HD.Science.Blog

MOVING TO A NEW, BETTER, SITE: www.hdscienceblog.com

2010-02-25T20:23:00.000-08:00

trying to be a bit more sophisticated

created a domain name.... please come join me at www.hdscienceblog.com

thanks

ignacio

CHDI Therapeutics Conference in Palm Springs

2010-02-21T06:50:00.000-08:00

From the 8-11 February we held the 5th annual conference on HD therapeutics. The conference brings together scientists from academia and industry (mostly CHDI funded investigators or collaborators), physicians, and patient relatives or support group representatives. The meeting focuses on discussing the most recent advances in drug development for HD, including exciting new clinical programs as well as academic research with fundamental implications for therapeutic development.

This year people left the meeting with a renewed sense of hope, since several programs in clinical stages for other indications were discussed in the context of a collaboration with CHDI for entering clinical development for HD. There are 2 in particular which I will comment on. The first is a CoQ10-analog (EPI-743) from the company Edison Pharmaceuticals; the second is an autophagy inducer, a Farnesyl-transferase inhibitor (FTI) coded LNK-754, from the company LINK Medicine. Since I want to discuss both of these approaches and my view on their relative potential, I will dedicate a single blog entry to each of them. I fear writing about them both now at length will make everyone fall asleep. The good news is that there are novel medical entities which have made their way into the clinic and which try to affect new mechanisms never tested in HD. This I believe is the beginning of a new period of hope for HD patients, since in the next few years we will see an explosion of new trials and potentially new medicines.

Before I conclude today I wanted to address the progress made in the clinical trials conducted by EHDN with Neurosearch on the Phase III evaluation of the molecule ACR-16. The results of the trial with this molecule (supposedly a 'dopamine stabilizer') have been positive in the motor domain, having an effect magnitude in both chorea (involuntary movements) and voluntary movements (including eye movements) in the UHDRS (the 'unified HD research scale') similar to that observed with Tetrabenazine. Dr Joakim Tedroff spoke about the mechanism of ACR-16 (Huntexil) and the results of the trial. In spite of the fact that this initial Phase III trial will likely not be sufficient for registration on its own, ACR-16 will very likely become a new drug for the treatment of the motor dysfunction in HD. A second Phase III trial in the USA will be conducted shortly, which hopefully will lead to a registration with the FDA and EMEA (the European equivalent of the FDA).

Please see the following link for more information:

http://www.neurosearch.com/Default.aspx?ID=16&M=News&PID=12&NewsID=15889

Currently the FDA requires at least evidence of positive effects on meaningful outcomes in two different trials. This view might be changing for orphan indications. A positive results from a smaller Phase II trial can sometimes be used for evidence of positive effects if the results from a single Phase III study are robust and there is a strong medical need for treating an orphan condition.

In spite of the fact that ACR-16 will not significantly enhance the cognitive or depression domains in HD, nor affect the progression of the disease (in my opinion based on this mechanism), there are reasons to celebrate. ACR-=16 was as effective as tetrabenazine in treating movement dysfunction (3 points in the UHDRS scale), but with far fewer side effects. ACR-16 was very well tolerated, suggesting that many more people might now be able to take a drug for controlling their motor dysfunction with few problems. The trial was also a large trial (over 400 patients completed the study) conducted in Europe under EHDN's monitoring. The trial was a clear success (and not only because the drug was effective): the coordination between the many centers, the high compliance rate, and the quality of the data processing and analysis, represents a clear advance in HD clinical work. I feel confident that, based on this work, we will be able to conduct large trials for other (more hopeful) drugs to slow the progression of HD.

The mechanism of ACR-16 is in my opinion very poorly understood - they term it a 'dopamine stabilizer' which means little (and is not a scientific term even if it sounds like one). I am speaking strictly as an individual scientist, and not as the head of biology at my company!

