New method increases accuracy of ovarian cancer prognosis and diagnosis

Nearly anyone touched by ovarian cancer will tell you: it’s devastating. It’s bad enough that cancer in almost 80 percent of patients reaches advanced stages before diagnosis, and that most patients are expected to die within five years. But just as painfully, roughly one quarter of women diagnosed have no warning that they are resistant to platinum-based chemotherapy, the main line of defense, nor that they will likely have 18 months to live.

Frustratingly, the diagnosis, prognosis, and even treatment of ovarian cancer have remained largely unchanged for 30 years. Until now, the best indicator for how a woman will fare, and how her cancer should be treated, has been the tumor’s stage at diagnosis.

Now, University of Utah scientists have uncovered patterns of DNA anomalies that predict a woman’s outcome significantly better than tumor stage. In addition, these patterns are the first known indicator of how well a woman will respond to platinum therapy. Published in the journal PLOS ONE, the patterns were discovered by using a new mathematical technique in the analysis of DNA profiles from the Cancer Genome Atlas, a national database containing data from hundreds of ovarian cancer patients.

“We believe this is a first step toward bringing ovarian cancer into the age of precision medicine,” says team leader Orly Alter, Ph.D., associate professor of bioengineering, adjunct associate professor of human genetics, and faculty member of the Scientific Computing and Imaging Institute. Pending experimental revalidation in the clinic, the patterns could be the basis of a personalized prognostic and diagnostic laboratory test. This test would predict both the patient’s survival and the tumor’s sensitivity to platinum-based chemotherapy, and doctors could tailor treatment accordingly.

For example, among patients that were diagnosed at late stages, the DNA patterns distinguished short-term survivors, with a median survival time of three years, from long-term survivors, with a median survival time almost twice as long. Among patients treated with platinum-based chemotherapy drugs, the DNA patterns distinguished those with platinum-resistant tumors, with a median survival time of three years, from those with platinum-sensitive tumors, with a median survival time of more than seven years. Alter’s team computationally validated the results by using data from independent sets of patients.

“If we have a tool that can more accurately predict survival, and distinguish who is who, we can revamp our entire approach to how we treat patients,” says Margit-Maria Janát-Amsbury, M.D., Ph.D., research assistant professor in obstetrics and gynecology, director of gynecologic oncology research at the University of Utah School of Medicine, and faculty member of the Huntsman Cancer Institute. She is collaborating with Alter to bring her team’s results to the clinic. “For those with a poor prognosis, we can suggest other therapies, or we can focus on taking measures to improve quality of life.”

“What made our discovery possible is our new technique for mathematical modeling,” said Alter. “It may very well be that the data needed to better treat cancer are already published. The ovarian cancer data, for example, were published back in 2011. The bottleneck to discovery is in the analysis of the data.”

In Alter’s Genomic Signal Processing Lab, Ph.D. graduate students and study co-authors Katherine Aiello and Theodore Schomay of the department of bioengineering develop algorithms to uncover patterns in datasets arranged in multidimensional tables, known as tensors. Rather than simplifying the big data, as is commonly done, the algorithms make use of the complexity of the data in order to tease out the patterns within them. Here, for example, by modeling DNA profiles of tumor and normal cells from the same set of patients, they were able to separate the patterns of DNA anomalies – which occur only in tumor genomes – from those that occur in the genomes of normal cells in the body, and from variations caused by experimental inconsistencies.

The algorithms extend a mathematical technique called the singular value decomposition, or SVD. The SVD helps us understand data arranged in two-dimensional tables, known as matrices, by breaking the data down into individual components. In physics, for example, the SVD describes the activity of a prism, which splits white light into its component colors. “It seemed natural that generalizations of the SVD could separate the multidimensional data that arise in personalized medicine into mathematical patterns that have biological meaning,” explains Alter, who has a Ph.D. in applied physics.

Alter says her algorithms could just as readily be applied to any type of data. She previously used a similar mathematical technique to uncover new prognostic and diagnostic DNA indicators for patients with glioblastoma, the most common brain cancer in adults. The best predictor of glioblastoma survival prior to Alter’s discovery was the patient’s age at diagnosis.

