Huntingtin and brain development

In April of 2013 the CHDI Foundation will host its 8th Annual Therapeutics conference, this time in beautiful Venice, Italy. I will be chairing a session entitled ‘from the beginning: what developmental systems tell us about HD’, together with Dr. Elena Cattaneo, who is one of the HD scientists working, among other things, in understanding the role in development of the Huntingtin gene. HD is typically defined as a degenerative disorder; that’s a disorder in which the brain degenerates, while it is thought that its development is normal. This view, however, might need a revision. As a developmental biologist, I always thought of HD as a disease of development; with no evidence for it, simply based on intuition. However, several facts suggest that I might not have been wrong. The reality is that in mice, normal huntingtin is needed for development of the embryo, and particularly for the proper emergence of the forebrain. However, the precise role of Huntingtin in development is still unclear. It is my belief that understanding this function – the first known function of huntingtin- will be important in elucidating the mechanisms by which mutant huntingtin causes disease … in adulthood.

It is a curious finding that many of the genes which cause degenerative diseases of the brain (and other organs, such as the pancreas in diabetes) are embryonically important genes. However, their function in development has not been well studied, and mostly because of a simple fact: these diseases are thought to occur from a ‘gain of function’, ‘toxic’ activity of the mutated proteins, and not a loss of function (the findings that implicate them in developmental processes). Therefore, if the diseases are caused by toxic ‘new activities of the mutant proteins’, why bother to study the role when the protein is not there?

Well, because the ‘mutated protein’ is likely doing something that the ‘normal protein’ does, and by inference the effects of the mutation somehow alter a function/s normally associated with the function of the gene in the absence of disease. So in order to understand what goes wrong, we need to understand what happens normally in the ‘huntingtin world’ – this is where developmental systems come in handy, as this is the ‘context’ in which Huntingtin is most needed.

During the TRACK HD longitudinal studies, researchers Sarah Tabrizi and colleagues imaged the brains of people at risk for HD, to understand the evolution of the ‘degeneration’, and to see whether we could predict when the carriers would manifest clinical disease. They surprisingly discovered that even 10-15 years prior to any clinical manifestation of HD, affected carriers had significant degeneration of the brain regions lost to HD. So how far does this process go? Is it possible that people start off this way? Or how early does the disease start killing brain cells? Another scientist, Peggy Nopoulos from the University of Iowa, and colleagues, has gone back to children at risk for HD and to study juvenile HD cases. There are already abnormalities in their brains, which suggest that it is very likely their brains develop abnormally in the first place. Remember in humans (as opposed to rodents), brain development continues through childhood – into adolescence. So a developmental function for Huntingtin could well explain the early effects of the disease, well before clinical symptoms emerge. Furthermore, in mice expressing mutant Huntingtin with large CAG repeats, there is also evidence of subtle –but observable- brain development abnormalities.

It is tempting to propose that Huntingtin mutation carriers have an abnormal brain development process that predisposes some parts of their brains to degenerate later on. This theory might explain something else in HD– the inherent variability in the spectrum of clinical symptoms. Small alterations during critical developmental windows in the brain regions affected by HD might have varied and profound consequences – in the number of cells that develop, the types of cells, in their connections with other cells, or in the wiring between different brain regions. This can directly affect how information is processed, perhaps explaining why the same mutation can give rise to very different medical problems.

Interestingly, the degree of regional brain size in childhood is also correlated with the length of the longest CAG Huntingtin allele (one of the 2 copies of the gene)– including in the normal subjects studied (although these numbers are small, the data point in this direction). It is almost as if the size of the brain (which might be associated with improved cognition for instance) might be influenced by the CAG repeat length, which might explain why during evolution Huntingtin versions have been selected for longer repeats – a good thing if it weren’t for the fact, that after a certain length of the repeat, HD develops with age.

All these facts make understanding development of the brain in the context of HD very important. The good news is that in spite of having brain differences that can be observed 20 years before clinical symptoms, the symptoms are not present, so we have plenty of time to intervene. The bad news is that the way we think about the disease might be significantly changed given this potential developmental trajectory.

Because of these reasons, several scientists have now derived human embryonic stem cells from HD subjects- and they are making neurons from these cells, so that we can study what normal and mutant Huntingtin does in the cells that eventually die from the disease. Given the critical role of Huntingtin in embryonic development, and the usefulness of developmental systems to identify signaling mechanisms, it is likely that by studying these patient-derived stem cells we will gain much insight into the disease. This is the topic of the session I will chair in Venice on April 10, 2013, and I will be joined by 3 great developmental neurobiologists: Steve Goldman (Rochester), Jeff Macklis (Harvard) and Ali Brivanlou (Rockefeller University). I will let you know how it goes later – but remember, how we develop is probably more important that we think!

Viruses and the brain

Viruses and the brain

JAN25 2015

I am certain most of you would have heard that some of the therapies being developed for HD and other neurodegenerative indications involve the use of viruses to deliver a gene therapy agent. This is true in the case of HD, we are working with 3 companies that have efforts in this regard: Shire/Sangamo, Genzyme, and Uniqure. All of them are working in late preclinical studies to identify the best agent and the best virus type to deliver the therapy. All of them are working on a type of virus called adeno-associated virus (or AAV). This type of virus comes in many flavors (serotypes), and they differ in some significant respects from each other: their ability to infect various cell types (called tropism) with different efficiencies (neurons or glial cells, for instance), their ability to be recognized by the immune system (some of these viruses have co-existed with humans for a long time, and the body has generated neutralizing antobodies to them), and finally, their ability to be taken up by axons. This latter part is critical for HD, because ideally we want to ‘transduce’ (infect) as many brain cells as possible once we administer the viruses. The viruses are non-replicative (eg they dont have the capacity to divide once injected into the brain), and typically their distribution in the brain is limited. Multiple injections directly into the brain areas affected by HD is being explored, and only a subset of neurons in these areas will be targeted by the viruses. Will this be enough??