ACR-16 can bind and affect signaling by the dopamine receptors (D1 and D2), the main 'controllers' of movement initiation, termination, and coordination. They can bind these receptors and block their signaling at certain doses. However, the dopamine system is such that the levels of dopamine in the brain are self-regulated. It is thought that there are two modes for signaling of dopamine: 'tonic' and 'phasic'. Tonic means that there is always a low level 'tone' of dopamine which, due to its higher preference ('affinity') for D2 receptors (which can be considered the 'brakes' in movement control), keeps us in full control of movement. When these receptors are significantly lost, for instance in HD, involuntary movements can occur (the 'brake is gone'). Signaling through D1 in the basal ganglia (the area most affected in HD) controls movement initiation.

The 'phasic' dopamine signaling refers to the observation that large increases in dopamine release at the synapses are seen when animals are about to initiate movement or upon the expectation of a reward, for instance. When one encounters new situation or are faced with choices, there is a surge of dopamine in the brain. This leads to the 'phasic' dopamine increases (because it returns to baseline shortly thereafter). Apparently scientists have shown that ACR-16 (even though it can act to inhibit dopamine signaling, it leads to a maintenance of tonic dopamine levels in the brain (hence 'stabilizer'). This is supposedly having an effect on initiation of movement (which is affected in HD since it is thought that there is a stronger D1-drive, which is manifested in the uncontrolled movements and lack of coordination seen in HD patients). I am not convinced that this is how this drug works, although i cannot give a different explanation. It is possible that the drug can bind other receptors we don't know off. What it tells us is that probably the modulation of dopamine signaling can be important for HD in some domains, but that the normalization of its signaling is not sufficient to slow disease progression or lead to a great improvement in the quality of life of HD (specially as the disease advances).

Latin American HD Network: Thoughts after the Initial Meeting

2010-02-10T06:02:00.001-08:00

This chapter, like many others, begun from the desire to help others, to not forget those less fortunate to have access to the same resources I and some of my Americana and European colleagues have. I was aware of the fact that the gene for Huntington's disease (Huntingtin) was identified through a heroic effort of a multinational team of scientists, who used DNA obtained from the blood samples of a large set of families from a region in Venezuela bordering Lake Maracaibo in the north west of the country. In this area, the prevalence of Huntington's disease was high; there were large families with 3 or 4 generations of affected individuals, which allowed for the type of genetic analysis necessary to identify genetic contributions to the disease. Through a process called 'positional cloning', patterns of inheritance of DNA regions, or 'markers', can be traced to isolate regions where the disease gene resides. These regions became progressively better 'mapped' and this lead to the final identification in 1993 of the gene harboring the mutation responsible for HD. The pictures below are from some of the Venezuelan patients, next to a wonderful person named Aleska de Zambrano, who is the voice of the Venezuelan HD patient and families association.

The importance of Latin America, and Venezuela in particular, has already been large in the field of HD. There are other regions in Colombia and Brazil, and probably others I don't know of as of yet, where HD is highly prevalent. Yet the representation of our efforts in Latin America, from a scientific and clinical perspective, is small. It is almost as if Latin American countries were largely kept 'outside' of many scientific and medical international enterprises. I felt we could do something to change this. I also thought that we needed our colleagues, doctors and scientists, as well as patients and their families, to be more actively involved with the efforts of CHDI. I was aware that recruiting patients for clinical and observational trials was proving challenging, and if we are to develop medicines, we will necessarily need additional patient participation, and also probably additional clinical sites to conduct these studies.

Through my friend Gerardo Jimenez, the then director of the Institute of Genomic Medicine in Mexico, I organized a visit to the National Institute of Neurology, where we met the team coordinated by Dra. Elena Alonso, the director of the medical genetics department. Even though this meeting was rather unsuccessful in initiating efforts to bring our efforts together with theirs, it represented an initial step in consolidating our interest in working with our Latin American colleagues. I invited Dr. Bernhard Landwehrmeyer, from Germany, who is the acting chairman of European HD Network (www.euro-hd.com), and a very accomplished scientist and neurologist. EHDN has established an impressive network through most of Europe of clinicians, patients, scientists and advocacy groups (this network is funded exclusively by CHDI). Bernhard was part of the initial team of scientists headed for Venezuela. His passion and dedication to help cure this disease are unparalleled. He immediately responded to my invitation to come to Mexico and shared his (unknown to me at the time) long standing desire to make a Latin American Network a reality.