Some of the specific genes that Alter’s team found to be perturbed in glioblastoma, and in ovarian cancer, may be actively involved in promoting or inhibiting cancer development and progression. Future work will explore whether existing drugs that target these genes are effective in treating these diseases.

To read the April 15, 2015 PLOS ONE article go to: http://dx.plos.org/10.1371/journal.pone.0121396

This work was supported by the Utah Science, Technology, and Research (USTAR) Initiative, National Human Genome Research Institute (NHGRI) R01 Grant HG-004302, and National Science Foundation (NSF) CAREER Award DMS-0847173.

Tensor GSVD of patient- and platform-matched tumor and normal DNA copy-number profiles uncovers chromosome arm-wide patterns of tumor-exclusive platform-consistent alterations encoding for cell transformation and predicting ovarian cancer survival. Sankaranarayanan P, Schomay TE, Aiello KA, Alter O. PLOS ONE 10 (4), article e0121396 (April 15, 2015); doi: 10.1371/journal.pone.0121396

Contact:

Julie Kiefer
jkiefer@neuro.utah.edu
801-597-4258

Rare Impact

By Carol Dutch

“Not every doctor would go to such lengths to help a patient; thankfully, my doctor did.” Words like these captured the attention of dozens of healthcare providers and medical residents assembled at Children’s Hospital of Orange County (CHOC) and Rady Children’s Hospital-San Diego. Throughout 2015, many more physicians will experience RAREMed Forums, a series of medical educational sessions prompted by Global Genes and hosted by academic centers and hospitals across the country.

I’m deeply grateful for the physician experts, patient advocates and industry colleagues who are bringing this idea to life. As co-chair of the healthcare provider outreach committee at Global Genes, I’m also tremendously inspired and encouraged by the dialogue at these sessions. Patients are sharing stories of courage and perseverance, and physicians are learning the nuances of diagnosing and managing rare disorders.

During the sessions, speakers present on a wide variety of topics, such as outlining steps designed to speed accurate diagnosis and ensure timely care of people with rare disorders. Physicians are encouraged to “think, refer, integrate and challenge themselves” when diagnosing rare diseases. The program also stresses the importance of physicians giving these conditions the consideration they demand and referring promptly to specialists and centers of excellence.

The RAREMed Forums are only one example of patient advocates, medical communities and industry working together to support education and awareness of the porphyrias, a group of rare and debilitating diseases. The American Porphyria Foundation is training the next generation of physicians in the diagnosis and management of these conditions. Called “Protect Our Future,” this program allows younger physicians to learn from the small number of world-renowned experts in the field. I am proud that my company, Recordati Rare Diseases, supports this program as part of our commitment to the rare disease community.

These programs – and many more – show the power of banding together to overcome challenges that seemed impossible just a decade ago. As with any family, our global rare disease community is strongest when united in a common goal. When patients, families, physicians, academic centers, policy makers and industry work together, we can improve our understanding of rare diseases, advance research, and improve diagnosis.

It’s my hope that programs like these will knock down some of the barriers to rare disease diagnoses for patients, reducing their suffering and helping them live fuller and healthier lives.

With 20 years of experience working with rare disease communities, Carol Dutch manages patient advocacy programs at Recordati Rare Diseases, a biopharmaceutical company that specializes in providing high-impact therapies for high-impact rare diseases. The company is passionate about partnering with rare disease communities to help restore the lives of people affected by these disorders.

For more information on RAREMed Forums, contact Katie Mastro at katiem@globalgenes.org.

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[Photo 1: For prominent placement near top of blog post] Global Genes was the catalyst for a RARE Rounds medical education session held at Children’s Hospital of Orange County (CHOC). Left to right: Carol Dutch, manager of advocacy at Recordati Rare Diseases and co-chair of the healthcare provider outreach committee at Global Genes; Raymond Y. Wang, M.D., director of multidisciplinary lysosomal storage disorder program at CHOC; and Andrea Epstein, executive director of Global Genes.