Some variants of AAV have recently been shown to be ‘taken up’ by axons or dendrites (the ‘branches’ of neurons), and the virus can then hitch a ride from there into the nucleus of the cell. In the nucleus, the virus will start expressing the gene therapy product. One injection -we hope- will be sufficient for those cells to express the gene therapy agent for life. In studies in primates and in humans, we know we can detect the gene therapy agents for at least 10 years after a single injection into the striatum. These studies were done in the context of expressing GDNF or Neurturin for the treatment of Parkinson’s. It is from these pioneering studies that we know that the AAV ’2′ serotype is safe in humans, and leads to long-term expression. This is a critical piece of the puzzle we are trying to solve.

One difference between AAV2 and other serotypes, however, is their ability to ‘travel’ up the axons…. why is this so important for HD?

Well, the striatum (the caudate and putamen areas of the brain) is a ‘relay station’ for the brain (think of the main train station in your town). Lots of axons arrive in the striatum from everywhere in the cortex and the thalamus. The striatum has the unenviable task of receiving many types of information, which it needs to bring together, and ‘decide’ what specific ‘response’ to trigger in response to that information, particularly in the areas of action selection and motor control. Well, the anatomy of the striatum makes it possible that, when injecting the viruses directly, they will be taken up by the many millions of axons, and infect cells far away in the cortex and thalamus. Since we still do not know where we need to suppress mutant HTT expression (although we are guessing the more cells without it the better for the patients!), the broader areas that we can target, the better. In this respect, not all serotypes of AAV are the same. There is a lot of effort now in selecting new variants that are better suited for broader distribution because of their ability to get transported by neurons.

OK, so this is where we are today. The therapies using AAVs (with some luck and good science) will reach patients, we expect, as early as next year. Exciting indeed.

BUT – as all of you know, HD is more than a disease of the striatum. Many other parts of the brain are affected, and cells also die in other regions of the brain. While we are excited about the current approaches (which are at the leading edge of scientific research today), we still think that if we could administer the viruses ‘systemically’ (eg take a pill or have an injection, so that the viruses go everywhere in your body), this would be the best way to approach treating HD. Remember we think that mutant HTT also causes damage to other cells of the body, outside of the brain. Recently, some labs have identified new AAV variants (some naturally occurring, some engineered in the lab), which when injected into the mouse bloodstream, they infect the brain. This is terribly exciting! Imagine if we could give an HD patient an injection once and be done with HD!!! We are FAR away from this scenario, but this is my personal goal, and that of many of my colleagues.

There are also other viruses which we are beginning to explore to achieve this ambitious objective. We are working with academic scientists (and will expand these efforts) to engineer viruses to do precisely that: cross the blood-brain barrier (BBB) and infect cells in the brain.

What are some of the hurdles in the way, briefly outlined?

  • Ability to make large ‘titers’ (number of active virus particles/volume) so that we can give enough virus dose to infect the brain when delivered via the bloodstream
  • Ability to bypass the immune system and ensure no negative immune reactions are seen
  • Ability to cross the BBB by retargeting viruses to utilize some of the brain’s existing ‘entry gates’ (called ‘transcytosis mechanisms’) and allow the viruses to get access to brain cells. For these, viruses will be engineered to express proteins or antibodies which recognize proteins responsible for mediating the normal entry of other molecules into the brain.
  • Ability to eliminate/decrease the ‘sinks’ that exist in the body, most notably the liver, lung and spleen. Most viruses, when injected into blood, accumulate very rapidly in these organs, so that in essence very little virus remains to cross into the brain. There are specific proteins, or glycoproteins, that might mediate these effects, so modifying viruses to eliminate their interaction with molecules in these organs might allow us to bypass them

OK- I think we have had enough information for today. This area -delivering gene therapy to the brain – is most critical for us. No one has yet succeeded in doing this for any brain disorder. We hope to do it. I am excited about this work…. are you?

have a great day


Stem cells and HD drug discovery

Last week, CHDI hosted a stem cell meeting in Princeton, NJ, chaired by Thomas Vogt (CHDI’s new VP for Discovery & Systems Biology), and myself. We hosted several eminent scientists working on the use of stem cells for understanding HD pathogenesis, and identifying new mechanisms for potential therapeutic treatments. The meeting did not cover the use of stem cells as therapeutics themselves, or the approach to treat brain disorders by stimulating endogenous stem cell/progenitor cell proliferation or differentiation. This will be the subject of another meeting in the future.

As people might know, stem cells are cells that have the capacity to both self-generate, as well as generate multiple cell fates; that is, we can use stem cells derived from HD as well as unaffected subjects, to generate the cell types most vulnerable in HD… this typically means we want to work with human cells derived from people carrying the HD mutation, so that we can study, and manipulate, human biology. The cells that -at the moment- we care about the most are cells that form part of the region of the brain that degenerates in HD: medium spiny (or also called projection) neurons of the striatum, cortical projection cells (the cells that originate in deep cortical layers and which innervate the cells of the striatum), and glial cells. All of these are affected in HD: we know they display pathology, and in rodent models of HD, we can identify abnormalities pretty much as early as we can identify any problems with those animal models of HD.

What we are struggling with is why those cells are dysfunctional when mutant HTT is expressed, and what are the critical mechanisms that lead from the mutation to their dysfunction. We also struggle with the fact that all of the mouse models of HD which display signs of disease contain mutations in HTT that bear a very large (juvenile range or superphysiological ranges) CAG expansion. So we need to understand whether the pathogenic and molecular mechanisms that apply to the ‘normal pathogenic range of CAG expansions’ in humans, are similar to what we see in rodents. We think that the use of patient derived stem cells will help us in this regard.

