Board awards three $30,000 grants to study NBIA in 2007 grant cycle

The NBIA board recently chose three exciting proposals to receive $30,000 each for research into NBIA disorders. The recipients are Dr. Susan Hayflick of Oregon Health & Science University, a familiar name among those receiving NBIA grants, and two first-time grant honorees, Dr. Paul Kotzbauer of Washington University and Dr. Soma Das of the University of Chicago.

These awards bring to 11 the grants the board has made in the past six years. They once again demonstrate the power of family fundraisers and private donations that make these grants possible.

These grants often help scientists compile preliminary research information so that they can obtain further funding from sources such as the National Institutes of Health. With NIH funding becoming more scarce, these grants are increasingly important to ensure that research into NBIA disorders continues. 

Dr. Susan Hayflick has received six grants in six years from the NBIA board. Her project, "Towards Clinical Therapeutics in PKAN" builds on 15 years of research advances.

“Our family studies led to the gene's discovery, which in turn led to understanding the biochemical and cellular changes caused by mutations in PANK2,” Hayflick said. Those new understandings of the changes allows Hayflick to test therapies in a mouse model of PKAN developed by collaborator Jane Gitschier’s team at the University of California, San Francisco.

“With Penny Hogarth's expertise in clinical therapeutics, our OHSU/UCSF research team is poised to perform the first drug trial in these mice,” Hayflick said. “Additional animal drug trials will follow, with the goal of moving these to human studies as soon as we find a promising agent. Although the mice do not show dystonia or brain iron accumulation, they have key disease characteristics similar to those in PKAN patients that enable these studies. This project marks the beginning of an important phase in NBIA research as we move ‘from discovery to cure.’”

Dr. Paul Kotzbauer’s project, “Combined disruption of mouse PANK2 and PLA2G6 genes to generate an improved animal model of NBIA,” said his goal is to develop a mouse strain that has the central features of NBIA.

“An improved mouse model of NBIA would enhance our ability to determine whether a particular therapeutic approach is likely to be helpful and guide decisions to pursue further studies in clinical trials,” he said.

Lab, or “knockout” mice that have mutations in one of the two NBIA genes discovered so far, PANK2 or PLA2G6 genes, each reproduce some aspects of the disorders but lack the changes common to all forms of NBIA, which include iron accumulation and neurodegeneration in a brain region called the globus pallidus, Kotzbauer explained.

“We speculate that the PANK2 and PLA2G6 genes have overlapping functions in the brain and that although brain cells in mice may be able to compensate for the loss of one gene, disrupting both genes together may be sufficient to cause a disorder in mice that is more similar to what occurs in humans,” he said. “ We will breed mice from the two existing knockout strains over several generations in order to generate mice that have mutations in both the PANK2 and PLA2G6 genes. We will then look for features of NBIA using tests for neurological function and microscopic examination of brain tissue.”

Dr. Soma Das’s project is “Deletion and duplication analysis of the PANK2 and PLA2G6 genes in patients with neurodegeneration with brain iron accumulation,” which could improve the diagnosing of NBIA patients.

Das explained that some patients with NBIA clinical symptoms may not have had any mutations in the PANK2 or PLA2G6 genes identified and their diagnosis remains uncertain.

While “DNA sequencing has been the traditional method of mutation detection/testing in patients with NBIA disorders, certain types of mutations, such as deletions and duplications within the PANK2 and PLA2G6 genes will be missed by DNA sequencing ,” Das said. “We will use some newer methods of DNA analysis that will pick up these types of mutations. We may therefore be able to identify mutations in patients in whom no mutations have been identified to date. Our studies should result in the development of a more comprehensive test for NBIA disorders.”

Our organization is excited about these new projects and the potential they have to enhance our knowledge of NBIA disorders. The research program, and the support families provide it, is the vital link to the organization’s quest for a cure.

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NBIA research sparks links to other labs, better known diseases 

The discovery of a second NBIA-related gene in 2006 has opened up new collaborations and new research frontiers, scientists reported at the Fourth International Family Conference in Cincinnati, Ohio. 

Fundraising by families continues to play a key role in ongoing research and provided crucial seed money that led to the latest gene discovery, said Dr. Susan Hayflick of the Oregon Health & Science University. 

“It reminds us of why we come to work everyday,” Hayflick told about 80 conference participants who gathered from around the world in early May. “We are trying to beat this thing.” 

A clinical test is now available at the OHSU DNA Diagnostic Lab to help families determine their chances of passing NBIA to their children if they have the second gene, known as PLA2G6. 

Hayflick’s lab worked with researchers from the University of Birmingham School of Medicine in the United Kingdom and from the University of California San Francisco to identify the gene, and those scientists continue to collaborate on research now underway. 

Mouse studies are helping to reveal the NBIA disease process and will also be used to test new therapies. In one area of research, UCSF scientists removed B5 from the diet of healthy mice and the animals developed dystonia, a common symptom of NBIA, Hayflick said. 

Dr. Paul Kotzbauer, a neurologist and researcher at Washington University in St. Louis, and Lars Timmermann at University Hospital in Cologne, Germany, also are among those collaborating on NBIA research. 

Kotzbauer has been studying mice with mutations in the PLA2G6 gene to examine changes in brain function that may be similar to those that occur in NBIA patients. He also noted that the same Lewy bodies – fibrous protein deposits in nerve cells – that are seen in the brains of Parkinson’s patients also can be found in NBIA patients. 

The connections between NBIA and Parkinson’s as well as Alzheimer’s disease have become more apparent since the discovery of the PLA2G6 gene. 

 “I can argue in grant applications to the NIH,” Kotzbauer said, referring to the National Institutes of Health, that NBIA “is important to study…because what we learn can be important for Parkinson’s disease and Alzheimer’s disease.” 

Pointing out such links can be increasingly important because money from the NIH, the federal agency that funds much of the nation’s medical research, is declining, Hayflick said. 

Timmermann is studying Deep Brain Stimulation and wants to learn more about how effective it is for NBIA patients. The data, while promising, is sparse. 

