Tag Archives: glycogen storage disease

World’s Top Researcher on Rare, Genetic Liver Disease Coming to Connecticut

ConnecticutChildrens.org

Leading pediatric endocrinologist and scientist, Dr. David A. Weinstein and his world-renowned Glycogen Storage Disease (GSD) Program is moving to Connecticut’s UConn School of Medicine and Connecticut Children’s Medical Center in early 2017.

Weinstein’s GSD Program, currently based at the University of Florida, is the largest clinical and research program of its kind in the world. Pediatric and adult patients living with the rare, genetic liver disease travel from across the globe for his team’s expert care, a number which totals more than 500 patients from 49 states and 45 countries.

He will serve as professor in the Department of Pediatrics at UConn School of Medicine and director of the GSD Program, a joint venture of UConn Health and Connecticut Children’s. UConn Health will be home to the GSD program’s research laboratories while the multidisciplinary team will provide comprehensive clinical care at Connecticut Children’s.

“Our team is very excited to be bringing the GSD program to Connecticut at UConn School of Medicine and Connecticut Children’s Medical Center,” said Weinstein. “This is a wonderful opportunity for the GSD community, our program and our institutions.”

Weinstein and his team are on the verge of testing in clinical trial the first gene therapy for GSD, developed in conjunction with Dimension Therapeutics of Cambridge, Mass. Testing of the gene therapy has shown great effectiveness in improving the health and life expectancy of canines born with the disease.

“UConn and Connecticut Children’s is the best place to house our GSD program and launch our clinical trial research,” said Weinstein. “I am very thankful to UConn and Connecticut Children’s for thinking outside the box and their dedication to making this dream a reality. Our team looks forward to working with these outstanding institutions to find better treatments and a cure for the devastating disease of GSD.”

GSD is a rare genetic childhood disorder with various forms (types 0, Ia, Ib, III, VI, IX, and XI) that impact the liver’s storage and release of sugar. It affects one out of every 100,000 people. Healthy livers store excess sugar from food for our body’s future energy needs and release it into our bloodstream when we need it as processed sugar enzymes known as glycogen. However, in GSD, the liver fails to breakdown glycogen into glucose causing the body’s blood sugar levels to drop dangerously low leading to seizure or potentially death, unless there is constant intake of glucose.

The condition was almost always fatal until 1971 when it was discovered that continuous glucose therapy could help these patients. Cornstarch therapy was introduced as a slow release form of glucose in 1982, and it allowed feeds to be spaced to every 3 – 4 hours. Thanks to cornstarch a greater number of patients with GSD are now surviving into adulthood. However, nearly 35 years later cornstarch is the only approved treatment available.

GSD patients are high risk for other health conditions because their bodies try to compensate for the liver’s dysfunction and find alternative energy sources. The harmful complications may include: kidney stones and failure, anemia, cardiovascular disease, elevated triglycerides, high cholesterol, liver tumors (both benign and cancerous), osteoporosis and inflammatory bowel disease.

“Finding a cure as soon as possible for GSD and a way to prevent its complications is critical,” said Dr. Juan C. Salazar, chair and professor of the Department of Pediatrics at UConn School of Medicine and physician-in-chief at Connecticut Children’s. “While the consumption of cornstarch every few hours is a lifesaving treatment for GSD patients, if one dose is missed it can be quite damaging and deadly. This potential burden is too great for any parent to stomach. We look forward to Dr. Weinstein and his team’s steadfast work to further advancing care and research for GSD children and finding a cure.”

“It is simply incredible that Dr. Weinstein and eight other members of his GSD program’s team are moving to Connecticut,” says Bruce T. Liang, dean of UConn School of Medicine. “It symbolizes their true commitment, selflessness and dedication – which mirrors ours– to GSD patients and stopping at nothing to find promising new treatments.”

Members of Weinstein’s prestigious GSD program planning to join him in Connecticut include: Youngmok Lee, Ph.D., the program’s basic science coordinator; Monika Dambska, MD, the clinical-research coordinator; Ana Estrella, MD, the laboratory coordinator; Kathy Ross, RD, LDN, the dietician; and the four registered nurses Gail Butler, Iris Ferrecchia, Betsy Potocik and Emma Labrador.