One challenge in the field has been to generate the relevant cell types in vitro, so that we can study how their biology is affected by HTT mutations. CHDI has been funding, alone or in concert with NINDS, the development of methods to generate these cell types, and there has been great progress in this regard. Multiple teams reported on their efforts to generate cortical and striatal cells, and also reported on identifying phenotypes in the HD cells. What this means is that we now have a (limited but useful) understanding that in normal CAG HD cells, we can uncover alterations in culture. the initial findings suggest that there is a CAG-length dependency of the cellular alterations discovered. But we still need to extend these initial studies to many more cell lines. After all, not all patients show the same symptoms of the disease (we are all different) so we need to ensure we analyze multiple cells derived from a collection of people at risk or suffering the disease. This is where the long-term efforts of CHDI and the medical community will help: since through Enroll-HD, TRACK, Predict, and other studies, we have been following the progression of many patients or subjects at risk for HD, we have a rich clinical history. This will allow us to select (with their consent and participation of course!!) the subjects from whom cells might be derived, and studied. This type of work will allow us to establish very important correlations between the clinical progression of HD, with the consequences of the mutation in a cellular context. We will continue to strive for alignment and cooperation within the field, which will be needed to ensure this approach matures to a level where we can identify the critical mechanisms that translate the mutation to a clinical phenotype. It is these mechanisms that we must target, and correct (or eliminate) so that we can treat HD more effectively.

 Time will tell whether the phenotypes identified using stem cells thus far will lead us in new directions. But what is certain is that now we can seriously start studying the human disease in a much more tractable system. There is reason to be hopeful and excited!

Human genetics research sheds new hope in modulating the progression of HD

Human genetics research sheds new hope in modulating the progression of HD

MAR23 2014

It is not unfair to say that almost the entire field of therapeutic development for the treatment of HD is founded on the learnings that stem from the cloning of the gene causative of HD, the huntingtin gene. As a monogenic disorder with 100% penetrance, the genetics of the disease told us that a single gene is the sole responsible agent for the disease. All of the work that we do has to bring us back to huntingtin, and to what it does to the brains of those affected by HD. When the gene was identified, everyone thought the ‘cure’ would be near. As things go in life, nothing is quite as easy as one would hope, and Huntingtin itself remains a bit of a mystery protein. Unlike other classes of proteins, we cannot develop traditional ‘drugs’ to attack huntingtin itself, so we are forced to develop novel approaches – these ones molecular, as opposed to ‘traditional chemical approaches’ to treat the disease. There are many other approaches we and others are taking to treat HD using traditional means (a ‘pill’), and those are developed using animal models of HD, which were possible to make because we cloned the gene in the first place. Without understanding the cause of HD, my work would be far far harder.

There is another aspect of HD (and of many other degenerative diseases that belong to the same ‘molecular class’ as HD – the trinucleotide repeat disorders) which has remained unexplained thus far. This is the fact that the age of onset of motor symptoms is highly variable across individuals, and this ‘age at diagnosis’ is inversely proportional to the length of the CAG repeat in HD. See the figure below:

As the repeat length is longer, the typical average age at diagnosis is earlier, and the variability decreases. However, 95% of all people suffering from HD have a repeat length in the low to mid-40s. If you look at the vertical line of the graph, you will notice that some people with a 40 repeat get sick at age 20, and some at age 60. This variability is extraordinarily large and it tells us that something, something can influence the progression of HD prior to diagnosis.This is an extraordinarily hopeful fact. Nature has indeed found a way to affect how huntingtin affects the body. If we could mimic this, we could push the disease back and allow people to have a much longer healthy life, or in some cases, to never develop HD. We also know that there is genetic evidence that this variability is inherited, suggesting that there is at least another gene which, when inherited, can either advance or slow the progression. So what is this gene or genes?

At the CHDI therapeutics conference in Palm Springs, one of the Harvard scientists who discovered that huntingtin causes HD back in 1993 (James Gusella), presented on the progress his group and others are making towards identifying the causes of the variable age of onset. His seminar focused on an approach called ‘genome wide association study’ (GWAS). They accessed over 4000 blood and DNA samples from patients, mostly of European descent, and for the first time presented strong evidence that they had found modifier regions in DNA for the age of onset. This is a true milestone, and after 20 years of searching for this ‘missing link’, they appear to have converged on something real. There are several regions in different chromosomes which statistically show that they are closely inherited with the disease in those who progress at different rates in terms of age of onset. This study would not have been possible were it not for the many, many doctors who have described the progression of the disease and symptoms over all these years. Without detailed records and the participation of patients (in the Registry, Cohort, and other studies), we would never be able to identify those whose rate of progression is different from the average (eg the ‘extreme progressors’). The GWAS studies are ‘association studies’: they do not reveal where the change in the DNA is that makes people develop HD at a different rate. They merely shed light on the regions of the chromosomes which are strongly correlated with the phenotypes. Now the adventure picks up and the researchers have honed into the areas where the mutation or mutations must reside.

The next step is to sequence the DNA in the regions that seem to be associated with the age of onset variation, and to identify what’s different in people who progress slowly or fast. This will take a few months, but there are some candidate genes whose biology we yunderstand somewhat, and certainly they will look into those genes first. regardless of what it is, this will be another milestone for human genetics, and for all of us working on HD. If we can harness that biology, i think we can make rapid progress in delaying the disease. But even if the gene(s) proves to be like huntingtin (eg difficult!), having a ‘second entry point’ into the disease will surely help us understand what we can do to treat it effectively- after all, nature found a way of doing it. And we biologist love to study nature, and to solve its mysteries… we are on our way to solve this one, and in the process change the course of this disease forever. Stay tuned!