Timmermann is seeking participants for a study so that he can follow patients having the procedure and see how they fare a year or longer after the procedure, he said. Such data could help parents and NBIA individuals make more informed decisions about whether to seek the procedure. (See article on DBS, page XX.) 

All of the research costs money, and the NBIA Disorders Association has provided eight $30,000 grants since 2003 and expects to award one or more this year, thanks to member-sponsored events.

Without the seed money from family fund fundraisers and other NBIA member-sponsored events, Hayflick said her lab might not have been considered for additional federal grants needed to move her work forward.  NIH grants are more competitive than they ever have been in her career, she said, and she is convinced: there are more NBIA-related genes waiting to be discovered.

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Family conference provides shot in arm to NBIA’s BioBank for scientific research
By Matthew Hodgson

A two-day marathon of blood giving during the Fourth  International Family Conference in Cincinnati provided the first opportunity to collect samples for the NBIA Disorders Association’s BioBank in the United States.

The collections follow a similar activity by our sister group in Germany, which obtained 22 samples from nine NBIA families at its third Family Conference in November. The combined efforts bring the samples in our BioBank to 101, representing 33 NBIA families. These families come from all over the world, including Canada, England, France, Germany, Iceland, India and the United States.

Although many families have donated blood in previous years, the new samples were necessary because the prior ones went to the registry at Oregon Health & Science University. They have been depleted by research. Faced with the choice of sending a miniscule amount of blood to the BioBank, the NBIA Disorders Association chose to collect new samples. It wants all NBIA affected individuals and immediate family members to donate to the BioBank, created by the Genetic Alliance, an umbrella organization for groups representing rare diseases.

The NBIA Disorders Association is a founding member of the Genetic Alliance BioBank, which provides storage facilities and support to organizations like ours. The NBIA Disorders Association’s BioBank collects, stores, processes and distributes biological samples to aid in research. The BioBank has the potential of collecting and storing many types of samples, such as blood, tissue, cells and DNA, from NBIA-affected individuals and their immediate relatives.

These biological samples, along with medical information from individuals with NBIA and their relatives, are essential for studying NBIA. The samples and information can be used to help researchers find other gene mutations responsible for NBIA and conduct research that will explore the causes of and potential treatments for NBIA.

Researchers interested in studying the samples submit proposals  to the NBIA Disorders Association’s Scientific and Medical Advisory Board. That board reviews the proposals and determines which ones merit approval.

At the association’s Cincinnati conference, collecting the samples was a remarkable endeavor on the part of many people. Thanks to the families who meticulously completed the many consent documents and clinical history forms. Their cooperation is greatly appreciated

On a personal note, it was a pleasure to finally meet all of the families with whom I corresponded before the conference. Fellow board member Susan Laupola coordinated the efforts of the phlebotomists; she and her staff were extraordinary and deserve much credit for their expertise.

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Have you or your child had DBS?  Thinking about DBS for the future?

Dr. Lars Timmermann, director of the Movement Disorders and DBS program at University Hospital in Cologne, Germany, is now actively enrolling NBIA patients with DBS and those planning to have DBS surgery in a new research study.  The goal of this important study is to create an international database of NBIA patients with DBS so that their progress can be followed and outcomes measured.  This will help show whether DBS helps people with NBIA, how it can best be done, and the most effective settings for the DBS stimulator. If you are interested in this study, please contact Dr. Timmermann or his collaborating PhD student, Karolin Wieland, at: karolin.wieland@smail.uni-koeln.de or lars.timmermann@uk-koeln.de.

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April 2007

NBIA board now accepting research grant applications

Once again, the NBIA Disorders Association board is accepting applications for one-year research grants from scientists interested in studying NBIA. That work can involve the early detection, diagnosis or treatment of patients with NBIA. Applications are available at our Web site at www.NBIAdisorders.org. 

These are $30,000 seed grants to conduct small clinical studies, the results of which can be used to obtain funding for larger studies from a corporate sponsor or a federal agency such as the National Institutes of Health or Food and Drug Administration. 

The NBIA board hopes to award two or three research grants this year, thanks to vigorous fundraising by families in 2006. 

Researchers are asked to submit letters of intent no later than June 15. Full proposal invitations are due July 31 with a deadline for submission of Oct. 1. Award announcements will be made in November with funding to begin in December. 

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Deep brain stimulation providing hope to NBIA patients worldwide
By Dr. Lars Timmermann 

He was 14, cheerful and in terrible pain. He suffered from severe dystonia — a movement disorder that causes muscle tightening, limb twisting and painful postures. This young man's problem was so bad he could not perform the most mundane daily activities.

He was suffering from the PKAN-form of NBIA, and his family asked me, a neurologist and movement disorder specialist, to help. My team and his parents were considering all options to alleviate his distress. 

Traditionally, generalized dystonia in NBIA patients is treated with high doses of medications like tri-hexiphenidyl, benzodiazepine or baclofen. However, powerful doses of those medications are often accompanied by strong side effects. A great alternative is Botulinum Toxin, a poison that can be locally injected for a temporary release of the abnormal muscle tension. Even still, the dose cannot exceed a certain limit. Therefore, Botox cannot help in all body parts of a patient with generalized dystonia. 

A new option for these patients is deep brain stimulation, or DBS. It affects the internal globus pallidus. The idea is that abnormal neuronal activity in parts of the brain can be "blocked" by a high-frequency electrical stimulation. To establish such an "electrical blockade" a specialized team of neurosurgeons, neurologists and anesthesiologists implant fine electrodes with submillimeter accuracy in specific target regions of the brain. 

DBS in generalized dystonia was described as a highly effective treatment in previous studies. Using it as a therapy for dystonia patients with NBIA has been shown in a few single case reports as well as in a small series of patients. 

Dr. Pierre Castelnau from France published in 2005 a study of six patients with PKAN treated with DBS. The authors could demonstrate in four patients with the classic form of the disease and two patients with the atypical form of the disease a dramatic reduction of dystonia with DBS. 