Through the support of Robi Blumenstein (the President of CHDI), myself, Bernhard and Dr. Michael Orth from EHDN, organized the first meeting of clinicians and patient groups in Rio de Janeiro (Brazil) this past Feb. 05 and 06. The meeting brought together neurologists and patient representatives from Argentina, Brazil, Cuba, Chile, Venezuela and Spain. The meeting was chaired by Dr Francisco Cardoso of Belo Horizonte (Brazil), who managed to get together several prominent neurologists, to discuss both the incidence and management of HD care in their countries, as well as to discuss common interests in establishing the network. Representatives from Colombia and Peru were unable to come, but will undoubtedly participate in future events. We discussed our vision for why having a Latin American network is important for CHDI and EHDN; why we think that by working together we can maximize the changes of being successful and shortening the time to an effective treatment. A few hours before the meeting begun in Rio, we received notice of the positive preliminary outcome of the ACR-16 trial (carried out by the company Neurosearch in collaboration with EHDN). It was an auspicious beginning. The meeting proved a clear success in terms of excitement among our Latin American colleagues, both the doctors and the lay people. The meeting lead to a selection of an initial committee to consider formalizing such network, and beginning to craft a set of initial objectives, a mission and a constitution for how they want to operate. We agreed to meet next in Buenos Aires in June for the International Meeting of the Association for Movement Disorders.

I don't know what my longer term role will be, as this is outside of my 'day job'… I can only thank the people who have participated and are trying to make this network a reality. I feel that HD is a global disease and therefore our efforts should be global. That together we have a stronger chance at defeating this disease. During the meeting, I met many patients and relatives, who came from all over Brazil, some from far away. They came to talk to us, to ask questions about whether there was any hope of finding any treatments soon… I felt powerless, frustrated, almost emasculated… I could not give them much good news yet… I realized my struggles with work and life are petty compared to the anxiety of knowing that a certain and terrible death awaits them and their relatives, their spouses and children. No statements such as 'please be patient', 'it takes years to do a clinical study', 'we don't understand the disease enough' make justice to the fear of imminent death for those one loves. They sound like a set of excuses for not being able to help… and yet I know we do the best we know, the best we can, to find answers. I went to Rio because I wanted to extend a message of Hope to those in Latin America – this is not an American or European enterprise, it's a global fight to find a cure, which should be made available to all, rich or poor, in NY or Maracaibo. But I also went there because we need more people to work with us. I need every affected person to participate: by donating blood, by speaking out, by enrolling in observational studies, in clinical studies. We simply cannot do it without the patients and the people at risk.

When I was asked many questions about potential therapies, like stem cell transplantation studies, I failed to understand their desperation. I want to communicate to them that right now there are no therapies available, and that therefore they should not expose themselves to treatments unknown to be effective, and which can cause them a lot of harm. My only advice is that they need to educate themselves, through the patients' international or national associations, and through their doctors. The patients should not remain paralyzed, waiting for a pill. There are ways to get involved, and we need to raise that awareness. Go to the following websites: HSG, HDF, EHDN and CHDI. Reach out and ask questions to those who only have the best interest of the patients in mind. I almost cried feeling the sincere gratitude the families and patients expressed to us. Because we had come to them, to be able to converse and answer some of the many questions they have. I left with a strong feeling of urgency, but also of fulfillment, of gratitude for being able to live this moment, and of being able to help in whatever way possible. After all, this is why I became a scientist… so thank you to all who believe in our mission and who understand that there are good scientists working for your health and your life. Obrigado!