NOV 06 2013


Habitat for humanity and Factor-H, my other ‘job’, started a collaboration together with the Colombian family association (AcolpEH), to raise funds for patients living in suboptimal conditions in Colombia. Find the link here:

We are very behind, and we need your help. So if you read this blog, please click on the donate page in link. The donations are tax-free, and they will go exclusively to help build better homes for people affected by HD in Colombia.

We identified 5 families living in Medellin, and 10 more families living in a very rural area of Northern Colombia (Magdalena State). These latter families live in extreme poverty and have no water or electricity. The houses are built of mud or wood, and lack floors and sometimes adequate roofs.

So please, please, help me make their lives better and donate to this project. You can find out more information through



Pfizer’s PDE10 inhibitor enters clinical trials for HD

Pfizer’s PDE10 inhibitor enters clinical trials for HD

JUN16 2013

This is a good year for HD, and for all working to develop medicines to treat all those affected. For the first time in CHDI’s existence, a clinical trial with a new drug entity will start this month. The collaboration between CHDI and Pfizer began over 3 years ago, where we reached out to them to obtain what we call ‘validating ligands’; that is, we suspected based on previous work inside and outside of the HD field, that a class of enzymes which play important roles in neuronal signaling (the phosphodiesterases, or PDEs for short) might hold some promise in HD. Or at least in understanding whether the synaptic problems known to exist in HD might be ‘modulatable’ via this mechanism. We asked Pfizer, the leading company in this area of investigation, if they would be willing to give us access to some of the advanced molecules they were developing for other indications, for us to try in the HD rodent models. We obtain several of these, after about a year of negotiations about the terms of our agreement. CHDI conducted most of the work which lead Pfizer to become very excited about the utility of their molecules, and particularly one which inhibits the activity of the enzyme PDE10, for a potential treatment for HD. Joint work over the next couple of years kept revealing ever more information about the potential of this mechanism for HD. We also enlisted some of the pre-eminent academic scientists in the field of synaptic plasticity to work with CHDI and to evaluate the molecule in their laboratories, replicating and extending our initial positive findings for this drug. This combination of approaches – industry working side by side with academia in a goal-, and hypothesis-directed manner, points to a future where the barriers between these 2 teams of the scientific research world will be lowered, and where we will promote the synergy across disciplines. Also during this time, the same PDE10 molecule, initially developed by Pfizer to treat schizophrenia, failed in Phase II clinical trials for this indication. This enabled us to move swiftly into planning clinical studies jointly. Meetings took place, and the result of these is the initiation of the first PDE10 inhibitor study in HD patients, set to begin towards the end of this month in France, at the ICM institute in Paris (led by Dr Alessandra Durr, a friend and colleague). I remain very hopeful that this is the beginning of a new phase for HD. The process by which we got here marks a change in the field- hypothesis testing in models of HD, and an understanding of the synaptic deficits in HD, at the level of individual neurons, as well as at the level of the entire neural system affected in HD, points to this mechanism as being potentially efficacious at least in the movement domain. The way this molecule modulates the circuitry affected in HD makes us hopeful that other symptoms of the disease might be improved too. Let’s hope we are right in how we think about the problem from a neural perspective. Nonetheless, even it this molecule fails (due to side effects or lack of efficacy), we will undoubtedly learn a lot in the process. A failure will also teach us what we did wrong – how we need to refine our understanding of disease mechanisms, what models or systems lead us astray, what we missed in our thinking… and it will lead us to exploring other, and hopefully better, ways to treat HD. The initial clinical study is a short study of 28 days, aimed mostly at evaluating whether patients can tolerate the drug, and also to explore the domains that might be modulated by this drug (motor, cognitive, apathy, for instance). I the molecule proves to be safe in HD patients, a longer, larger, efficacy study is being planned between Pfizer and CHDI, to begin early in 2014. These are indeed exciting times for all of us who wake up every morning thinking about HD, or living with the disease in our families. Stay tuned!

The importance of biomarkers

As I have described before, the age of molecular therapies for the treatment of HD is around the corner. But a critical component of the drug development process is still lacking: the identification of Htt-dependent biomarkers. Why is this important?

Imagine what will happen over the next 1-3 years. Several of the molecular therapeutics aimed at lowering HTT expression will be tested in patients. The initial studies will be to assess safety and tolerability of the new drugs. They will involve a few patients, the studies will be conducted to ensure the invasive delivery of the agents will be safe. Remember that of the 4 programs currently in development, all require a surgical procedure, and two of them (the Sangamo/Shire and Genzyme/Sanofi programs) involve the administrtaion of the therapeutic agent in a viral vector. The vector will be adeno-associated viruses (AAVs) which is a one-time therapy. The virus will infect brain cells, will integrate into the host genome, and the therapeutic will be expressed for many years. The only other time where this has been tried in clinical trials has been in the context of Parkinson’s disease, when the growth factors GDNF and neurturin were delivered to the striatum of patients. We know from these studies that a one time injection of the AAV viruses leads to susteined expression of the forgein genes for 10 years or longer, and that the therpeutic was well tolerated (albeit with mixed efficacy results). However, once we administed the viruses, they are there for life. If something goes wrong, it will be a serious problem, so safety is paramount for these types of approaches. Simply put, they cannot be reversed.