Deep brain stimulation is an invasive therapy with the minimal potential of lethal complications. It is therefore even more necessary to broaden the knowledge about this potentially highly effective therapy. Because NBIA is a rare disorder, an analysis of the treatment results will always on one hand have the burden of small numbers of patients, and on the other hand lead to different treatment approaches around the world. Consequently, a detailed international analysis of results is even more important to answer clinical questions based on evidence-based data. Decisions of patients, relatives and clinicians about invasive therapeutic procedures have to be based on the best information we can provide. 

From our point of view, a series of urgent questions regarding DBS in NBIA patients need to be answered:

• What are the worldwide experiences and treatment results with DBS in NBIA patients?
• Which NBIA patients benefit most from DBS and which patients do not benefit?
• Which stimulation settings are most effective for NBIA patients?
• How long does it take before DBS benefits are seen in NBIA patients and does this change as time passes?
• Can we create a standardized treatment plan for doctors to achieve “best medical treatment” with DBS in NBIA patients?

We have designed a new study and are asking NBIA patients to help us answer these important questions. It has been approved by the ethics committee of the University Hospital Düsseldorf (International Master Votum) and is designed in accordance with the strict German Data Protection Act. With the support of the NBIA Disorders Association and Hoffnungsbaum e.V. (Germany) we intend to contact all worldwide DBS centers who have experience with DBS in NBIA patients. 

We will request information and data from the treating physicians, patients and relatives, including MRI findings, dystonia rating scales, target point, stimulation parameters, as well as information about quality of life before and after the operation. Data will be pooled and statistically analysed by an independent institution, with financing established by the German Hoffnungsbaum e.V., the sister organization of the NBIA Disorders Association in the United States. Results of the study and a "standardized treatment plan" will be published together as an international multi-center cooperation paper including all participating physicians as well as an international supervising board of DBS experts. 

A few weeks ago I saw my young patient with NBIA again. After trying all other treatment options he, his family and our team decided to try DBS. It was a long journey of treatment, rehabilitation and adaptation of the stimulation. To my delight, his posture is remarkably improved, his hand function is much better and his overall functioning in every day life considerably better. 

If you or your child has been treated by DBS and you are interested in participating in this international project we would be happy if you or your doctor would contact us via email: lars.timmermann@uk-koeln.de or timmermann@neurologie.uni-duesseldorf.de. Please don't hesitate to contact our group if you are just considering or planning DBS. We are happy to answer any questions you may have on this topic.

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NBIA board awards new research grant to study patients with two NBIA genes 

Fundraisers by NBIA families have paid off, enabling the NBIA Disorders Association board to award another $30,000 research grant. It will go to Dr. Susan Hayflick’s lab at the Oregon Health & Science University and is the fifth such grant her lab has received among eight the board has awarded in five years. 

Hayflick’s latest project will look at molecular changes in cells of patients with two genetic forms of NBIA. The genes involved are PANK2 and PLA2G6. By identifying cellular changes that are common to both forms of NBIA, her lab expects to generate new understanding of the disease process and also identify promising new targets for therapies.  

Research support from the NBIA Disorders Association continues to be a critical resource to enable investigators to generate preliminary results so they can compete for funding from the National Institutes of Health to carry the research further. In the past, $30,000 of seed funding has blossomed into $1million in federal grant support. The NBIA board considers that a good return on its investment. 

This is the first time the organization has used its Scientific & Medical Advisory Board to review grants and advise the Board of Trustees, which has the final say on grant awards. Before, the National Organization for Rare Disorders evaluated the grant proposals and recommended awards, for a fee of $5,000 per grant. 

Dr. Hayflick serves on NBIA’s SMAB and recused herself from the review process to avoid a conflict of interest.

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An international team of geneticists, led by Dr. Susan Hayflick of Oregon Health & Science University and Dr. Eamonn Maher of the University of Birmingham in Manchester UK, discovered a new gene that causes NBIA. The finding, which is the second NBIA gene to be discovered, is significant because it will accelerate research into the disease and help scientists in their quest for a cure. 

The first gene, PANK2, believed to cause about half of NBIA cases, was discovered in 2001 by the laboratory of Dr. Jane Gitschier at the University of California, San Francisco in collaboration with the lab of Dr. Hayflick.
 
Discovery of the new PLA2G6 gene is documented in a study published in the July print issue of Nature Genetics. Researchers describe PLA2G6's discovery using DNA from families with a diagnosis of infantile neuroaxonal dystrophy, or INAD, and NBIA.  A clinical test for this gene will be available in the next few months to help families with diagnosis and prenatal testing. 

It has long been thought there was an association between INAD, also known as Seitelberger disease, and NBIA. This new gene discovery confirms that, although there is still much to be learned about how this gene causes disease. 

Two seed grants from NBIA Disorders Association through the National Organization for Rare Disorders were used to help in the search for this gene. One was to Dr. Natalie Canham of the University of Birmingham in England in September 2003 and one was to Dr. Hayflick in 2004. It became an international effort with many groups participating and is a great example of how NBIA families and the association's research grants can make a difference and indeed already have! 

We asked Allison Gregory, a genetic counselor at Oregon Health & Science University, about the discovery.  

Q:  What is the new NBIA gene?
A:  The gene is named PLA2G6.  This gene has been known and studied by researchers for some time, but nobody knew that changes in this gene could cause a disease. Our studies led us to discover that when a change, or mutation, occurs in PLA2G6, it will cause neurodegeneration.  People with mutations in this gene may have been diagnosed with NBIA or INAD. We use NBIA as an umbrella term here, to encompass all the disorders that fall into this spectrum. 

Q:  What is INAD? 
A:  INAD stands for infantile neuroaxonal dystrophy.  This is a progressive neurodegenerative condition that we started studying because many patients with INAD have brain iron accumulation similar to that seen in NBIA.  Like NBIA, patients with INAD develop abnormal axons (a part of nerve cells) which are called spheroid bodies. Some of the people we studied with INAD do not have brain iron accumulation and we do not yet know why this is.  

