to availability one of the most significant variables or “unknowns” is in fact the rate of patient recruitment for progress and completion of clinical trials which is dependent upon decisions to participate.

The results of the specific clinical trial will be required to determine how and to what extent people with Down syndrome may benefit. Based on the research to date it is anticipated that some of benefits would be as described above in answers to questions above and particularly question #8.

13. Who will benefit from this treatments? Many parents of adults with DS are afraid, no matter how effective the new treatments will be, they come to late to be used with their charges?

Many advances in brain/neuroscience research over the past 10-20 years indicate that our brains and associated functions remain incredibly plastic and changeable throughout our lives (from infancy through adulthood). The cognition research to date in Down syndrome indicate the same is true for people with Down syndrome, thus cognitive, learning and memory function can be modified even in adults.

The potential for cognitive improvement in both children and adults is underscored by the determined age range of participants in clinical trials. For example, in the current Roche Phase II clinical trial which is focused on improvement of cognition, learning and memory associated with the developmental intellectual disability in Down syndrome, the evaluation includes participants 12-30 years of age. It may be likely that benefit could extend to both younger and older people with Down syndrome.

Certainly, potential new drugs, including those in ongoing or near-term clinical trials with people with Down syndrome, addressing the prevention or halt of progression of the earlier onset Alzheimer’s disease in people with Down syndrome would be expected to have significant impact on adults with Down syndrome.

Again, the results of the specific clinical trials will be required to determine how and to what extent people with Down syndrome at various ages may benefit.

14. Assuming – all of the research will end up with success – how would life of a person with DS look like in 10, 20 or 30 years?

First, the major objective of Down syndrome cognition research, as successful, is that it will create significant new opportunities for all children and adults to realize their dreams. This is includes creating new opportunities for all individuals with Down syndrome to lead more independent lives, participate more successfully in schools & employment, and prevent additional early cognitive decline with aging & Alzheimer’s disease, all with great impact throughout their lives. Again, s there are more than 4 million people with Down syndrome around the world, this research and its potential impact can be hugely significant

15. In the US image of people with Down Syndrome is strongly influenced by Self-Advocates, most schools and universities seem to have programs allowing people with disabilities to take part in academic life. What are the most severe limitations, that society is setting to people with DS? ( In Poland they hardly get into education above elementary level, even if they intellectual ability allowed them to!)

Unfortunately, there remain many and varying limitations for children and adults with Down syndrome around the world. From my perspective, there is not just one but many varying limitations in different places around the world. Many Down syndrome advocates and organizations, including local, national and international have been working to identify and address these various limitations; certainly more work is needed. As appropriate, LuMind works together with individuals and groups to support these efforts. A major contribution that LuMind is making to this effort stems directly from its mission and work, that individuals with Down syndrome deserve the very best, cutting-edge biomedical research to address their health-related issues, and further, in changing beliefs that treatments and improvements in cognition associated with the developmental intellectual disability and Alzheimer’s disease in people with Down syndrome are intractable or unimaginable, and that real progress is being made…again, to underscore how far this has advanced, as described above, over the past three years 3 new major clinical trials have been initiated and are progressing…Even as recently as 5 years ago these are accomplishments that were widely considered unimaginable. This adds and effectively increases awareness about Down syndrome and that perceived limitations can overcome.

16. Do you, as LuMind Foundation work on the social perception of Down Syndrome as well?

This is partly addressed in answer to question #15 above; on this issue, LuMind also significantly works together with individuals and groups in the Down syndrome community and beyond to support these efforts.

11 Listopad 2014