When entering a new frontier, special efforts are needed to ensure we inflict no harm, and in order to know that the therapeutic is doing what is should. We expect that lowering HTT will lead to significant improvements in the progression of HD. But what about if we do these studies and we see nothing? We need to understand where the therapy was acting (what region of the brain?) and that it was indeed leading to a lowering of HTT levels. How much HTT do we need to suppress to see a beneficial effect? and how do we measure this decrease? This is why we need to identify biomarkers for the therapies, and biomarkers that are sensitive to HTT levels. Without these, it will be difficult to persuade companies to continue development of these potential life-saving therapeutics. Imagine we complete Phase II studies, see little evidence of efficacy (these studies willinvolve 30-50 people/arm) over a period of 1 year. Without making sure we know that HTT is being suppressed for the duration of this trial, would you enroll several hundred patients for a 2 year trial that costs many millions of dollars?

In order to prevent this question from being asked in the first place, we need to develop ways of measuring in patients that HTT has been lowering, and that an early measure of the lowering of HTT can be visualized in the patients. In order to do this, most of my work and that of my colleagues at CHDI and outside will be studying the earliest consequences of lowering HTT. We assembled a panel of experts to advice us as to methodologies we can incorporate to study the changes that the brain will experience when we stop HTT from eing expressed. Some involve an exploration of biomarkers using CSF, some involve imaging readouts. We have organized 2 symposiums at CHDI, and a third one is upcoming. After this initial assessment, the scientists at CHDI will be very busy trying to identify, explore and validate biomarkers that can be incorporated into the clinical trials. We are exploring whether HTT is detected in CSF through the use of novel assays which can detect very small amounts of HTT in this fluid. We are also trying to develop novel small molecules which can bind HTT and which can be developed as imaging tracers (similar to what has been done in the Alzheimer’s field). But we will also be exploring other imaging reagents, routinely used clinically in other fields, to evaluate whether the system is responding to a context where the patients no longer express HTT, at least in some part of their brains.

This is a very important component of our work over the next couple of years, and I hope to be reporting on our progress often. Even though we are just entering the era of molecular treatments, this will undoubtedly be a difficult and torteous road, but one which we hope will lead to the most effective treatment possible for any brain disorder.

Have a good day!

Molecular therapies for HD – Ready, Set and GO!

Huntingtin targeting therapeutics are entering the clinical realm… after many years of work, 4 big players in the biotech/pharmaceutical industry are planning clinical trials in HD. Recently you might have heard about Roche, the Swiss pharmaceutical giant, acquiring the rights to develop ISIS’s lead antisense molecule to lower HTT expression in clinical studies. This represented a milestone for CHDI as well, as initialy one of the goals of the donors and of CHDI’s president, Robi Blumenstein, was to enable and fund work to a level of maturity where a large company would become interested in developing a therapy for HD. As with the Pfizer new PDE10 inhibitor drug, CHDI has succeeded in getting a lot of attention from big players in the drug development world. Even before Roche acquired ISIS HD program (set to start trials in 2014 we hope), the orphan-disease pharmaceutical company Shire acquired the rights to develop Sangamo’s exciting zinc finger protein (ZFP), the most advanced allele-specific molecule in clinical development. CHDI continues to work with Sangamo and Shire to bring this therapy to patients as soon as possible. The ZFP developed collaboratively with Sangamo has shown efficacy in vivo in HD models, and the prospect of testing it in the clinic in the next couple of years is extremely exciting.

Two other players are also in the game for being the first to take a molecular therapy for HD to the clinic. Medtronic and CHDI continue to work to develop a surgically-delivered siRNA molecule into patients in 2014. And the latest to enter the game, Genzyme and Sanofi-Aventis, are also in late preclinical studies. All in all, the meny is varied and plentiful. Lets remain optimisitc that one of these experienced players will succeed. The stakes are high, and so are the risks (this type of therapy has never been attempted before in a brain chronic disorder), but equally high is the enthusiasm and the promise of effective, and long-lasting, treatment if they work. To enable this process, CHDI has assembled a ‘biomarker task force’, headed by CHDI’s chief medical officer (Cristina Sampaio) and chief scientific officer (Robert Pacifici). The goal of this task force is to bring the world’s experts in HD and other fields, to identify how best to measure that these therapeutic approaches yield a change in the slope of the progression, or to monitor for a biological effect of lowering HTT in the brain. Not an easy task, but one that is essential for the success of these trials. in the 5+ years I have been leading CHDI’s drug disocvery programs, this is by far the most exciting and challenging year, but one that fills me with hope.

Evolution, Huntingtin and Cancer?

A recent manuscript by a Swedish group (Ji et al., The Lancet, 2012) has revealed that the incidence of cancers amongst individuals bearing mutant expanded polyglutamine genes (and particularly Huntingtin expansions) is significantly lower than in the general population, even after adjusting for age. This study is a continuation of previous work done by this group and others, conducted to investigate whether mutations in genes containing expanded polyglutamine regions confer a biological advantage. As for other fatal genetic conditions, people have often wondered why the prevalence of disorders which kill people remains steady in the population. One can assume that if these mutations (with a  high or complete penetrance, and of dominant genetic nature) kill those bearing them, natural selection would slowly operate to eliminate these detrimental mutations, and the incidence should decrease over time. This is clearly not the case in HD – prevalence is steady, and there are no signs that the expanded alleles are under ‘negative selection’. So why is this?

Negative selection refers to the process of natural selection by which changes in the genome which are deleterious, or which decrease ‘fitness’ (the ability of the mutations being passed on to the next generation), will be eliminated (or decrease) as time passes. Some arguments were made initially to explain the lack of negative selection in HD because of the late onset of the disease. After all, most people who start having symptoms of HD develop them after they have had children. If this is the case, then bearing the mutation should not affect the number of offspring, and therefore negative selection would not operate to eliminate these mutations from the population. To a large extent, it is correct that most HD carriers have children prior to the onset of the disease, however other factors might affect the number of children in families at risk for HD. For instance, it is well known that society rejects people with genetic disorders in their family. Marrying into families known or suspected of suffering from a genetic disorder is unwelcome. From this psychological and social perspective, fitness can be affected merely due to the fact that people might not want to marry and have children with people suspected to have HD or to be potential carriers for the gene. This is well known in many cultures, but perhaps the isolated populations of HD in South America (Maracaibo townships in Venezuela perhaps the most poignant example) illustrate this point all too well. Yet even in these populations there is no evidence of negative selection as far as I am aware of (although rigorous genetic epidemiological studies have not been conducted).