The beginning of my diary as a scientist

2010-01-30T19:23:00.000-08:00

I have decided to change the blog content- i want to use it more like a 'diary' of my scientific life. hopefully i can help make people understand how scientists do their job, and our daily struggles at work and with science. I have also made my identity known. I am the head of biology at a non for profit foundation (www.chdifoundation.org) trying to develop medicines for HD. I oversee work carried out around the world by many teams of dedicated people, whom we contract work to develop medicines and find out how HD develops and progresses. We fund work in basic and applied research, and I work with a very talented set of chemists, biologists, pharmacologists and clinicians. I also work with project managers, business and legal people who help make our foundation a reality. We all work together to develop treatments for HD. I want to show you how I think about this problem, and the issues that I, like most scientists, have to solve to translate ideas to medicines. It is a long process, sometimes tiring and frustrating, because we don't know enough. But we try, as hard as we can, to develop rational approaches based on our current understanding of the brain and of the human body. We could not do this alone, science is built out of a history of studies and on the shoulders of many generations of people who have dedicated their lives to understanding how the brain works and what happens when things fail to work properly. Science is never a lonely enterprise, even if our daily work sometimes is. We are preceded by a history of knowledge. We generate a legacy to our successors, who will inevitably take our learnings and apply them to advance our understanding of any given process. In spite of how small our contributions might be, they will always help future generations. A small finding might be a clue in the future about something truly meaningful.

TRACK HD publication

2010-01-20T18:41:00.000-08:00

Recently the CHDI Foundation, in collaboration with 4 clinical groups in Europe and Canada (led by Dr. Sarah Tabrizi of London) reported their findings of the first year of a study called 'Track HD. The study is a longitudinal evaluation of disease progression over 3 years. In a longitudinal study, the same subjects are repeatedly monitored (in this case, once every 3 years) to assess how their symptoms and the degree of anatomical brain changes, are varying over the length of the study. This manuscript describes the initial findings from the first year evaluation. The study aimed to monitor general domains of interest to the management of the disease. In HD, there are several 'domains' which are affected: these are related to clinically distinct symptoms, such as anxiety and depression (psychiatric changes), cognitive abilities, and motor components (such as chorea, visual tasks, finger tapping, etc.) In addition, and importantly, the study incorporated imaging studies, where the structures of various anatomical regions of the brain are studied.

The goal for this comprehensive evaluation is 2-fold: first, the researchers need to identify the most sensitive tests which identify the most people (at risk for HD) which are showing symptoms of the disease (even before the traditional diagnosis of the disease, which is typically made by neurologists based on the motor symptoms defined as chorea, or abnorma uncontrolledl movements). The identification of such tests is an essential process to identify novel therapies which might be effective in delaying or improving the symptoms of HD. The current rating scales (typically, the UHDRS, or unified HD rating scale) does not incorporate sufficient tests in the cognitive or psychiatric domains, and therefore it is not a useful scale to assess for efficacy in these domains. This represents an area of considerable importance in developing new therapies, one that is usually not accounted for when conducting clinical trials.

The second goal is to understand the evolution of the symptoms - can we predict when someone at risk to develop HD will develop obert symptoms? Ideally, we would like to start treting patients before the disease is fully developed. Therefore, we need to monitor subjects at risk and understand when is best to start treating them. In order to do this, the authors of the manuscript are monitoring unaffected subjects, people with diagnosed HD, and people carrying the mutation, but who are not yet 'diagnosed' with HD because their symptoms are below the detection level of the UHDRS. What the authors are trying to do is to see how these people perform on all these tasks, to understand how the disease develop (as some of the 'carriers' will develop HD during the course of the study) and how variable the performance on these tasks is over time.

Several findings are notable in the study. One of the most significant findings is that, even in people who are expected to develop HD ten years from now, there are significant differences from unaffected people. Among these, one of the most significant changes is anatomical. The brain regions that degenerate (where the neuons die) in HD are already very affected in un-diagnosed HD carriers. Essentially, one can describe this as being a 'hole' in their brains. Scary? Yes. But.... think about the fact that largely, these people can lead normal lives. They dont have symptoms that physicians would think need medication. This is good news: the brain is capable to operate normally even if many neurons are already dead. I think this offers HOPE since if we are able to slow down the progression, patients might be able to lead normal lives.

Another finding is that there are many tests which are sensitive enough to select 'people at risk' with unaffected people (carryign a normal gene). Some of these tests involve motor coordination (such as finger tapping or a test monitoring what is called saccades (the movement of the eyes directed at following an object that is itself moving within the visual field). In both of these tests, people with HD or people carrying the disease, perform less well than normal subjects. Because the brain areas which are responsible for being able to perform these tasks (for instance, if you are asked to maintain a constant rhythm when tapping your fingers) are the same areas in which the neurons of the brain die over time, these are very 'sensitive' tests that there is a problem in that part of the brain.