INAD usually develops during very early childhood, causing loss of early milestones.  Affected children eventually lose their ability to move or speak.  Common features of INAD include optic atrophy and incomplete development of a brain structure called the cerebellum.  Like PKAN and other forms of NBIA, INAD is inherited in a recessive fashion.  This means both parents are carriers and an affected individual has no working copy of the gene.  

Q: Is INAD a form of NBIA?
A: We think so, but the answer is open to debate. Since many INAD patients have high brain iron and all have neurodegeneration, it does fit into the NBIA family of disorders. Also, we now know that the same gene can cause either NBIA or INAD depending on the type of mutation that occurs. We also believe that for many disorders there are other important genes, called modifiers, that also play a role and probably cause much of the variability that we see. As researchers and care providers, we find it helpful to think about all of these disorders together. 

Q:  Why is the gene named PLA2G6? 
A:  PLA2G6 is one of 18 lipid-metabolizing genes in a protein family known as phospholipase A2 (PLA2).  The name designates that this gene is from group six (G6).   

Q:  How does this gene cause the disease?
A:  PLA2G6 is thought to encode an enzyme that breaks down lipids involved in the reconstruction of a cell's membrane following damage by light and other toxins. When the gene is mutated, lipid metabolism is altered and iron builds up, triggering disease.  We do not yet know the specific details of how metabolism is altered or what causes iron to build up in this case.   

Q:  How was the gene discovered?
A:  We were able to find that mutations in PLA2G6 cause NBIA and INAD with the help of many affected families and many physicians in the U.S. and abroad who contacted us about their patients.  Since most families with INAD are small and have only one affected child, it was very important for us to find several families and add all of their information together.  This pointed us to a region where about 100 genes sit on chromosome 22. At the same time, scientists in England linked the INAD region of chromosome 22 with NBIA in a large family. 

Once our labs identified this region, OHSU worked on one half while our collaborators, Drs. Eamonn Maher and Neil Morgan at the University of Birmingham in England took the other half. This was very detailed work that involved searching through each gene systematically to find changes in the code that could cause the disease.  It took many months of searching before the lab in England finally found the first changes in PLA2G6.  We were quickly able to verify gene mutations in many of the INAD families that we had collected in our lab. 

Q:  Is there a blood test for this gene?  Is prenatal diagnosis possible?
A:  Dr. Hayflick and her team are partnering with the OHSU DNA Diagnostic Laboratory to develop the test.  Since Dr. Hayflick's lab is a research lab and has not been certified to do clinical testing, we cannot provide the testing on our own.  Dr. Hayflick has close ties with the DNA Diagnostic Laboratory and will have continued involvement with providing the test for INAD and NBIA.  We think the test will be ready in a few months.   

Once it is available, the test should take about three weeks to complete and will require a blood sample.  For families in which the mutations can be identified in the affected child, prenatal diagnosis will be an option for any future pregnancies.
 
Q:  Who should be tested? 
A:  Families with children diagnosed with INAD or suspected of having INAD should talk to their doctors about the test.  Since INAD is very difficult to diagnose, the genetic test could help confirm the diagnosis for many individuals.   

Our recent studies have taught us that people who were diagnosed with NBIA (not INAD) can also have mutations in PLA2G6. For this reason, people with NBIA who have tested negative for the PANK2 gene should ask their doctors about testing.  Based on what we know now, it is likely that some people from this group will have changes in this gene.   

Q:  Why is the discovery of this gene important for the entire NBIA community?
A:  The discovery of the new gene provides an important piece in the puzzle of NBIA. Research can now focus on the workings of the cell that are disrupted when PANK2 and PLA2G6 are defective. PANK2 is important for energy metabolism, nerve signaling, cell membrane repair and other functions. PLA2G6 is involved in inflammation, programmed cell death, and membrane repair. The intersection of these two groupings is cell membrane health, which we think may be a problem common to all forms of NBIA.

The new gene discovery also gives scientists a new target for developing NBIA therapies. Up till now, ideas for therapies have been focused on pantothenate, coenzyme A and iron. PLA2G6 functions differently from PANK2 in membrane repair. As we better understand its precise role in this process, new ideas for therapies will come. 

We don't have a cure yet for any of the NBIA disorders, but now is a good time to reflect on how far we have come in the past 5 years. Two major NBIA genes have been identified. An increasing number of scientists from around the world are working to advance understanding of the NBIA disorders. New symptomatic treatments have become available (e.g. deep brain stimulation). And the NBIA Disorders Association is gaining in strength (new research programs) and numbers (new members and affiliates). Our model of families working in close partnership with the research community is at the core of these successes.

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The NBIA Disorders Association board has enough money in its research kitty this year to award two $30,000 seed grants, thanks to fundraisers by families. 

These grants are a significant part of the association's mission. They encourage important clinical studies designed to improve the diagnosis and treatment of Neurodegeneration with Brain Iron Accumulation. They can also be used to attract additional research money to further the scientific work from corporate sponsors or other agencies, including the National Institutes of Health and the Food and Drug Administration. 

The grant process for this year is well underway. The NBIA Scientific & Medical Advisory Board is now reviewing letters of intent from researchers and will soon determine whom to ask to submit full proposals. 

The deadline for full proposals is Sept. 30. The advisory board will review them and make recommendations to the NBIA board of trustees, which have the final say in grant selection. 

Awards are to be made by Nov. 15. If no proposal meets the board's requirements, monies will be held over until next year when the process starts again for grants in 2007. 

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New board member will coordinate collection of DNA BioBank samples

With the addition of a new board member, the NBIA Disorders Association will launch a new effort to encourage families to donate blood samples to our BioBank. 

We are grateful to families who have sent in the paperwork to release DNA samples and medical records from the Research Registry housed at Oregon Health & Science University. And we appreciate any who have requested consent forms, agreeing to send samples directly to our BioBank. 

We apologize that we have not, until now, had someone on board to expedite this process. But new board member Matthew Hodgson, who joined in May, is now ready to coordinate this effort and will be in touch with families who have responded to our request for samples and others who have not yet been in touch. 

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April 2006
 
Research grant to be offered; deadline looms for application
By Patricia Wood 

Fundraisers make a big difference. 