If anything, small studies have revealed that the number of offspring of people carrying the HD mutation is increased! This was true when measuring the number of children of people carrying the HD mutationas compared to the general population, but even more informative, the fact that mutation carriers had more children than their siblings which did not carry the mutation! (see Carter and Nguyen, BMC Medical Genetics 2011). This finding, if reproduced in larger population studies, suggests that perhaps the Htt mutation confers an evolutionary advantage to those bearing it (and contributes to maintaining the mutation in the population in spite of its fatal nature). These reports highlight an often overlooked aspect of the genetic contribution of these mutations, that of selective advantage for those carrying them. This phenomenon is called ‘antagonistic pleiotropy’. Pleiotropy is a term used to define the fact that most proteins carry a myriad of functions in the organism – the mutation in HD leads to HD and the death of the individuals, but it might also confer other functional effects distinct from HD, which might be beneficial to those bearing the mutant protein. While Htt function is still rather unclear, we know that it plays multiple roles: it is critical for embryonic development; it modulates transcription, energy production, and other functions still ill-defined in molecular terms. ‘Antagonistic pleiotropy’ refers to the fact that two functions of the same protein might ‘be antagonistic’ with each other in terms of natural selection. This is best illustrated by sickle cell anemia mutations (which can cause death) and resistance to malaria. The mutation leads to disease, but it is maintained (or selected for) because in areas where malaria is endemic, the mutations make people more resistant to being infected by the malaria-causing pathogen. While the story is not so clear-cut in HD, the principle might apply. Something about the expansion might confer a positive effect on those carrying the mutation, which is why it might be maintained in the population. Since most people though history did not live very long (lifespan for most of our time as a species was less than 40 years of age), perhaps dying of HD was not a strong negative pressure since people did not live that long!

The beauty of epidemiological data is that it provides unbiased information: the findings regarding the lower incidence of cancer, and the increased number of offspring amongst HD carriers are descriptive in nature; it highlights that this happens, but it does not tell us how or why. But they are important clues as to what mechanisms Htt and polyglutamine expansions might be modulating. Now these observations open the door widely for the research community to try to investigate how this is taking place. A key mechanism known to modulate cancer susceptibility is a protein called p53, a key ‘gate-keeper’ of cancer progression. p53 mutations account for a large percentage of cancers in the general population, and the biology of p53 has been linked to HD for quite some time. p53 is a critical protein in cell cycle control and the DNA damage response (perhaps the most important cancer-relevant mechanisms known). The Htt-p53 link might be the explanation for the reduced cancer incidence in HD, but how this happens indeed is unknown at this point. With the genome sequencing project, understanding the link between cancer pathways and HD is feasible and should be expanded to the realm of molecular analysis. With the ability to obtain human patient derived cells(and stem cells), researchers can now begin to understand if indeed there is a strong connection between HD expansions and p53 signaling, and what exactly is this interplay. This is important, as we might, through these studies, be able to pinpoint specific molecular pathways which Htt mutations might work in. No doubt, future work will answer the question whether p53 or other cancer pathways are relevant to the function of mutant Htt.

Another interesting point is the fact that HD is caused exclusively by mutations in the polyglutamine tract. However, the ‘normal’ expansion of polyglutamine tracts is a novel development during evolution (see for instance the great and comprehensive work of Elena Cattaneo’s group in this area). That is, the polyQ tract does not appear until late in evolution, and the expansion is larger in mammals that in other species. Therefore, the polyQ tract is not required for the most ancient, evolutionarily conserved functions of Htt! For instance, in insects and other organisms, there is no Htt polyQ region; in rodents, the ‘tract’ if rather small (7-10 glutamines). It is only in large mammals and particularly primates, that the polyQ stretch is large within the ‘normal range’ (for instance, in the human population, the average length is 15-25 glutamines). This begs the question of why the expansion is promoted so late in the molecular evolution of the Htt gene, and why mostly in large mammals. Clearly, the expansion is conferring some advantage to animals with large brains, and it is likely that this function is what underlies the expansion both in the ‘normal’ range but also likely in the ‘pathogenic’ range. Again, molecular evolution is sending us a clear message here: Htt polyQexpansions have been selected for because they do something advantageous to the organism – the question is what, and how can we use this information to our benefit! Making the polyQ tract larger seems like a good idea judging by the genetic data, but going a bit too far is not so good… seems like a common theme in human biology and psychology!

Have a nice weekend!


Visiting the Colombian and Venezuelan communities

Dear all – I am sure you are all aware of the importance of the Maracaibo communities in Venezuela for HD research. The incredible milestone of identifying the Huntingtin gene was possible because of the cooperation of the peoples of Venezuela. The large cluster in Maracaibo, the largest in the world as we know today, has a prevalence of HD about 1000 times higher than in the general population (up to 2.5% of all people in some areas are affected with HD). However, there are other clusters that we know of in South America, such as the ones in Colombia, Peru and Brazil. In February, myself and Claudia Perandones, a geneticist and director of the RLAH (the Latin America HD clinical network), will be visiting the communities suffering from HD in those countries. We are visiting the communities to strengthen our ties both from a scientific, medical, and humanitarian perspective (see our efforts for the Factor-H project; Both Claudia and I will be giving talks to all the local physicians, as well as speaking directly with the patients, their caregivers, and the local authorities. Our mission is to build trust, to engage local people to help us define humanitarian and clinical management projects, and eventually prepare the communities to participate and benefit from clinical studies. I think this is the first time in many years that a visit such as this is conducted, and I believe this is the first time that a trip to Latin America includes the communities in Colombia. With the invaluable help of the local patient associations, we have crafted a trip which will be a terrific opportunity to make a change and to bring a message of hope for all those living in very difficult conditions. We will also meet with the Colombian representatives of Habitat for Humanity in Bogota, to start laying out a specific plan to build homes for those affected in Colombia. As part of our trip, we will engage the mayors and government representatives of each community, because without their cooperation, we will fail in our mission to bring change there. I am a bit nervous about this trip, which I suspect will be extremely difficult emotionally: 9 days, 8 communities, and several internal flights later, I hope that this is the beginning of a fruitful collaboration.

