GRANTS FUNDED in 2011

People with Huntington’s disease have too little cholesterol in their brains. And even mice with the HD gene inserted in them have too little cholesterol in their brains. Could giving cholesterol be a treatment for HD?

We gave funds to Mike Levine and Giovanni Tosi to coat nanoparticles with cholesterol. They are now testing in HD mice if increasing brain cholesterol improves HD symptoms. If this treatment helps – it will be a promising avenue to pursue in people with HD. The ideal goldmine drug would be a compound that takes cholesterol from your body and delivers it to your brain – special delivery! Keep tuned as we learn about their progress!

For description, see Anne Messer, above.

Michelle, like Ralf, seeks to understand the structural reason why disease-causing huntingtin protein is toxic to cell.

Rebecca is looking at modifiers of HD that may impact symptoms. She tests these modifers in both cell lines made from neurons and HD mice.

Nicholas is working with longtime Scientific Advisory Board member Marie-Francoise Chesselet to compare two different HD mouse models. He is studying both their behavior and their brains

Geraldine is looking at the behavior of specific molecules in causing HD. She is also looking for treatments.

Jane is working with Ron Kopito to see if HD is infectious. Does it make you sick like Mad Cow or Kuru?

Amanda is working with Jim Gusella to study the normal role of the huntingtin protein in slime mold. These organisms have almost the most CAGs in the planet! What are they doing for a living there?

Antonio is looking at molecules that influence a survival dependent pathway to discover therapeutic targets.

Esther and her spit-fire, very smart and energetic mentor, Ana Marie Cuervo, are studying the garbage collection system of cells. Why do they put up with these clumps? Esther is boosting the cell’s own garbage collection system by ordering new garbage disposal systems in the cell.

Developing gene silencing as a treatment for HD is an area of research in which the HDF plays a very significant role. In December 2002, we held the first workshop ever on RNA modalities and gene silencing in HD therapy. The Workshop focused on the use of gene-silencing techniques as one of the most promising strategies for developing new therapies and even cures. We continue to play a critical role in funding, guiding and shaping the field. In 2005, a proof-of-concept study by HDF grantee Beverly Davidson and her team demonstrated that silencing the HD transgene in an HD mouse, using siRNAs delivered with an adeno-associated virus (AAV), ameliorates disease phenotypes and neuropathology. Davidson is now using siRNAs in an artificial microRNA context. These microRNAs are expressed at much lower levels and have fewer off-target silencing toxicities while remaining efficacious at silencing expression of the HD gene. Davidson is targeting a sequence found in all HD genes sequenced to date, so treatment should work for everyone.
How to deliver therapies to the relevant cells raises some questions. Delivery of nonviral silencing constructs, either antisense oligonucleotides or siRNAs, into the CNS using implanted continuous-delivery pumps appears capable of spreading fairly widely within the brain. Advances in brain-injection technologies, such as convection-enhanced delivery, permit silencing viruses, such as AAV, to reach the entire human caudate and putamen.

Christian, with Bob Hughes, Juan Botas and others, is assembling a giant database. He is using systems analyses to integrate data and get priorities for which molecules and targets to pursue.

The Inspector Clouseau of clumps, Alex has tamed these wild beasts and found more than we ever thought were possible!

For description, see William Yang, below.

For description, see William Yang, below.

Recent HDF Workshops have focused on helping scientists validate mechanisms that could be responsible for causing toxicities. A bewildering array of pathways and factors are changed in cells expressing abnormal huntingtin. These changes impact cell function and dysfunction, survival and death. Determining which factors are causative and which are only correlated is critical. The combined investigations of Leslie Thompson, Joan Steffan, Ronald Wetzel, and X. William Yang, all funded by the HDF, have been ground-breaking in this respect. Thompson and Steffan and colleagues, working with Drosophila and cell-based models, demonstrated that secondary modification, via phosphorylation of the amino acid serine at positions 13 and 16 of huntingtin, changes the toxicity of N-terminal fragments.

Yang has created many transgenic BAC (Bacterial Artificial Chromosome) mouse models, including fragment and full-length, to capture and elucidate different aspects of the HD phenotype. One model, a full-length BAC, with 97 glutamines, developed significant abnormalities in movement, behavior, and cognition. Additionally, these mice developed aggregates and cell death. Phosphorylation are modifications made in a protein – like traffic lights in Los Angeles. In order to test the impact of differential phosphorylation – or signalling, Yang created two new BAC transgenic mice. Both were full-length, with 97 glutamines. In one set, Yang converted serines 13 and 16 to alanines, which rendered them incapable of being phosphorylated – or changed. These mice also developed motoric, cognitive, and psychiatric symptoms, as well as cell loss and aggregates. They resembled Yang’s original BAC mice. Amazingly, when Yang converted serines 13 and 16 to aspartate, an amino acid that serves as a phosphomimetic, the animals were virtually cured. They had no disturbance in gait and no cognitive or behavioral symptoms. Even more striking, they had no aggregates or cell loss.

