Posted to the HDL: 27 Aug 2006

Hereditary Disease Foundation meeting: HD 2006: Changes, Advances and Good News (CAG)n

Marsha Miller, Steve Ireland, and Jim Tretheway

Dr. Carl Johnson, Executive Director for Science, HDF

As our longtime readers know, the Hereditary Disease Foundation (HDF), led by Dr. Nancy Wexler and her research director, Dr. Carl Johnson, encourges, organizes and funds HD research.

Every two years they host a major conference so that researchers can share important developments long before publication. The goal is to speed the research to find a treatment or cure for Huntington’s disease.

We were invited to attend this year’s meeting to learn about the progress being made and to share the broad findings with other HD family members. There were 350 participants from around the world, 66 speakers, and 231 research posters on display. The areas covered were wide ranging, starting with basic research into HD pathogenesis and including novel therapeutic strategies, RNAi advances, new therapeutic compounds and screens, biomarkers, and clinical trials.

Most of the research presented has not yet been published so we will wait to discuss it in depth at that time. But attending the conference does give us a ‘heads up’ on the molecular biology we need to read about and the upcoming articles we need to watch for. It has also given us a sense of where the research is going, the progress that has been made, and what still needs to be done. In another month or two, HD family members interested in more details may be able to find a more technical summary of the meeting on the HDF web site, www.hdfoundation.org.

Pathogenesis

All of the presentations relating to HD pathogenesis were interesting. You wouldn’t think that there was much more to learn about how HD contributes to cell death and dysfunction, but there is. Some of this work may be on problems that are too far “downstream” from the key cellular events to be very useful for developing an effective treatment, but there still is the possibility that new discoveries will lead researchers to new therapeutic targets.

One area that was unfamiliar to us and which the HDLighthouse will be following is the role of profilin in the disease process. Profilin is a small and abundant actin-binding protein that is depleted in the brains of HD patients. Since it is involved in many cellular processes, its depletion may well be a factor in a number of HD pathologies.

Other topics covered included calcium dysregulation, transcriptional dysregulational, nuclear transport of the huntingtin protein, protein folding and clearance, somatic instability of the CAG repeat, the contribution that glial cells may make to the disease process, and genetic modifiers of age of onset.

Huntington’s disease is called a polyglutamine disease, caused by an repeated genetic pattern that puts too many glutamines in the huntingtin protein. During a plenary session, Dr. Albert La Spada spoke about commonalities across all polyglutamine disorders. These include:

• proteolytic cleavage (toxic fragment hypothesis)
  
• importance of protein context
  
• excitotoxicity/glial dysfunction
  
• transcriptional dysregulation
  
• bioenergetics/mitochondrial abnormalities
  
• loss of function/altered function
  

All of this is very technical, but it means that answers found in Huntington’s disease research are likely to help individuals who have other polyglutamine diseases. And, importantly for HD families, it means that research done on these other diseases may help bring treatments to HD patients. Research from some of these related diseases was presented at the conference.

Dr. Steven Finkbeiner discussed why it has been so hard to understand the Huntington’s disease processes. Many changes within the affected cells have been observed. Some may be incidental to the disease process while others contribute to it and still others are coping mechanisms within the cell. Some problems give rise to others while some represent independent pathways of harm caused by the HD gene.

His automated quantitative imaging approach allows him to observe, record, and quantify multiple cell processes in real time. Taking a systems approach may go a long way toward unlocking Huntington’s mysteries.

Therapeutic strategies

Research aimed at finding therapeutic targets was covered. These targets are things that a drug or other treatment focus on to alter the course of the disease. Quite a number of studies pointed to the critical role that a protein called BDNF (brain derived neurotrophic factor) can play in reducing the effects of HD. Drugs or other interventions that serve to increase the amount of BDNF in the brain may be an effective way to treat the disease.

The Lighthouse has been following the research of Dr. Steven Goldman and colleagues in promoting neurogenesis (growth of new neurons) by using a combination of two proteins, BDNF and noggin. (see http://www.hdlighthouse.org/research/bdnf/updates/1255bdnf.php) The research has continued with the HD mice and the we look forward to covering the results when the new study has been published.

We learned that progress has been made towards locating modifier genes that delay the onset of HD, using data from the work done on a cluster of HD families in Venezuela (the Hereditary Disease Foundation’s longtime Venezuela Project). Knowing what genes delay onset can point to treatments. On a side note, HDLighthouse readers who are able to give charitably should not forget these Venezuelan families whose willingness to provide their time and biological samples have immeasurably contributed towards the goal of making treatments a reality.

Participants were very excited to learn of the progress being made by Dr. Elena Cattaneo and her colleagues in Milan, Italy in turning embryonic stem cells into neurons.

Another therapeutic strategy covered is the overexpression (making more) of the normal huntingtin protein. For a long time, researchers thought that HD represented a ‘gain of function’ disease. In other words, the idea was that the mutant (bad) HD protein did its normal work in the cell but also did other toxic things. We will be very interested to learn more about this.

Cell transplants

Dr. Elena Cattaneo reported on progress with embryonic stem cells.

There was a thorough review of fetal cell transplants by Dr. Anne-Catherine Bachoud-Levy from France and Dr. Steve Dunnett from the United Kingdom. This is the procedure where individuals with HD receive transplants of fetal brain cells to attempt to slow down or reverse the progression of the disease. This work is controversial and might be difficult to deploy due to the challenge of finding transplantable tissue and the risk of the procedure. But some of the transplant recipients have experienced relative stability for up to eight years now, and the procedures being developed may be useful in other types of transplants at a later date. These transplants are being expanded to cover more than 60 patients in Europe over the next few years.