Scientifically and medically, the Latin American communities will be extremely important, once again, in our quest to treat HD. The large number of patients and their unaffected relatives living in concentrated, well-defined geographical areas, will enable (assuming their consent to work with us) a greater understanding of how genetic and environmental factors affect the symptoms and the progression of the disease. At the same time, by building these communities, we hope to provide access to better medical care, train the local physicians and caregivers to improve the quality of life of all living in these areas. I will posting regularly here and on the Factor-H website about the details of the trip and my reflections during this exciting moment. Please follow me and continue to support our efforts to bring change to all affected by HD.

Happy 2013!


JAN01 2013

Lets hope for a great 2013 for all those living with HD and those working to find treatments! This will be a critical year in the development of new therapies for HD- several new investigational treatments will enter clinical trials, including novel molecular approaches to treat HD… it will also see a close integration of the Latin American communities with the rest of the clinical networks across Europe and North America. We are a global community, and together, I have no doubts we will change the course of the disease… lets celebrate a new year in our quest for improving the lives of HD and let’s keep each other motivated to end the fatality of this disease! Happy New Year!

Factor_H together with the International Huntington Association is collecting funds to help the Latin American communities- at the moment you can wire money directly into an account for this effort. In 2013 we hope to enter into collaborations with large NGOs to work on large infrastructure and housing projects to help those most in need in Latin America… thanks for your help in advance!

Factor_H: a new humanitarian project to help affected communities in Latin America!

Dear all- it is with great pride that the project I have named “Factor_H” will launch in Mendoza, Argentina on October 12, 2012. This is an initiative that originated during a visit to Rio de Janeiro when I and CHDI clinical started officially the Latin American Network of clinicians and scientists. During this visit, I met with patients and their advocates as well as with Latin American scientists and physicians. In one of the most moving moments in my life, an affected person in a wheelchair approached me after my seminar. He held my hand and asked his wife to translate from Portuguese. While holding my hand, he said to me: “I know you will not be able to help me; it is too late for me, I know. But please, please, help my daughter!”

It was during this moment that I realized that I needed to do more. Science unfortunately works slowly, and until we find effective treatments, there is a need to get involved and do whatever possible to help those in need. Latin America is an area where the prevalence of HD is higher in certain communities than in the general population, including many cases of juvenile HD. Discrimination, inter-marriage, geographical isolation, and poverty have all contributed to a situation where people in those areas lack the most basic needs. Food, clothing, housing, access to care. During this trip to Brazil, I also was influenced by a comment that Asun, the head of the International Patient Association, made during a roundtable discussion about the emerging Latin American Network. She became visible upset when we spoke of how those communities could help us scientists understand HD better by donating samples and collaborating with us. She mentioned that this had happened in the late 80s, early 90s, when the gene was identified because of the involvement of the large community that resides in Venezuela. She also mentioned that in spite of their contribution to scientific research, their living situation had not changed, and many were literally dying on the floor and living in extreme poverty conditions.

It was this trip that marked a turning point in my life. I became convinced that in addition to my role as a scientist, I could do much more. Given the fact that through my scientific work I got to know everyone in the HD field, and I had earned their respect, I had the opportunity to help those affected communities through humanitarian efforts. I started then thinking about what to do, and how to do it. The outcome of this process is “Factor_H”, a social project aimed at helping those most in need in Latin America. “H” stands (in English) for Hope, Huntington’s, Humanity (In Spanish, Hermandad, Huntington’s, Humanidad). These efforts are still nascent, but we are collaborating with Habitat for Humanity to build homes for those in need of more adequate housing, as well as raising funds to build care facilities or schools (depending on the need of each community). Soon, Habitat for Humanity ( will add a project for HD and a link for people to make tax-exempt donations towards this effort. I am also trying to reach other international NGOs (Unicef etc) for other types of help. I will create a website for the project so people can track our progress and donate money.

The initial areas of focus are located in Venezuela, Colombia, Brazil, Peru, Chile and Argentina. I am planning on visiting these communities in the next few years but I have already been in contact with the local physicians and patient advocates.

Below I explain the goals of “Factor_H”. Read it please!!!

I could not do this alone: I am blessed to have ‘enrolled’ Claudia Perandones and Federico Michelli (doctors form Argentina), Maria Beconi and Celia Dominguez (scientists at CHDI), Rodrigo Osorio (the founder and president of the HD Chilean association), Asuncion Martinez (president of the Internation HD Patient Association), and Juan Negrillo (my childhood best friend and an organizer of large events through his company). Others will help in due course. It is important to note that this initiative is completely independent of CHDI and all of us involved are doing this during our free time!

The ‘launching event’ will include a fundraising concert in Mendoza on October 12, 2012. Maria Volonte (, a very talented Tango singer and a dear friend, will perform, along with a Tango dance company and Charles Sabine who will speak about his experience of living with HD.

Below is the ‘explanation for Factor_H’

Thanks to all for reading and for your (future) support!!