Because families held several last year — and we hope more of them will step up with fundraisers this year, the NBIA Disorders Association will be able to offer at least one research grant worth $30,000 in 2006. 

Our organization has used the National Organization for Rare Disorders to administer seven research grants that we awarded in the past four years. But we have evolved. Thanks to our new Scientific & Medical Advisory Board, we now have the in-house expertise to do the work ourselves, saving $5,000 in administrative costs per grant. The advisory board will review proposals and make recommendations to the Board of Trustees, which will have final say in grant selection. 

Any advisory board members wishing to apply for grants will recuse themselves from the selection process to avoid conflicts of interest. 

We are accepting applications for one-year grants for clinical research studies related to the early detection, diagnosis or treatment of patients with NBIA. The application and instructions can be found at our Web site at www.NBIAdisorders.org under the RFP link on our home page. The deadline for letters of intent is  June 15, 2006. The grant will be awarded in November. 

The purpose of these grants is to encourage meritorious clinical studies designed to improve the diagnosis or therapy of Neurodegeneration with Brain Iron Accumulation. The research will be conducted in the United States, Europe, Canada, Australia, New Zealand, Brazil, Argentina, Chile, South Africa, Japan, or Israel, and where supervision of grant administration is possible. 

Grants will be awarded to academic researchers to initiate small clinical trials, the results of which could be used to obtain funding from NIH, FDA or other funding agencies, or to attract a corporate sponsor. Procedures or proposed therapeutic trials may be new, based on recent biochemical or pharmacological evidence, or be in preliminary states of clinical investigation. 

Evaluation of proposals will include careful consideration of protocol design, objectiveness of parameters measured, and statistical evaluation proposed. Protocols that will focus on early detection, diagnosis, or treatment (Pharmacological, devices, surgery or dietary) will be given priority. 

For more information, contact Patricia Wood at pwood@NBIAdisorders.org.

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Did you get your letter yet?

The NBIA Disorders Association mailed letters the first week of March telling families about our BioBank and why we need their help with this important endeavor — even families who have already donated blood. For previous donors, a few signed forms are all we need.

Specifically, we are requesting that families who have previously donated blood samples for the NBIA Research Registry housed at Oregon Health & Science University send in the release forms to our office that were included in the packet.

This release asks OHSU to send a sample of the DNA and the medical records of NBIA individuals to our BioBank. We need a separate release form for each individual who donated blood.

OHSU will still have DNA available for its research, but these samples will now also be available to other researchers who wish to study NBIA.

Instructions for those who haven’t donated blood also are in the packet, and we are urging families to take part in the BioBank. 

Our membership in the BioBank greatly increases the odds of encouraging new researchers to study NBIA. All researchers desiring samples and data must have their projects approved by the association’s Scientific & Medical Advisory Board to make sure their research is an appropriate use of our valuable resources. Researchers will also have to report back to us on their findings and we will then inform everyone on their progress through our Web site and newsletters. 

The BioBank eliminates families having to donate blood multiple times for different research projects. It also protects the privacy of those donating. Names and identifying information will be removed and researchers will not have access, but will have anonymous data. Our organization will also be able to gather information from families over a period of years, giving a clearer picture of how the disease progresses. 

As many of you know, this is crucial information in working toward a cure for NBIA. 

So, if you have donated blood previously to OHSU, please send in your release forms as soon as possible. If you are a newly diagnosed family or have not yet donated blood to OHSU for other reasons, you can fill out the request for consent forms and we will send you the necessary paperwork to participate. Please contact me, Patricia Wood, at pwood@NBIAdisorders.org or call 619 588-2315 if you have any questions. 

Any NBIA families not receiving the packet should also contact me to make sure we have your correct address and that you are listed in our NBIA families database. 

We are very excited to be moving forward with our BioBank. As one of seven founding members of the Genetic Alliance BioBank, we envisioned this repository moving research forward at a faster pace. Our participation was possible with a $50,000 grant from the Wright Family Foundation. 

One of our other founding groups, CFC International that is also a small, rare disease group, recently made news with the discovery of three genes related to their disease. This research was possible only because the organization had DNA and medical records available to a researcher that otherwise would have had no access to this material. It took only a few months for her lab to discover these genes, but it would never have happened without CFC International’s participation in the Genetic Alliance BioBank. CFC International was named a co-author of the gene discovery, only the third time that a lay advocacy group had accomplished that feat. 

The discovery may help with the study of cancer, as these three genes are part of a complex pathway called Ras/MAPK that has a central role in cell growth, where disruptions can lead to cancerous tumors.  As cancer is not part of CFC, this sheds new light on the complex process of this pathway. 

Please do your part to help NBIA Disorders Association further critical research. Many families report feeling helpless in their fight against NBIA, but this is a way to fight back and make a difference.

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December 2005

Hayflick lab awarded NORD research grant

Dr. Susan Hayflick’s lab at the Oregon Health & Science University has been awarded the 2005 research grant from the National Organization for Rare Disorders, sponsored by funds from NBIA Disorders Association and Hoffnungsbaum e. V. (NBIA Germany organization). The title of the project is “Dynamics of Brain Iron Distribution in PKAN.” Her lab will study how iron moves into the brain of individuals who have PKAN, a form of the disease, and in individuals who have the non-PKAN form of NBIA. 

­ “We were very pleased to be awarded the 2005 grant from the NBIA Disorders Association and Hoffnungsbaum ,” Hayflick said. “Since this is the only way for us to explore new research ideas and obtain preliminary data for larger federal grants, these funds are extremely valuable in supporting NBIA research.” 

She is hopeful the research will lead to insights into problems of vitamin B₅ metabolism and brain iron accumulation, links that still are not clear. “We hope that by understanding these patterns we can generate new ideas for blocking iron deposition,” Hayflick said. 

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December 2005
 
Association expects to award at least one research grant in 2006

The NBIA Disorders Association will be offering at least one research grant this year, thanks to fundraising efforts by NBIA families in 2005. There is still time for more families to hold fundraisers so that more grants can be offered before the awards are made at the end of the year. 