Other tests such as apathy and irritability also show significant differences between people at risk and unaffected subjects. Overall, this study is very good news for the HD community: it shows that there are several sensitive tasks that can identify who is at risk, and who might be starting the symptomatic process which will culminate in a clinical diagnosis of HD.

One additional comment: all of the centers which participated in this study, which recruited close to 100 subjects in each group, are outside the USA. why is this? how come it is so difficult to get Americans to enroll in these studies? Maybe it has to do with the fact that the US does not have a national health plan? maybe that insurance companies in the US are still discrimating against people at risk for a chronic lethal disease? All those affected should act in whatever way they can to change these terrible social aspects - all people deserve to have health insurance, and to be treated in the best way possible!

Finally, soon the results from the second year will come to light. It is important to know whether some of these tests which were able to distinguish unaffected subjects from people at risk are good tests to assess whether people are doing 'worse"- this would be a good outcome, since it will mean that these test can assess whether a new therapy makes things better! Lets keep our fingers crossed!!

have a great day and see you soon!

Season Greetings!

2009-12-26T12:28:00.000-08:00

The beginning of a New Year is always filled with new possibilities.... with Hope...

My Christmas wish for everyone out there affected or touched by Huntington's disease is a gift of Hope. Without hope, we would not be waking every morning looking up to a future where this disease will be managed adequately. I personally know that many people, just like me, go to work every day hoping that our efforts will one day bring a cure for those affected by HD. You can rest assured that, as certain as the sun will rise every morning, we will be thinking day and night about you. You are not alone. This is a blog to instill Hope, to let you know we are here with you.

My next entry will be to review a remarkable study funded by CHDI, a non for-profit Foundation aiming to develop drugs for HD. CHDI is funded by an anonymous donor, who invests millions of dollars each year to cure this disease. The study I will review is called TRACK HD, a longitudinal (multi year) study aiming to map out the development of HD. The study tries to follow many people with HD, people who carry the gene but are yet not 'symptomatic' (that is, a neurologist has not yet diagnosed their symptoms as having HD), and control subjects. The study aims to identify the most sensitive 'markers' of disease progression, a step that is necessary to develop drugs for HD, particularly disease-modifying therapies. By understanding the rate of progression, we can one day assess whether early intervention changes the rate of progression (hence 'disease modifying').

The results from the first year of TRACK have recently been published (see Tabrizi et al., Lancet Neurology, 2009). Among the many important findings of this work, two issues stand out: first, people who are carriers, even ten years before the predicted 'onset' of the clinical symptoms, already have significant neuronal degeneration, and perform significantly worse on some tests that unaffected people. Even though this finding might be troubling, it also highlights that, in spite of that damage, people can go about their daily lives largely unaffected, which gives us reason for Hope. The brain can deal with a lot of damage before we succumb to such injuries. This is in itself is a property of the way the brain developed, and is in my opinion a sign that, if we intervene early enough, we might prevent the disease from progressing to a stage where it really affects people's quality of life and ability to function normally.

Second, this type of study was only possible because many people carriers of the HD gene mutation volunteered for the study. Without them, we could not understand how best to identify such disease modifying therapies, given that, most likely, the successful development of such therapies is dependent on accessing early manifest patients. It is well known that even for TRACK, the centers had difficulty in enrolling all the subjects. Other studies had to be abandoned because it was too difficult to enroll patients, particularly in the US (where issues linked to lack of national health plans and insurance discrimination issues might deter people from enrolling). Without all of you who are at risk (or mutation positive) participating in observational trials such as TRACK, we will never be able to understand how the disease progresses. We need your help!

My wish for 2010 is that, with renewed Hope, all of you might consider how you can help us, the scientists and doctors dedicating their lives to finding a cure, your families and caretakers, your friends, sons and daughters who care for you. You can help by being educated about your disease, by being empowered to make a difference in your life. In many ways, the probability that we scientists find a treatment rests on your shoulders: if you get involved, I have no doubt we will find a way to help you. So get involved!

Merry Christmas!