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[Photo 2: for secondary placement] Dozens of health care providers and medical residents attending the RARE Rounds session at Rady Children’s Hospital-San Diego.  

Family spotlights rare disease

Most parents of a 6-year-old don’t regularly think about their child’s bone marrow. But Denton resident Elyse Barnard constantly has her daughter’s bone marrow on her mind.

At 13 months old, Hallie Barnard was diagnosed with Diamond Blackfan anemia, or DBA, a rare blood disease that prevents bone marrow from producing red blood cells.

DBA can be maintained with blood transfusions and steroid treatments, but the only cure is a complete bone marrow transplant from an identical marrow match.

Barnard and her husband are not matches for Hallie and their other two children are perfect matches for each other, but not Hallie.

“The worst feeling for a parent is not being able to make them better,” Barnard said.

Since Hallie’s diagnosis, Barnard and her husband have seen their daughter endure numerous blood transfusions and regular hospital visits while patiently waiting for a marrow match.

“She’s really mature for her age because she’s had to be,” Barnard said.

Fewer than 35 new cases of DBA are identified each year in the U.S, according to the Diamond Blackfan Anemia Foundation.

With such a low number of affected people, Barnard said the foundation gets little exposure and even fewer financial donations needed for research and resources.

Barnard is working to raise awareness and encourage people to join bone marrow registries so Hallie and children like her have a better chance of finding the match they need.

“It’s a process, but we have some great people that are willing to help,” she said.

Barnard is hosting a community call to action at 7 p.m. March, 26th at St. Andrew Presbyterian Church, 300 W. Oak St. Information on how to join the national bone marrow registry will be provided.

On Friday, March 27th Chick-fil-A at 460 Grapevine Highway in Hurst will donate 20 percent of sales made between 4 and 9 p.m. to the foundation in honor of Hallie.

The restaurant is also hosting karaoke at the same time as part of the foundation’s “Sing Away DBA” fundraising campaign. Marrow registry Be the Match will be on site offering cheek swabs for people looking to join.

The owners of the Hurst Chick-fil-A have been hosting blood and marrow drives in Hallie’s honor for the past four years.

The Barnard family met the restaurant owners when they moved to Fort Worth five years ago from Virginia for Hallie to be treated at Children’s Medical Center of Dallas, one of four hospitals in the country that specialize in DBA treatment.

The family relocated to Denton two years ago and Barnard wants to host similar events locally. She created the Hallie’s Heroes Facebook page in February to get the community involved.

“We’re hoping this will spawn more events up here,” she said.

Hallie is a student at Ryan Elementary School and school faculty and students help however they can. Librarian Desiree Peden is organizing a Hallie’s Heroes fun run on May 9 in Denton.

Peden said the run will be an opportunity to sign people up for marrow registries and to rally the community around Hallie’s cause.

“It’s very important to me,” Peden said. “She’s a really special kiddo.”

For more information, visit https://ww.facebook.com/HalliesHeros?ref=br_rs

What lies beneath the surface: examining water-borne parasites

Water is essential for life on Earth. It is crucial for environmental and human health, necessary for food and energy security, and indispensable for continued urbanization and industry. One in nine people lacks access to safe water, but what does this mean?

We often think about getting sick from drinking unsafe water, but what lives in the water can also affect our health. For eight years, University of Alberta researcher Patrick Hanington has been studying parasites that infest water and affect human and animal health locally and internationally.

Hanington’s research focuses on schistosomiasis. It is one of the world’s widely neglected diseases, yet it is second only to malaria in terms of overall public health impact for parasitic diseases. The disease is caused by parasitic worms called schistosomes that live in specific species of freshwater snails. Infected snails release cercariae, the form of the parasite infectious to humans. When released, the cercariae look for a host and are attracted to human secretions. If people are in nearby water, the cercariae can penetrate through the skin, causing infection.

“In Canada, the schistosomes that lead to human disease are absent. However, similar parasites that naturally infect other animals can be found within resident snails. Cercariae released from these snails can encounter people in the water, causing what is commonly known as swimmer’s itch. The result is a temporary, itchy rash, which eventually goes away within two to five days,” says Hanington, assistant professor with the School of Public Health. “But in tropical, developing countries where good sanitation is often lacking, three species of schistosome exist that specify in infecting humans. These parasites lead to much more serious health complications.”