To save money and to exploit the association’s growing expertise, our Scientific and Medical Advisory Board will review grant applications and recommend awards. In the past, the National Organization for Rare Disorders reviewed and administered research grants at a cost of $5,000 per grant. 

The NBIA board is compiling a mailing list of researchers to solicit proposals for grants. NBIA families also are encouraged to send the names and addresses of researchers they believe might be interested in studying NBIA so the board can notify those prospects of the program. This contact information should be sent to board member Kris McGourthy at rural9@aol.com. 

After receiving letters of intent, our Scientific & Medical Advisory Board will decide who will be asked to submit full proposals to be reviewed and scored. That board will then make recommendations to the NBIA Disorders Association Board, which has the final say on funding proposals. 

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December 2005
 
Kelsey’s last gift brings hope for a cure
By Scott & Rhonda Mayfield 

Our daughter Kelsey didn’t stop giving when she passed away. In life Kelsey brought smiles to the faces of those she loved, and now, with her passing, Kelsey is giving the gift of hope to people who have NBIA and their loved ones. 

With the gift of Kelsey’s brain tissue, researchers now have the means to explore a central mystery of NBIA, the ‘eye of the tiger,’ a key feature of the disease. It is an area in the brain encased in a layer of iron that distorts the view of the brain that can be seen by Magnetic Resonance Imaging. This distortion prevents the MRI from detecting the mass held within the iron cell, the contents of which doctors say are primary to the cause of NBIA. 

Donations such as Kelsey’s help doctors gain a crucial piece to the puzzle of NBIA. The end of the marathon race for a cure is in sight, but without a strong finish, without continued funding and without continued research and donations of tissue, the first 23 miles will have been run for nothing. History has shown us that nothing is impossible, that no disease is incurable. What started as an uphill battle against the odds is close to victory. All the pieces now lay before us; we just have to put them together. 

When Kelsey was diagnosed with NBIA little was known about the disease aside from the eventual and inevitable outcome: death. Kelsey’s battle with NBIA, we were told, would not simply be a difficult one, but a futile one. Doctors tirelessly searched for a cure, but ultimately were stuck trying to complete a puzzle without all the pieces. Kelsey’s parting gift provides a crucial piece to that puzzle – and hope it will be solved. 

If you would like to make a designation for a future brain tissue donation, please contact info@NBIAdisorders.org for more information.

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The NBIA research teams at UCSF and OHSU recently published an article in the journal Human Molecular Genetics describing the creation and analysis of a PKAN knock-out mouse.  Knock-out mice are animals that have had a certain gene inactivated, or “knocked out.”  In this case, the Pank2 (the mouse gene is referred to in lower case letters, while the human PANK2 gene is written in all capitals) gene was knocked out, which resulted in a mouse version of classic PKAN. 

Knock-out mice can be extremely helpful to researchers by giving clues about the underlying causes of diseases.  They also provide an initial way to test possible treatments.  Since mice reproduce relatively rapidly (a female mouse is pregnant for only about 20 days before giving birth to a litter of pups), it is possible to design different crosses of mice and collect several generations over a short period of time. 

How to make a knock-out mouse

Several advances in technology have made what was previously a stupendous feat a common research tool.  The first step is to knock out the gene in a group of mouse embryonic stem cells.  Only one of the two copies of the Pank2 gene is knocked out at this point, leaving the second working copy. 

Once the gene has been knocked out, the stem cells are injected into very young mouse embryos created by in vitro fertilization techniques.  At this early stage, some of the new cells are incorporated into all the different organs of the developing mice, including the cells that will become sperm and eggs. These embryos are then transferred back into surrogate mouse mothers.  About 16 days later, a litter of pups is born.  The pups have a mix of normal cells and knock-out cells. 

Some pups will have the knock-out gene incorporated in their sperm and egg cells.  They are mated and pass on this trait to some of their pups.  The pups have the new change in every cell of their bodies and are PKAN carriers.  Then, carrier mice are mated to create the true knock-out mouse, which has mutations in both copies of its Pank2 gene.  After three generations of mice and much hard work, several male and female  knock-out mice are available to study. 

Studies of the PKAN knock-out mice

Several aspects of the mouse’s development, health, and physical skills were studied.  They were always compared to healthy carrier mice (one working copy of Pank2) and healthy normal mice with two working copies of the Pank2 gene. 

The mice were monitored for feeding difficulties and poor growth because these are problems seen in people with PKAN.  The knock-out mice were smaller in size and body weight--about 80% the size of the control mice.  However, they ate the same amount as the normal mice and did not appear to have trouble with chewing or swallowing.  This suggests that there are probably differences in their metabolism that make them smaller. 

Fertility was studied in male and female Pank2 mice.  Pank2 mice cannot mate with each other. The females were found to be fertile when mated to normal mice, but they produced much smaller litters.  The males were found to be infertile.  Although they produced the precursors to mature sperm cells, their development stopped prematurely and no fully developed sperm were made. 

Like people with PKAN, the mice had retinal disease.  This was shown by electroretinogram studies and by looking by histology at retinal tissue in the laboratory.  As in humans, the damage to the photoreceptor cells of the retina worsened over time. 

The neurological assessment of the mice was of special interest since PKAN is primarily a neurological disorder.  The mice were followed for over a year, which is roughly equal to 34 human years (lab mice usually live about two years).  Surprisingly, no evidence of iron accumulation was seen in the basal ganglia and the mice did not have any noticeable neurological impairments.  Their brains were evaluated both by magnetic resonance imaging (MRI) and by studying tissue samples from deceased mice.  They were given several tests weekly to measure their strength, balance, and muscle coordination. 

Discussion of the research findings

The researchers successfully created a mouse that lacks pantothenate kinase 2, the enzyme that is deficient in PKAN.  In studying the mice, they found growth problems, retinal degeneration, and absent sperm in the males. 

Most surprising was the finding of infertility in the male mice.  This has not been described in human males with PKAN, probably because many of the affected individuals with classic PKAN have a shortened lifespan or are very ill.  A question for future research is how the Pank2 protein is involved in the development of mature sperm cells. 