Introduction and mission for the project


  • To enhance the quality of life of the affected communities of Latin America
  • To increase awareness at a local level of the communities most affected by HD
  • To mobilize local communities and local youth to provide social and medical assistance to affected populations
  • To fundraise and publicize the needs of the affected communities.
  • To influence legislative issues to facilitate access to government assistance through local governance

What is ‘Factor-H’?

A non-for-profit social project to increase the awareness of people living with and affected by Huntington’s disease, to facilitate social aid to diminish the suffering of local communities in Latin America; An effort to unite socially minded individuals through creative social, journalistic, medical, scientific, and political means to eliminate suffering to those affected by genetic disorders and Huntington’s disease specifically; A movement born in order to mobilize youth in Latin America, and to change the neglect and suffering of those affected by genetic conditions and poverty; A way of bringing a smile, a friendly hand, and a sense of hope to those in desperate need of help.

A project sprung from a desire of physicians, scientists, musicians, affected and unaffected people to change the lives of those suffering from rare genetic disorders and Huntington’s disease specifically.

Introduction to the problem

Huntington’s disease (HD) is a genetic, fatal, and progressive neurodegenerative disease. It affects people with a worldwide prevalence of 0.5-1 per 10,000 people. HD does not discriminate based on ethnicity or gender. It advances slowly, but relentlessly. The disease is caused by mutations in a single gene, called Huntingtin, and the penetrance of the mutation is 100%. If one is born with Huntingtin mutations, today one will die from Huntington’s disease (provide he/she lives long enough). The progression of the disease is variable depending on the type of mutation one inherits. Although less common than the adult-onset Huntington’s disease, a juvenile form of the disease exists, and it is rather prevalent in many Latin American communities.

Latin America holds a special place in the history of HD; in its scientific history. The identification of the mutations causing HD was achieved after an international effort because of the large numbers of related, affected people living in the Maracaibo region of Venezuela. However, after 20 years since the discovery of the gene, the quality of life of affected people in Venezuela and elsewhere has changed very little. It is out of this fact and out of a desire to help these affected communities, that the concept behind ‘Factor-H’ was born. HD is highly prevalent across many communities in Latin America. Geographical isolation and the individual histories of these communities have contributed to a prevalence of the disease that in some cases is 500-1000 times higher than in other regions. The consequences of this high prevalence, and the poverty conditions in which these communities exist, have led to a situation that requires immediate attention. Poverty, ignorance and disease are a terrible combination that leads to inadequate healthcare, nutrition and living conditions. Juvenile HD cases are abundant, and in many instances entire families are incapacitated to care for themselves because so many of the family members are affected.

Factor-H is a project that aims to address the medical and social issues that most hurt people affected by HD in Latin America, through raising awareness, mobilizing communities, and providing infrastructure to help these communities grow with dignity and hope.

A genetic condition renders one unable to change one’s fate; it should not destine someone to a life without hope. A person with special needs requires special attention. Factor-H aims to raise awareness and aid so that one day that special attention is provided regularly, and so that people affected with HD can live productively and with dignity in an environment of respect, care and love.


Location of affected communities (Location, Local Representatives or physician contacts)

  • Peru/Cañete

    Dr. Carlos Cosentino

    Dra. Pilar Mazetti

    Dr. Mario Cornejo

    Huntington Society of Peru

    Mrs. Maria Begazo Viza (Arequipa, Peru)


    • Chile
      • Patients are dispersed. Main focal point is Santiago de Chile

    Rodrigo Osorio:


    • Argentina
      • Buenos Aires area

    Dr. Federico Michelli,

    Dra. Claudia Perandones

    Asociacion Para el Apoyo a los Enfermos de Huntington (APAEH)

    Catamarca 19, Rufino (Santa Fé) CP 6100,


    Tel mobile: 54-9-3382-578922 ;

    Tel : 54-3382-4-28658 03382 4 28658

    Email :

    Website :

    • Venezuela/Maracaibo

    Dr. Ernesto Solís Añez

    Dr. Olmedo Ferrer Ocando


    Mrs Aleksa Gonzalez de Zambrano

    Tel: +58-212-7517 654; Fax: +58-261 5011


    Website :

    • Brazil
      • Feira Grande, Maceio; Aparecida Alencar;
      • Sao Paulo, Dra. Mónica Santoro Hadad, Dra. Vanderci Borges
      • Ribeirao Preto, Dr. Vitor Tumas





    Fundación Huntington Colombia:

    Meeting in Mendoza, Argentina

    below - Old blog entries from

    here we will discuss science news relevant to HD

    OCT10 2012

    Dear all – I am writing today from Argentina, I am here to present CHDI’s work at the second movement disorders meeting, organized by Freddy Michelli and Claudia Perandones from Argentina. Today I met with 3 incredible ladies from Venezuela, Rosa, Aleska and Zulay, who live daily with the incredible suffering of HD patients in this country. I heard their stories, and in spite of their struggles, I am confident together we will do something to help. I heard of towns where 60% of all people are HD positive, of families with 10 children affected by HD, of towns with no running water or houses. This makes my project Factor_H more needed, and more pressing that we raise funds to help the people who need it the most. During the meeting I will speak also to the relatives and physicians of other affected communities in Latin America: Peru, Brasil, and Colombia. This is an extremely moving moment for me, and one that makes me happy as well because it is bringing me together with the true “warriors” in this disease. We are now part of an extended social family working together around the world to make life better for all people suffering from HD.

    Check out the website for Factor_H: it is now ‘live’!!!

    I will be soon putting plans together to start raising funds, among the NGOs I am contemplating or discussing specific projects are Habitat for Humanity, Caritas, and Engineers Without Borders.

    Please make sure you check often to see if we have signed agreements to start collecting funds/donations for these communities

    All the best