The implication of these discoveries is that phosphorylation of serines 13 and 16 protects against the toxicity of the expanded glutamine stretch. Efforts are accordingly under way to develop therapies that enhance or mimic the phosphorylation of serines 13 and 16. We also seek to elucidate the protective mechanism engaged by this modification as a potential target for HD therapy. The HDF is strongly encouraging and facilitating work in these promising therapeutic avenues.

In 1977, the Commission for the Control of Huntington’s Disease and its Consequences recommended the creation of a centralized resource to catalyze research. This was the first Commission recommendation realized by the National Institute of Neurological Disorders and Stroke, National Institutes of Health (NINDS, NIH). The National Research Roster for Huntington Disease Patients and Families was established in 1979 at Indiana University.

The National Research Roster for Huntington Disease Patients and Families has served successfully as a genetic roster and more since 1979 – for over 30 years. We immediately requested a Certificate of Confidentiality so that people joining the Research Roster could feel confident that their identities would be protected. Unless someone had committed a crime, no one could have access to this information – not even the Federal government, the NIH, insurers, interested parties, employers or people with malicious intent. The Principle Investigators of the National Research Roster for Huntington Disease Patients and Families have been scrupulous about obtaining IRB permission for all aspects of its functioning.

Over the past 30 years, the National Research Roster for Huntington Disease Patients and Families has gained the unqualified respect and trust of Huntington’s disease families and researchers worldwide. This is because of the unique chemistry between families and the leaders of the Research Roster – who have been assiduously honest, approachable and rigorous. The National Research Roster for Huntington Disease Patients and Families is also being carried out by an academic institution, and funded by the NINDS, NIH. The HD Research Roster actually serves as an HD Registry, in all aspects of the meaning of the word “registry,” and even beyond:

1) They gather pedigree information on patients and families. They actually create computerized pedigrees which can be printed and given to family members with their permission, if asked, keeping identities confidential. They can often link parts of the family, even in different states, who have no awareness of their relationship. They are trusted to keep this information confidential, unless the families themselves request to be notified if additional family members are discovered.

2) They collect two types of information on patients and family members. The Family History Questionnaire is specifically geared to getting information about genetics, demographics and epidemiology. It asks about ages of onset, symptomatology and birth and death information from family members.

3) The Affected Questionnaire inquires, in depth, about medical and behavioral health habits. It asks about smoking and alcohol use, and other medical conditions, i.e. heart disease, stroke, or diabetes. It asks about medications taken.

Annual update information is obtained from all contact persons to sustain longitudinal data and acquire new information.

4) The National Research Roster for Huntington Disease Patients and Families is the largest database of HD families worldwide. A tremendous amount of information about individuals and families is easily accessible through computerized forms. The Roster contains family history, clinical and other related data from 138,788 individuals from 2,419 families, including 14,120 affected individuals.

5) The National Research Roster for Huntington Disease Patients and Families at Indiana University was instrumental in creating the first DNA bank for HD families in the U.S. and probably the world. This DNA bank is also at Indiana University.

The DNA bank currently stores 4,100 DNA samples.

This DNA bank was critical to families with a known genetic disorder, while we were conducting DNA linkage research to identify the location of the HD gene. The DNA bank at Indiana University offered families the opportunity to have blood drawn from family members and the DNA banked at Indiana University for future study, once the gene for Huntington’s disease was linked or identified.

Family members paid to have their samples banked. They or their descendants, if they had passed away, could decide in the future whether that sample should be sent for molecular testing. For example, people at 50% risk could choose to store their DNA sample with the Indiana University DNA bank. These individuals may or may not choose to be tested, but wish to make their DNA available for future generations. This permits future generations to determine if they are at risk for Huntington’s disease.

This unique benefit of the Indiana University DNA tissue bank and the National Research Roster for Huntington Disease Patients and Families enables families not to require testing on each individual. With the family member’s permission, they could test the relative’s blood. If it turns out to have an expanded CAG repeat, family members know they are at risk. If it turns out to be normal, the entire family is liberated.

The National Research Roster for Huntington Disease Patients and Families still receives many requests annually for DNA to be sent for genetic testing. If the Roster disappears, we would lose a valuable connection between the family information and the samples that are stored.

The National Research Roster for Huntington Disease Patients and Families, while not officially responsible for these DNA samples, is considered by almost all families as the conduit through which they can request that the sample be sent to a laboratory for molecular testing for diagnostic purposes.

6) The HD Research Roster and DNA bank currently stores 8 boxes of DNA and 47 boxes of cell lines from the Venezuelan Huntington’s disease families. These are unique samples and are only accessible here.

7) The National Research Roster for Huntington Disease Patients and Families also serves as the primary engine – recruiting for clinical trials for Huntington’s disease throughout the country. These studies include observational trials such as PHAROS, PREDICT and COHORT, as well as drug trials, including co-enzyme Q-10, creatine and many more that are listed in the Research Roster’s Progress Report. The Roster is currently recruiting for more clinical trials than ever before.