Intestinal schistosomiasis leads to liver and spleen enlargement, intestinal damage and hypertension. Urinary schistosomiasis leads to progressive damage to the bladder, ureters and kidneys. For women, this can also cause lesions in the urinary tract, meaning an infected individual has a greater risk for acquiring or transmitting HIV.

To further explore schistosomiasis internationally, Hanington is collaborating with William Anyan, a researcher at the Noguchi Memorial Institute for Medical Research at the University of Ghana. Together, they are building on their combined expertise in the snail stage of the schistosome life cycle. They plan to integrate their research with existing chemotherapy-based control programs in small rural communities in Ghana.

There, schistosomiasis infection rates are the third highest in Africa, ranging between 10 and 20 per cent prevalence and as high as 40 per cent in the south. In many of the smaller rural communities, infection rates are even higher, sometimes reaching 100 per cent of the children in a community. Often, everyday activities in these communities revolve around water.

“Local people are in the water every day, whether they are using it for fishing, cleaning, drinking, playing or bathing,” explains Hanington. “Avoiding interactions with water to prevent schistosomiasis is not reasonable. We’ve had to ask ourselves, ‘What can we do to work both with the community and with the environment to improve health and reduce the burden of schistosomiasis?'”

Hanington and his team are developing tools to estimate the risk of schistosome transmission from snails. They are also evaluating the snail and schistosome population structures. If they are able to understand the rate of transmission and how quickly the schistosomes are reinfecting both people and snails, then they will be better able to tailor control strategies to prevent new infections, avoid reinfection and assist those currently infected.

Ultimately, the objective is to complement drug administration programs by providing tools for measuring treatment effectiveness and reducing schistosome prevalence in both snails and people.

Hanington says that his research in Ghana has just scratched the surface, and he is looking forward to further discovery.

As part of ongoing efforts to build closer relationships with communities and researchers, Anyan was recently invited to the School of Public Health.
“Health knows no boundaries,” says Hanington. “The more we can collaborate on a common issue, exchange knowledge and assist one another, the more likely we are to have a significant health impact and alleviate human suffering.”

Contact:
University of Alberta
Tel: (780) 492-0437
michael.davies-venn@ualberta.ca

Author: Rachel Harper
Source: University of Alberta

Rett Syndrome Revelation

Scientists have known for 15 years that mutations in a single gene lead to Rett syndrome, a severe neurological disorder that affects girls around their first birthdays. In the years since the MECP2 gene was pinpointed, researchers have struggled to understand how it functions in the brain in Rett syndrome.

Now the enigma of Rett syndrome and perhaps other disorders on the autism spectrum could be one step closer to being solved.

A Harvard Medical School team has discovered that when MECP2 is mutated in Rett syndrome, the brain loses its ability to regulate genes that are unusually long. Their finding suggests new ways to consider reversing the intellectual and physical debilitation this disruption causes with a drug that could potentially target this error. The team, led by Michael Greenberg, reported its findings in Nature.

“The longer the gene, the more disrupted it becomes when you lose MECP2,” said Greenberg, the Nathan Marsh Pusey Professor of Neurobiology at HMS. “Rett syndrome may be a defect in this process of fine-tuning the expression of long genes.”

Scientists, including Greenberg, have figured out over the last 10 years that MECP2 plays a role in sculpting the connections between neurons in the developing brain. These synapses are refined by exposure to sensory experiences, just the sort of stimulation a one-year-old would encounter as she learns to walk and talk.

MECP2 is present in all cells in the body, but when the brain is forming and maturing its synapses in response to sensory input, MECP2 levels in the brain are almost 10 times as high as in other parts of the body. The new study connects MECP2 mutations to long genes, which may be more prone to errors simply because their length leaves more room for mistakes.
Speed Bump

“Normally, MECP2 may act like a speed bump, fine-tuning long genes by slowing down the machinery that transcribes long genes,” said Harrison Gabel, a postdoctoral fellow in the Greenberg lab and co-first author of the Nature paper. In transcription, the information in a strand of DNA is copied onto a new molecule of messenger RNA, which is then turned into a protein. “Without MECP2, the machinery may be moving too fast, making too much mRNA from these genes, resulting in problems for the neurons.”