2009-12-13T13:07:00.000-08:00

Some clarifications and thoughts…

Well, welcome to the Huntington’s Disease Science Blog, a very personal web site dedicated to increasing awareness about this terrible disease, to attempt to dispel myths about research, scientific processes, scientists, and drug development, and to inform (you) of the latest attempts to understand and treat HD. But before we commence with my regular (probably biweekly) reviews of recent findings, I wanted to make a few comments about our work (that of the scientists and physicians trying to solve this very difficult problem). Our goal is to improve the lives of people and families affected by HD, and we hope that out small contributions will bring forth a treatment (or better yet, a cure) for HD, so that future generations will be spared of a life struggling with the decline brought forth by this (thus far) incurable, inherited, disease.

Science’s goal is to “disprove hypothesis” – not to prove them. The ‘theories’ that are prevalent are the ones that have withstood the test of time (so far) – people viciously try to bring them down, but they can’t: the evidence argues that these theories best fit available evidence. This is an important concept: it explains why scientists are always argumentative, and are apparently hard at work to bring someone else’s work to the ground. This is how our knowledge builds. We (scientists) acknowledge that we should only make claims based on available evidence. What seems correct today might not be applicable tomorrow, as new facts are described which change our understanding of a process or an observation. So we can never claim ‘we are right’, or ‘this is the way it is’… however, just because we accept our limitations, this does not mean that anything else is possible! Note, for example, the debate between evolution and ‘intelligent creation’…. Accepting that we might be wrong (unlikely in this case) does not immediately imply that any other (unsubstantiated theory) must be right or holds equal ground… we still base our statements on the best available evidence. Show scientists evidence of an alternative explanation, and undoubtedly and very quickly, most scientists will jump ship and trash the work of those (always the others) who got it wrong!
Let me again reiterate an important fact: scientists are human beings - we make mistakes, we are often wrong. Society sometimes forgets this fact and assumes that scientists should have answers for everything… Even though I am a scientist, I acknowledge there are areas where scientists should not mess with…. Stick to your area of expertise!

Let me tell you a bit about publishing… when we publish our work, typically we have to write a story that is cohesive and complete (especially for ‘high impact’ journals such as Science, Nature, Cell, Neuron, etc). Often times this leads to the (wrong) perception that we really understand what is happening. This is seldom the case, even though eventually the cumulative efforts of many people will yield some answers – of that you can be certain: we have learned a lot about this disease, but not enough yet. So hang in there with us, we are all walking together in the same direction. It is simply a long, arduous road.

The nature of scientific peer-review publishing is such that unless one is able to offer a report which leaves out ambiguities, it will have a tough time getting published. This is very unfortunate because some of the ‘loose ends’ are the interesting ones, and it is through the ambiguities in the work that arise important questions about the main hypothesis driving the work. I have often times found myself torn between including data I could not fully explain, or excluding it for the sake of publication. As the livelihood of most scientists working in academia relies on publishing, the decision invariably leads to not including those results.

Drug discovery is a tricky business. It takes on average almost a billion US dollars and over ten years of work to market a drug…. These are average figures: it is thought to be even more costly and lengthy for mental indications. So when you read a paper suggesting that a ‘treatment’ has been identified that works well in mice or rats, adjust your expectations!
Most of the time many of these positive results cannot be replicated, and even if they are, and assuming the biology is conserved between the disease states in the rodent and in people, it would still take many years to make as drug to treat people. I want to illustrate some of the steps that are required in drug discovery before a drug can be approved by the FDA (USA) or EMEA (European Union)… fasten your belts, as it is a bumpy and lengthy ride!!

The initial period (usually 1-3 years) involves identifying a mechanism or a single molecular target (an enzyme, or a receptor, for instance) which might positively affect some aspect of the disease process. For instance, in the case of HD, the identification of the gene causative for the disease (termed huntingtin, or IT-15), can be the focus of developing therapies aimed at modulating its function (or in this case, eliminating the mutated protein). In the case of huntingtin, developing a small molecule chemical to restore its function to a ‘normal state’ is not possible, as huntingtin is not a protein which can be modulated via small molecules. In other instances, say in the case of finding an enzyme which can be inhibited or activated, a chemical campaign is initiated to find molecules with the right activity. For example, if we take the example of the serotonin reuptake inhibitors (SSRIs) used to treat depression, small molecule chemicals were developed which inhibit its function. In this case, the serotonin reuptake transporter is a protein whose role is to take serotonin, a neurotransmitter, from the synaptic medium (outside the cells), and bring it inside of cells. This was based on the observation that there was a decrease of serotonin (or 5-HT, 5-hydroxytryptamine, a chemical neuro-transmitter) in people suffering from unipolar depression.
The development of such chemicals is slow: it involves finding a molecule, which can act at the protein target in a potent and selective way (that is, it does not interact with other related proteins). This typically takes several years, as the molecules have to be optimized to be selective and safe.