Although the retinal degeneration in the mice provides a model for studying this problem in people with PKAN, the mice did not have a movement disorder or show any abnormal iron accumulation in their brains.  The next step is to see whether the researchers can bring out these features in the mice.  They are currently experimenting with giving the mice various compounds, including a diet that is low in vitamin B5, to see how deprivation of the vitamin will affect them.

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December 2004
 
Dr. Susan Hayflick and her team at OHSU get new NORD grant award for gene search 
By Allison Gregory

Dr. Susan Hayflick and her team at Oregon Health & Science University (OHSU) were recently awarded new NORD funding made possible by NBIA Disorders Association to support their search for other genes causing NBIA.

Hayflick and her collaborators found the gene that causes pantothenate kinase-associated neurodegeneration (PKAN) in 2001, called PANK2. About half of all people diagnosed with neurodegeneration with brain iron accumulation (NBIA) have mutations in the PANK2 gene. The other half has genes that remain to be found.

Even before the recent NORD funding was awarded, Hayflick was on the trail of the next gene. She received support last year from the NIH-funded Center for Inherited Disease Research, or CIDR.

This center provides many critical services to researchers. For Hayflick, CIDR took on the task of processing almost 200 DNA samples from the international NBIA family registry that is maintained in her lab.

An individual "fingerprint" of each person's DNA was generated so that the team could start narrowing down the location of the next NBIA gene among the 24 unique human chromosomes. This is done by looking at each family and checking what parts of the fingerprints are always different between the people with NBIA and those without it. This first step is like starting with the entire world and narrowing down the possible location to a few countries.

The NORD funding will support the next steps. These include doing some additional fine mapping, which narrows down the location even further. Fine mapping is like finding cities inside the countries. Once the location is narrowed down to a smaller region of a certain chromosome, new techniques can be combined to find the gene as quickly as possible.

Since such great progress has been made in recent years with mapping the entire human genome, candidate genes can now be identified within specific 'regions of interest.' These candidate genes are screened to see whether there are any mutations, or typos in the genetic code, that could cause someone to have NBIA.

The identification of another major NBIA gene will be a launching pad for progress in several areas. A molecular test could be developed to help make the diagnosis of NBIA. This would also make prenatal diagnosis possible for many couples concerned about the chance of having another child with NBIA.

The research team hopes that by identifying the genetic basis of the disease in these remaining families, progress will be made towards better understanding the processes that cause NBIA so therapies can be developed.

This could benefit everyone with NBIA, including those with PKAN, since we may find a related gene that sheds light on pathways common to all forms of this disorder.

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December 2004
 
Data from PKAN Clinical Study Analyzed 

By Allison Gregory

Dr. Susan Hayflick and her collaborators at Oregon Health & Science University (OHSU) have finished analyzing the ophthalmological data that was collected during the Clinical Investigations of PKAN study.

This part of the study, led by doctors Richard Weleber and Robert Egan of OHSU’s Casey Eye Institute, found that 11 of 16 participants had abnormal electroretinogram, or ERG, results.  This test measures how well the rod and cone cells in the back of the eye are working and can detect dysfunction even before someone notices vision changes.  Four of the 11 had true retinal disease, and their ERG findings were the most severe.

For the others, the ERG changes were mild to moderate and showed that PKAN has affected the rods and cones of their retinas, but not yet to a significant degree.  Almost all the participants also had ocular motility changes, meaning they had trouble moving their eyes to track objects or do other tasks. 

None had optic nerve atrophy, which confirmed the theory that this is a feature of non-PKAN NBIA. 

Egan, a neuro-ophthalmologist, also noticed some interesting similarities between the PKAN study participants and two other patients he has seen recently, one with non-PKAN NBIA and one with Wilson disease, a copper storage disorder. 

The OHSU team will continue to keep the NBIA Disorders Association informed about the findings of the clinical PKAN study.

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Washington DC – October, 2004 Seven genetic advocacy organizations, including the NBIA Disorders Association, established the Genetic Alliance BioBankTM, a repository for the standardized collection, storage and distribution of biological samples and clinical data for research purposes.

This novel, advocacy-owned and managed repository focuses and accelerates research, providing a way for many advocacy groups to build a valuable resource for scientists.

“Our organization has longed for the day when we can focus research with this resource and create a dynamic consortium of researchers driving toward the same goal — accurate and timely diagnosis followed by effective treatment of inflammatory breast cancer,” said Owen Johnson, president of the Inflammatory Breast Cancer Research Foundation, another organization co-founding the BioBank.

The other founders of the bank are CFC International, Joubert Syndrome Foundation, National Psoriasis Foundation, Noonan Syndrome Support Group and PXE International.

The Genetic Alliance BioBank~ follows a model established in 1995 by PXE International. That rare disease organization has initiated and conducted research on pseudoxanthoma elasticum (PXE), actively participating in the gene discovery and patenting.  PXE International and the other groups came together through their work with the Genetic Alliance, a coalition of over 600 advocacy organizations. These founding members developed standardized model documents for the bank, designed and approved by the Genetic Alliance BioBank Institutional Review Board.

Researchers who wish to receive samples submit an application to the disease-specific advocacy organization. These organizations then release coded samples to the researcher and hold the key that connects specific samples to individuals, offering a unique opportunity for follow-up studies while protecting participant confidentiality.

The Genetic Alliance BioBank~ will also provide an opportunity for cross-disease research that may shed light on pathways and causes for both common and rare diseases.

The BioBank represents the next generation of patient advocacy, said Genetic Alliance BioBank~ founding President Sharon Terry. “But this is only the beginning. We are managing this resource, this community, with our eye on the prize — we will positively impact health outcomes. Solving these problems is often the work of generations, but we are taking one giant step in our lifetime.”

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August 2004

Update on Research in Chicago

A Chicago researcher who received a grant from the NBIA Disorders Association reports that he is making progress in using a mouse model to study a form of the disease known as pantothenate kinase-associated neurodegeneration, which affects about half of the people with NBIA.