Finding this effect of MECP2 on long genes was no small feat. In a typical search for the mechanism behind a genetic mutation, mice are engineered to lack the normal gene so that its absence reveals how it functions. However, work in many different labs has shown that knocking out MECP2 had only subtle effects when analyzed across the genome. The changes in gene expression were inconsistent, small and, using Gabel’s word, “fuzzy.”

Gabel took another approach, querying massive genomic databases such as ENCODE to ask a simple question: What do genes that are affected by mutated MECP2 have in common?

Answer: They are long. Most of them are at least five times longer than the average gene, with many of them more than 50 times longer than the average. It is important to note that the genes identified across dozens of data sets were very long, giving the researchers a common finding where previous conclusions from these data sets had lacked a common theme.

Harrison and co-first author Benyam Kinde, an MD-PhD student in the Greenberg lab, found the long-gene misregulation in multiple mouse models of Rett syndrome and confirmed it in the brain tissue of deceased Rett patients.

For MECP2 to function normally as a speed bump, it binds to a form of methylated DNA found in long genes in the brain. Methyl groups are chemical modifiers of gene activity, and in other parts of the body MECP2 binds methylated CG sites on genes. The methylation pattern that appears to be important for MECP2 in regulating long genes is known as methylated CA, and there appears to be a special mechanism operating as synapses are forming.

“It seems that evolution has used MECP2 and methylated CA to put in place this speed bump so that the expression of long genes is restrained in the brain,” Greenberg said. “As far as Rett syndrome, the thought is now that this subtle but widespread overexpression of long genes might be contributing to the disorder.”
Corrective Strategy

The scientists can’t be sure of what these overexpressed long genes do, but many of them appear to be very important to the function of the brain. This suggests that if they could correct the defect in long-gene expression, they might be able to reverse at least some of the symptoms of Rett syndrome. As a first attempt at a corrective strategy, the researchers selected a cancer drug called topotecan because it blocks an enzyme known to be important for long-gene transcription.

In a lab dish, they added topotecan to neurons lacking MECP2. The drug reversed the long-gene misregulation, suggesting that restoring normal long-gene expression might be a way to correct neurological dysfunction in Rett syndrome and in other autism spectrum disorders with long genes, such as fragile X syndrome. Topotecan, a chemotherapeutic agent, is too toxic, Greenberg said, but derivatives of topotecan might be a worthwhile avenue to pursue.

“We think this issue of long-gene misregulation may be more generally occurring in other disorders of human cognition,” Greenberg said. “The potential is pretty significant because one now has a common regulatory mechanism to target with drugs.”

This work was supported by grants from the Rett Syndrome Research Trust and the National Institutes of Health (1RO1NS048276 and T32GM007753), the Damon Runyon Cancer Research Foundation (DRG-2048-10), the William Randolf Hearst fund and the Howard Hughes Medical Institute

Author: ELIZABETH COONEY
Source: Harvard Medical School

Study sheds light on how malaria parasites grow exponentially

A University of South Florida College of Public Health professor and his team of researchers have become the first to uncover part of the mysterious process by which malaria-related parasites spread at explosive and deadly rates inside humans and other animals.

As drug-resistant malaria threatens to become a major public health crisis, the findings could potentially lead to a powerful new treatment for malaria-caused illnesses that kill more than 600,000 people a year.

In a study published online March 3 in the high-impact journal PLOS Biology, the USF researchers and their colleagues at the University of Georgia discovered how these ancient parasites manage to replicate their chromosomes up to thousands of times before spinning off into daughter cells with perfect similitude – all the while avoiding cell death.

“How these parasites preserve fidelity in this seemingly chaotic process is one of the great mysteries of this pathogen family,” said USF Health’s Michael White, PhD, a professor in the Department of Global Health who partnered on the study with fellow USF researcher Elena Suvorova, PhD, in the USF Departments of Molecular Medicine & Global Health and the Florida Center for Drug Discovery and Innovation, as well as with two researchers from the University of Georgia.