RNA interference

RNA interference is one of the most exciting areas of research for Huntington’s disease. In simple form, the normal process in our body is that our genes are used as a pattern to make an intermediate molecule called RNA that the body then uses to make the proteins that then control our body’s cellular processes. By “interfering” with this process by using special forms of RNAi (RNA interference), less of the Huntington’s disease protein is made and this should stop the disease in its tracks.

The effectiveness of RNA interference has been shown in mouse models of the disease.

Research has been taking two directions. Studies are underway in mice and primates to discover whether shutting down the expression of the huntingtin’s protein (normal and mutant) altogether causes damage to the adult brain. Huntingtin’s is known to be necessary for embryonic development. Knock out mice die in utero. However, the normal functions of the huntingtin’s protein are still unknown.

One way around the problem of reducing the production of both the “good” and “bad” huntingtin protein at the same time is to find a small stretch of the HD gene that is different between the “good” gene and the “bad” gene. Studies are also underway to locate these differences, one type being single nucleotide point mutations (SNPs) that would allow allele specific silencing. Enough SNPs have been discovered to allow this technique to work on three-quarters of the HD population.

Work continues on the technology itself. Although Dr. Beverly Davidson at the University of Iowa and Sirna Pharmaceuticals are working on viral delivery of siRNAs, they are also pursuing the intriguing avenue of a nonviral delivery of synthetic siRNAs. This approach is also being researched by Alnylam and Medtronics who may be even further along in their research.

Therapeutic compounds

Research is continuing with trehalose and green tea, two substances of particular interest to Lighthouse readers. Research was presented on compounds that modulate chaperone (heat shock proteins), on antioxidants, on molecules that enhance protein clearance in the cell, and on histone deacetylase inhibitors (HDACs),

Dr. Steve Hersch presented updates on a Phase I study of high dose creatine. The data is very promising and funding is being sought for Phase II and III clinical trials.

Work continues to locate new potential therapies.

Biomarkers

Unlike fast growing cancers or wound healing, the progression of HD is normally slow and difficult to measure over short periods of time. It also is likely that any effective treatments may be difficult to directly measure using direct observations by a neurologist or by standard cognitive and physical reaction tests. This creates a problem in testing new treatments for Huntington’s disease, since they then need to be very long so that improvements can be measured.

One way around this problem is to find easily measurable, indirect measures of disease progression or regression. These measures are called “biomarkers”. The use of validated biomarkers as surrogates for progression or regression can shorten clinical trials considerably, both in reducing the time it takes to find the most effective dosage and in determining whether a compound has been effective in slowing or stopping the disease.

Research on two biomarkers which have been covered by the Lighthouse was discussed:

• Gene expression changes that can be measured in blood samples
  
• Serum 8-hydroxy-2'-deoxyguanosine (8OH2'dG) levels

Changes in the brain which can be documented through neuroimaging are also promising as biomarkers.

Clinical care

Sir Michael Rawlins, Chairman, National Institute of Health and Clinical Excellence, UK

Sir Michael Rawlins, who is the director of the National Institute for Health and Clinical Excellence in the United Kingdom, attended the conference to announce an international effort to develop standards for clinical care of Huntington’s disease patients. The European Huntington Disease Network and the Hereditary Disease Foundation will collaborate in this effort which will involve the following steps:

• Define the scope of the effort
• Identify stakeholders, including health care professionals as well as HD families
• Recruit guideline development members (about 15 people)
• Decide the questions to be answered
• Conduct a Systematic review of published and unpublished evidence
• Develop the recommendations
• Consult with the stakeholders
• Revise recommendations
• Disseminate the guidelines

What this means for HD families is that they and their doctors will be able to access treatment recommendations developed by worldwide experts in treating the symptoms of HD. When this work is completed and the results published, doctors even in rural areas will be able to find up-to-date recommendations and use them with their HD patients. In addition, HD families can read this same information and bring it to their doctors so that they can work together to treat the symptoms and eventually the course of this disease.

In conversation, Sir Michael demonstrated a real understanding of the effects of this disease on patients and families and so we have great hopes for the outcome of this project.

Concluding thoughts

Dr. Albert La Spada, Dr. Patrick Weydt, and Dr. Kurt Fischbeck, enjoying the conference.

The general consensus among researchers was that remarkable progress had been made in just the last year. We were encouraged too, but the proof will be there only when we have an effective treatment for our family members.

As the research continues, the more we learn of the broad effects of the HD protein within cells and within the brain. HD affects cellular energy, the expression of genes, protein interactions, signaling, neurotrophic support and more. At first this knowledge seems overwhelming. One cannot help but wonder just how many targets have to be addressed for treatments to make a real difference in health and survival.

However, our thinking has come to more closely approach ideas expressed at the end of the conference by Nancy Wexler. It is remarkable to think of how well our cells and our brains and our bodies compensate for the mutant Huntington’s disease protein over time.

It may be that just a small number of effective interventions to boost the cell’s coping mechanisms may make a huge difference.

# # #

We are moved by the awesome and selfless contributions of the Venezualan families who contributed to the discovery of the HD gene. To help out these families who live in unbelievable poverty by donating to the Casa Hogar, a care facility and clinic established to help these families, send your donation to the Hereditary Disease Foundation. You can make a notation on the check saying, "For the Casa Hogar." They will then send it to Dr. Margot de Young, the Venezuelan physician who oversees the Casa Hogar, who will use it for the HD patients. You can send the check to: Hereditary Disease Foundation c/o Karen Dean, Controller 3960 Broadway, 6th Floor New York, NY 10032

Source: HDlighthouse.org

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