Dr. Han-Xiang Deng of the Northwestern University Feinberg School of Medicine is using gene-targeting techniques in his research. The goal of his project, for which he was awarded a grant, is to learn how chemical changes contribute to the disease so that useful therapies can be developed.

Deng said his lab’s first two attempts at gene-targeting techniques did not succeed, but that the work yielded useful information. “We have made considerable progress in targeting the PANK2 gene responsible for PKAN,” he said. “Our current strategies are based on the lessons learned and we should soon have the knock-out mouse model for PKAN.”

If the work proceeds as planned, the new mouse model will enable Deng and his crew to study how PKAN develops and “a rational approach to its treatment,” Deng said.

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April 2004

NBIA Disorders Association joins Genetic Alliance Bio Bank

By Patricia Wood
  

Thanks to a grant from the Wright Family Foundation in September, our organization will be on the front lines of an effort that we expect to reap huge benefits for NBIA research. The $50,000 foundation grant will be used to cover the estimated five-year costs of joining the Genetic Alliance Bio Bank. 

This bank will store blood and tissue samples from patients with various disorders. These samples will be used for research purposes, so scientists can learn more about NBIA and other disorders. The ultimate hope, of course, is that researchers will discover cures for the diseases being studied.

Patient advocacy groups representing these individuals, such as the NBIA Disorders Association, will own the samples. It is less expensive to have a group form a bio bank, rather than each organization trying to go it alone.

But there also is power in numbers. Together, our organizations can mentor and support one another as we learn more about the illnesses affecting our members. The bio bank also can empower advocacy groups to work more closely as partners with the researchers. The hope is that the bio bank will make the research more streamlined and coordinated so that beneficial treatments can be gotten to patients more quickly.

Often, research into rare disease is hampered because the number of samples being used in studies is very small, too small to give a clear picture of the disease. This can lead to inaccuracies in how the disease is described in the medical literature. Also, researchers don't typically follow up on affected individuals after they donate, so the progression of symptoms is not seen and valuable information is lost.

Many times, affected individuals and their families never hear back about any research findings on tissue donations. And some researchers are reluctant to share their samples with colleagues or may have legal problems doing so because of regulations.

With a bio bank, researchers given access to samples will report back to the NBIA Disorders Association on their results, and the organization will inform families.

If the bio bank lives up to its potential, it can change the way research is being done today.

There are a variety of advantages for those who participate. Privacy and confidentiality are assured for those donating blood and tissue samples. Only samples stripped of identifying information are given to researchers. Affected individuals and their families only have to donate once, rather than multiple times for different research projects. Donors go through a consent process to help them make the decision freely before participating.

Researchers have access to samples that follow the same collection and storage protocols and access to follow-up data. A goal is to have a research database that will help researchers and pharmaceutical companies study similar symptoms across different diseases, possibly opening the door to new treatments.

Dr. Susan Hayflick, a key NBIA researcher, said she strongly supports the decision to join the bio bank.

"A significant hurdle to attracting new researchers to study a rare disorder is limited access to tissues," Hayflick said. "Most scientists are not physicians and so do not have a patient connection for obtaining tissue for their studies. Just as fundraising has encouraged and supported new NBIA investigators, better access to tissue will remove a key barrier to progress in understanding and treating the NBIA disorders. Participation in the bio bank is a very wise way for the NBIA Disorders Association to support research."

The Genetic Alliance Bio Bank is still in its infancy. It was incorporated on Oct. 14 in Delaware with Sharon Terry as president, husband Patrick Terry as secretary and Joan Scott as treasurer.

Sharon Terry also is president and chief executive officer of the Genetic Alliance, an organization that helps individuals and families living with genetic conditions. She is the founding CEO of PXE International, a non-profit dedicated to finding a cure for pseudoxanthoma elasticum. She’s on numerous advisory boards at the National Institutes of Health, Johns Hopkins University and the Centers for Disease Control and Prevention, among others.

Patrick Terry is the president of the International Genetic Alliance and the co-founder of Genomic Health, Inc., a business dedicated to improving the quality of treatment decisions for patients with cancer. Joan Scott is the Deputy Director of the Genetics and Public Policy Center in Washington DC.

The bank’s estimated budget for 2004 is $97,182. Seven organizations, including ours, have joined and agreed to pay entry fees of $13,883 each as founding members. Annual fees in future years will either be $5,000 or $10,00, depending on how many groups join.

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With last year's grant, Hayflick teamed up with researcher Dr. Penny Hogarth to bring NBIA patients and their families to the Oregon Health & Science University in Portland for a study. There, families were able to tour the research lab and meet those involved in NBIA research. Each participant in the study also underwent two procedures; a flash electroretinogram and magnetic resonance spectroscopy, which were discussed in detail in our August newsletter.  The team is continuing to recruit families. If interested, contact Allison Gregory at (503) 494-4344 or gregorya@ohsu.edu.

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December 2003

Office of Rare Diseases asks for ways to help with research needs of NBIA and other rare disorders
By Patricia Wood

Leaders of lay advocacy groups representing rare diseases, including the NBIA Disorders Association, had a chance to present their research needs and seek guidance from experts at the Office of Rare Diseases. The opportunity came during the Genetic Alliance conference in August when Stephen Groft, director of the Office of Rare Diseases, chaired a focus group to hear from us.

Groft's office, which is part of the National Institutes of Health, has a budget of $11 million in 2004 to support and stimulate research of rare diseases. The focus group discussed the upcoming establishment in 2004, of a network of seven clinical research centers across the United States which will focus on rare diseases, of which there are 6,000 disorders affecting more than 25 million Americans.

Obviously, there is a need for people to have champions, such as this federal agency, to help get researchers interested in their disease.

We discussed ways to create research partnerships with scientists, how to tap into the financial and educational resources of the National Institutes of Health and various ways to help cover travel costs for patients taking part in clinical studies -- a problem directly related to rare diseases with so few patients spread throughout the world.

Another important topic was how the national institutes could help finance scientific workshops on rare diseases. As a result of my participation in this focus