In studying the malaria-relative Toxoplasma gondii, the team found an explanation for that puzzle.

To understand it, consider that malaria-related parasites are professional multipliers, unlike plant and animal species and single-cell organisms like yeast – where chromosomes get one shot at replication or else the cell dies or turns into cancer, Dr. White explained.

With malaria-related parasites, once transmitted into an animal or human, they can hide out in a single cell in many different tissues replicating silently tens, hundreds or even thousands of times before the host’s immune system can detect that they are there.

Then with the stealth of a Trojan horse, they burst forth as “daughter cells,” which are unleashed in massive quantities in waves, like a small army into the host’s system – quickly overwhelming a patient’s immune response, Dr. White explained.

What the study found was that the Toxoplasma parasites pull this off thanks to a “modified ‘control room’ called the centrosome that imposes order on the replication chaos,” Dr. White said. “Unlike the comparatively simple centrosome present in human cells, the parasite ‘control room’ has two distinct operating machines; one machine controls chromosome copying, while the other machine regulates when to form daughter cell bodies. Working together, but with independent responsibilities, parasite centrosome machines can dictate the scale and timing of pathogen replication.”

This groundbreaking understanding and novel discovery of the centrosome’s function leads to a critical conclusion: disruption of the centrosome machines – like cutting the cables between two computer systems – kills the parasite, Dr. White said.

Breaking any part of the highly efficient but highly fragile replication functions shuts everything down.

“They are literally Humpty Dumpty,” he added. “If they break, they can’t be put back together.”

With these findings and the new knowledge of the parasites’ vulnerabilities, Dr. White and his fellow researchers will delve into drug development.

That process could take anywhere from four to 10 years of further research and clinical trials before a new drug is on the market, he said. The length of time depends on whether the researchers hit upon effective application of prior-FDA approved cancer-related drugs or develop a new treatment from scratch.

Whatever treatment they develop, Dr. White stressed that it will be used in conjunction with other types of drug therapies.

Currently drugs used to treat malaria go after the pathogens’ metabolism, while the new research will seek to undermine the parasite’s foundation in enough of the spreading cells in order to allow the human immune system to fight back and not become overwhelmed, Dr. White said.

A major challenge today in parts of the world is the lack of access to drug treatments at all or until it is too late and the patient succumbs to malaria-related illnesses and brain hemorrhaging.

Because of the parasite’s high-adaptability, current drug treatments are constantly susceptible to the development of drug resistance, Dr. White said.

A potential global health crisis is unfolding as drug-resistant malaria continues to move across Burma, reaching the Indian border, according to British newspaper The Independent, commenting on a recent study in the journal Lancet. Doctors fear it will continue to spread and enter Africa, home to 90 percent of the world’s malaria cases.

Malaria caused about 207 million cases and 627,000 deaths in 2012, according to the Centers for Disease Control and Prevention. About 3.2 billion people, or half the world’s population, are at risk of malaria, according to the World Health Organization.

Dr. White said that this study, which he called the first for a USF Health laboratory in publishing original research in PLOS Biology, will help get more potential treatments in the pipeline.

“The more we understand their vulnerability,” he said of the parasites, “the better chance we can keep that pipeline full.”

The study was supported by a grant from the National Institute of Allergies and Infectioius Disease (NAID), National Institutes of Health.

“A Novel Bipartite Centrosome Coordinates the Apicoplexan Cell Cycle,” Elena S. Suvorova, Maria Francia, Boris Striepen and Michael W. White, PLOS Biology, March 3, 2015; DOI:10.1371/journal.pbio.1002093.