“Our goal is to very soon finally find a cure for GSD and its complications,” adds Weinstein. “The strong synergies and collaborative team science happening at UConn and Connecticut Children’s is world class and the most fertile ground to make a GSD cure reality.”

“It is good to be back in Connecticut,” shared Weinstein who attended college in the state and has cared for many patients here, especially in the West Hartford community. “For the last 20 years the Connecticut community has really been supportive of my ongoing GSD clinical research work,” said Weinstein.

Weinstein graduated from Connecticut’s Trinity College and earned his medical degree at Harvard Medical School. At Boston Children’s Hospital he completed his residency, chief residency, and fellowship in pediatric endocrinology and completed his masters in clinical investigation at Harvard and MIT. He became the director of the GSD program at Boston Children’s before moving to Florida in 2005 to pursue gene therapy on dogs with naturally occurring GSD.

Prior to joining UConn Health, Weinstein served as professor of the Division of Pediatric Endocrinology at the University of Florida and director of its GSD Program. As a physician-scientist he has authored over 80 articles and 26 textbook chapters on GSD. He is the recipient of the prestigious international humanitarian award, the Order of the Smile, for helping children around the world with GSD, a recognition shared with Pope John Paul II, Mother Teresa, Nelson Mandela, and Pope Francis. Weinstein was named one of the inaugural Goldwater Scholars in 1989. He is a former Jan Albrecht Award winner from the American Association for the Study of Liver Diseases, and he received the George Sacher Award from the Gerontological Society of America. Weinstein was inducted into the Rare Disease Research Hall of Fame in 2013.

In addition to local GSD community outreach, Weinstein’s team partners internationally with institutions and scientists in Argentina, Brazil, Canada, China, Faroe Islands, Israel, Mexico, and the Netherlands.

“Dr. Weinstein’s recruitment to UConn and Connecticut Children’s is yet another example of the strong ties between the two institutions, and more importantly our commitment to providing state of the art clinical care and promoting innovative research that benefits children and adults,” said Jim Shmerling, president and CEO of Connecticut Children’s.

Dimension Therapeutics to Develop Gene Therapy Treatments for Patients with Glycogen Storage Disease Type Ia (GSDIa)

NEWS RELEASE

Dimension Therapeutics to Develop Gene Therapy Treatments for Patients with Ornithine Transcarbamylase (OTC) Deficiency and Glycogen Storage Disease Type Ia (GSDIa)

Severe Forms of These Diseases Have Devastating Consequences for Patients and Families, with Few or No Effective Treatment Options

CAMBRIDGE, MASS., April 23, 2015 – Dimension Therapeutics, Inc. (“Dimension” or the “Company”), a rare disease company advancing novel, liver-directed treatments for diverse genetic disorders, today announced that the company is advancing programs to treat two rare diseases with often devastating outcomes for patients and their families – Ornithine Transcarbamylase (OTC) deficiency and Glycogen Storage Disease Type Ia (GSDIa). Both diseases, due to genetically inherited inborn errors of metabolism, usually present in the neonatal period or infancy, and can have grave effects on patients of all ages. For severe forms, there are few or no effective treatment options other than liver transplantation, leaving patients with significant unmet needs. Dimension is developing novel gene therapy approaches to replace the missing or faulty gene, correcting the underlying defect to restore metabolic function.

“In an important step for both patients and for Dimension, we are launching our first two liver-associated, metabolic disease programs to address rare disorders with the greatest needs and fewest treatment options, other than liver transplant. Transplants are often associated with significant risks both during the procedure and over the long term,” said Dimension’s CEO Annalisa Jenkins, MBBS, MRCP. “Our mission – working in collaboration with patient advocacy communities and with the world’s leading clinical investigators and advisors – is to rapidly and responsibly develop new therapies that can offer hope and better health to those patients in the greatest need.”