The field of drug metabolism and pharmacokinetics (DMPK) is needed to assess that the chemical can effectively reach the protein target (in this case, brain neurons) at a concentration effective to inhibit this process. If you think about it, this is not simple: an animal must take a chemical (preferably through oral administration), the chemical must make it outside of the gastrointestinal tract, get into the blood stream, travel to the brain (most chemicals cannot get into the brain as the brain/blood barrier (BBB) prevents most chemicals from reaching the neurons in the brain), and interact with the target in question. Most importantly, the chemical must do this without negatively affecting other mechanisms (hence not causing toxicity). The development of a safe and effective chemical is a very difficult task and it involves the work of many chemists and biologists working together very closely. The teams involved in drug discovery involve chemists (medicinal and synthetic chemists) and biologists (pharmacologists, molecular biologists, neuroscientists, experts in animal behavior and other disciplines).

After animals are given the chemical, we must assess not only that the drug is doing what is supposed to (in the case of SSRIs, increase serotonin levels), but we must also assess that increasing serotonin levels leads to a biological effect which we think will be of benefit to the disease in question. This sounds easy but it is hard to do: often times we do not know whether the brains of animals used in research (mostly mice and rats) respond in the same way that human brains do. Therefore, a large area of research is to develop animal models of disease. In the case of HD, we have developed mice and rats genetically engineered to carry the human mutations. These animals develop a progressive degenerative process which we feel represents a state similar to some aspects of the human condition. Although imperfect, these models help us in deciphering the mechanisms which might be affected in the brains of people suffering with HD, and act as ‘models’ to assess whether drugs are effective.

After we have shown that the chemical does what is supposed to, we invest a lot of time in improving its characteristics in terms of potency and safety. We must ascertain that a chronic administration of the molecule (over months) does not pose any safety issues (such as liver damage, the most common source of safety issues since the liver is the organ which breaks down most chemicals in the body). The safety studies required to get approval to initiate a clinical study (in people) take at least 12 months (these are called IND enabling studies; IND= investigational new drug).

The process of the clinical trials takes on average more than 5 years (with few exceptions), since drugs must be tested in unaffected individuals (to assess safety, as in Phase I trials), or in affected people (Phase II) and to determine a dose which is predicted to be effective, but without reaching doses which might pose a risk in terms of toxicity. The Phase III trials are the most costly as they involve a large number of patients and they take a long time to complete (typically 1-2 years from initiation of the trial; this does not account the time it takes to get all the patients enrolled and all the paperwork required for the hospitals and clinical centers to be ready to start a study of this magnitude!)
Typically, most drugs these days (especially for mental indications) fail in the clinic because we got the biology wrong. The drug is safe (somewhat) but it does not yield the expected improvement in clinical symptoms. This is probably because we did not understand the disease properly, the animal models did not accurate mimic the human disease, or we had the wrong hypothesis.
One of the areas that requires more work (and hence an area where all of you can help) is gathering more information from the patients suffering from the disease.

After all, we are trying to cure the human disease. Yet, due to ethical and societal issues, we know least about the biology of the human species. We tend to know a lot more about how the brains of mice and rats work, that those of people. This is a significant reason why we got things wrong often. If there were more people participating in clinical research (through imaging their brains, for instance), we might be able to develop better theories. At my work, we try to gather as many observations as possible from people suffering from HD, so that we can assess if the models we have developed mimic the disease. Your help in participating in observational trials (no drugs being taken) helps tremendously in gathering such data, and refining our understanding of the disease.

I hope these words are helpful in understanding some basic concepts about the work we do.