USF Health’s mission is to envision and implement the future of health. It is the partnership of the USF Health Morsani College of Medicine, the College of Nursing, the College of Public Health, the College of Pharmacy, the School of Biomedical Sciences and the School of Physical Therapy and Rehabilitation Sciences; and the USF Physician’s Group. The University of South Florida is a Top 50 research university in total research expenditures among both public and private institutions nationwide, according to the National Science Foundation. For more information, visit http://www.health.usf.edu

Contact:

Anne DeLotto Baier
abaier@health.usf.edu
Tel: 813-974-3303

Catching Up With 3 Rare Disease Families

Four-year-old Eliza O’Neill’s viral videos, the subject of my last two blog posts, continue to dominate the news media with another appearance on The Today Show June 17. Hopefully, her family’s fight to fund gene therapy for her rare disease, Sanfilippo syndrome type A, will focus more attention on the entire rare disease community – 30 million people in the U.S. alone. That’s a lot of families. Four years ago, I spent the summer getting to know the families whose stories became my gene therapy book. Thanks to social media we’ve stayed in touch, and I’ve met many others. All continue to astonish me. Here’s a catch-up with three families featured in past posts. Laura King Edwards ran the Thunder Road half marathon blindfolded, in honor of her sister Taylor. Beside her is Dr. Steve Gray, PI of gene therapy trials for two brain diseases. RUNNING BLIND TO BATTLE BATTEN DISEASE Laura King Edwards posted at DNA Science a year ago about her younger sister Taylor, now 15, who was diagnosed with ceroid lipofuscinosis, neuronal type 1 – aka Batten disease – when she was 7. Recalls Laura: “In the worst hour of our lives, we learned that my bright-eyed, golden-haired, intelligent sister – a second grader who loved to sing and dance and run and play – would go blind, have seizures, and lose the ability to walk, talk, and swallow food. She would deteriorate … confined to a wheelchair. She would have to have a feeding tube. Eventually, she would die – blind, bedridden, and unable to communicate.” Laura eloquently captures her sister’s life and her family’s efforts to help fund a gene therapy clinical trial at her blog, Write the Happy Ending. A post from last week is particularly heartbreaking. Rather than charting her sister’s decline with brain scans or mobility tests, Laura notes that in the 6 weeks between haircuts, Taylor lost the ability to walk. Last week, she had to be carried up the stairs to the hairdresser. This week, she’s in the hospital. To better get into her sister’s head, Laura runs races blindfolded. “I do the runs for a variety of reasons. I’ve always been a runner, and running helped me face Taylor’s illness when she was first diagnosed. After watching her run the first of two 5Ks with her Girls on the Run team despite battling Batten disease (and she was already blind at that point), I started running in her honor. I mainly run for Taylor to raise awareness, but my runs have also raised money for Taylor’s Tale. The Thunder Road half marathon I ran with Dr. Steve Gray in November raised money for the (gene therapy) project at the University of North Carolina. I’ve run 18 races for Taylor. Thunder Road was the only race I ran blind, but I went on 18 blind training runs to get ready for it. 635205790291677074During my months of training to become a blind runner and far more so in the months following the race, my sister slipped farther down the chasm of Batten disease. It is a deep, dark chasm. There are no footholds for climbing out, and some days, no light reaches her ledge. And yet, each day she teaches me something new about courage; each day, she imparts some great piece of wisdom without having to say anything at all. My next challenge is to run a race in all 50 states for Taylor to continue spreading awareness of Batten disease and build support for the rare disease community. I’m kicking it off this summer!” HANNAH’S HOPE AND LOVE BALL Ten-year-old Hannah Sames also has a very rare inherited disease of the nervous system, giant axonal neuropathy (GAN). DNA Science told her story about a year ago too. In GAN, intermediate filaments composed of a protein called gigaxonin overgrow and run askew, hampering nerve function. Hannah is very slowly losing mobility, and suffers from kidney stones and visual loss, as the lack of gigaxonin in various body parts makes its presence known in ebbing motor and sensory functions. Dr. Gray (behind Laura in the photo above) began working on gene therapy for GAN before he took on the Batten disease project, and the GAN trial is set to begin within the next few months at the NIH Clinical Center. The trial is largely possible due to the constant networking, meeting-holding, and fundraising efforts of Hannah’s family – parents Lori and Matt, and sisters Reagan and Madison. Their Hannah’s Hope Fund (HHF) was born in the days following the diagnosis in 2008. The highlight is the annual ball, held in February in snowy Albany, NY, near the Sames (and my) home. From Lori: Doris Buffett's Sunshine Lady Foundation donated $500,000 in matching funds to Hannah's Hope Fund for GAN. “The Hope and Love Ball began 5 years ago when friends, Todd and Beth Silaika and Tim and Lee Wilson, approached us with the idea. The first formal gala in 2010 netted $90,000 and was a Valentine theme, fitting for February. Other themes followed: Monte Carlo, Mardi Gras, Midnight in Paris, and Candyland this year, which netted more than $165,000. In 2010, HHF was awarded a $500,000 all-or-nothing matching challenge grant from Doris Buffett’s Sunshine Lady Foundation. The deadline to raise the funds was the night of the Ball. Snow kept Ms. Buffett (Warren’s sister) away the evening when more than 450 HHF supporters celebrated the success of the $1.2 million, 6-month “Hope for a Million” fundraising campaign. Ms. Buffett was the highlight of the event the following year. To date, HHF has raised $6 million in 6 years, grassroots, with the vast majority of funds spent on the GAN gene delivery Investigational New Drug (IND) work. The FDA placed the protocol on “Active” status at the end of May, awaiting IRB approval of the GAN gene delivery system. Then trial recruitment can begin. Unfortunately, Hannah, the inspiration of HHF, has a homozygous deletion mutation. She isn’t a candidate for the phase 1 trial because only missense mutation patients will initially be included. Hannah is awaiting the results of a non-human primate study aimed at inducing tolerance to an intracellular transgene in the CNS. If tolerance is achieved, it will likely be 10 months to a year before Hannah can receive gene delivery.” (Hannah doesn’t make gigaxonin at all, and so introducing it into her spinal cord, via healthy genes in viral vectors, could trigger an explosive immune response. The other kids who will be in the trial make abnormal forms of the protein, and so their immune systems are already alerted that gigaxonin is a “self” protein.)

BIKE THE BASIN FOR CURING BLINDNESS Michael and Mitchell Smedley and their friends brainstormed the Bike the Basin event. A few months ago at DNA Science, Kristen Smedley told how she and her husband Mike assembled a research team to pursue gene therapy for the CRB1 form of Leber congenital amaurosis, which has robbed their sons Michael and Mitchell of sight. But the boys are more interested in having fun than recruiting researchers, so they dreamed up the hugely successful Bike the Basin event, a half-mile race at the Northampton Civic Center Basin in Bucks County, PA. Kristen continues. “Back in summer 2011 when the Curing Retinal Blindness Foundation launched, I asked my kids to come up with a fundraiser that could get their friends involved and start getting the word out about our big mission. I wanted my boys to take the lead because while it’s nice that so many people want to help them due to their blindness, my guys need to be able to show the world that they can help themselves. We gathered about 15 of their closest friends at my kitchen table and the boys pitched their idea of a bike event fundraiser. The kids brainstormed ideas of how to make it work (with parents taking notes and serving lots of ice cream) and Bike the Basin was born! Just under three months later, the first event raised $20,000. The first three BTB events raised just over $200,000 combined, and the goal for 2014 (Oct 5th) is $250,000. We’ve raised about $80K so far!” LOOKING AHEAD Hannah and her sisters and parents. The families who raise funds for gene therapy clinical trials begin with their own relatives in mind and perhaps as a way to channel their anxiety and fear into something productive. But their generosity extends much farther. As rare disease-based communities form and strengthen, certain individuals emerge as catalysts. Laura King Edwards, Lori Sames, and Kristen Smedley are three. Gene therapy will almost certainly be too late for Taylor, and possibly for Hannah. But the Smedley boys may one day be able to see. And Eliza O’Neill may find her way into a clinical trial before Sanfilippo syndrome darkens her sunny childhood, thanks to the efforts of the media to share her story, and the kindness of so many strangers. But Eliza is one child, representing one unicorn. There are so many more. Whatever the future holds, the efforts of these brave families will reverberate for years to come, measured in the numbers of lives improved or saved.