Dimension looks forward to continuing the work previously championed by advocacy organizations, including The Children’s Fund for GSD Research, which has funded much of the existing preclinical work in GSDIa. Eric Crombez, MD, Dimension’s Chief Medical Officer, commented, “Dimension is developing and strengthening partnerships with the patient communities, families, and physicians focused on improving the lives of patients affected by OTC deficiency and GSDIa. We will ensure that patient organizations, as key partners, will play an active role in developing these clinical programs.” The company anticipates commencing clinical trials in both patient populations in 2016.

Mark L. Batshaw, MD, Principal Investigator of the Urea Cycle Disorders Consortium (UCDC) and Physician-in-Chief of Children’s National Health System, stated, “In order to solve the most pressing issues in pediatric medicine, we encourage diverse constituencies to come together in a true spirit of collaboration. This approach has been critical to the success of programs at the UCDC, and we believe it will be paramount in addressing the needs of patients and families affected by OTC deficiency.”

David A. Weinstein, MD, MMSc, Director, Glycogen Storage Disease Program at the University of Florida, noted, “Our research program, the largest of its kind pursuing treatments for GSDIa, has dedicated substantial resources to enabling gene therapy, which we ultimately believe will be the most promising approach to long-term care of

patients with GSDIa. New therapies are critically needed, and I look forward to Dimension’s progress in advancing its gene therapy program into the clinic.”

Dimension’s Adeno-Associated Virus (AAV) Vector Platform

Dimension is advancing therapies based on a next-generation AAV platform that has demonstrated early validation and compelling preclinical in vivo proof of concept across multiple disease states in leading academic research centers. Dimension’s current efforts focus on AAV8 and AAVrh10, two forms of AAV vectors that selectively target liver cells and have been optimized to deliver missing intact genes in diseases associated with the

liver. Initial indications of positive net benefit of this approach in patients living with hemophilia B, plus demonstration of robust gene expression in multiple preclinical in vivo models and commercially viable novel CMC approaches, provide a strong foundation for Dimension’s proprietary programs.

Background on OTC Deficiency and GSDIa

OTC deficiency, the most common urea cycle disorder, is caused by a genetic defect in a liver enzyme responsible for detoxification of ammonia. Individuals with OTC deficiency can build-up excessive levels of ammonia in their blood, potentially resulting in neurological deficits and other toxicities. Neonatal onset disease in males is severe and can be fatal at an early age. The greatest percentage of patients experience late-onset disease, representing a clinical spectrum of disease severity. It is estimated that more than 10,000 patients are affected by OTC deficiency worldwide. Currently, the only curative approach is liver transplantation.

GSDIa, the most common glycogen storage disease, has significant unmet needs. Patients have a defective gene for the enzyme glucose-6-phosphatase, resulting in the inability to regulate blood sugar (glucose). If chronically untreated, patients develop severe lactic acidosis, progress to renal failure, and die in infancy or childhood. There are no approved pharmacological therapies, and no ongoing clinical development beyond dietary approaches. An estimated 6,000 or more patients are affected by GSDIa worldwide.

About Dimension Therapeutics

Dimension Therapeutics, Inc., is a rare disease company focused on developing novel treatments for devastating disorders associated with the liver and based on an industry-leading, extensively validated adeno-associated virus (AAV) platform. The company is advancing multiple programs toward clinical development, including: programs addressing unmet needs for patients suffering from OTC deficiency and GSDIa; a collaboration with Bayer HealthCare in hemophilia A, and a wholly owned program in hemophilia B, which is expected to enter clinical testing in the second half of 2015. Dimension has preferred access to multiple best-in-class AAV vectors from REGENXBIO, which founded Dimension with Fidelity Biosciences in October 2013. The Dimension team and senior advisors include biotech industry veterans and renowned thought leaders in gene therapy and rare diseases. For more information, please visit www.dimensiontx.com.

Dylan Siegel, left, has raised more than half a million dollars to help Jonah Pournazarian, right, his friend who suffers from a rare liver disease. (Credit: ABC News)

Boy Author Raises $750k For Sick Friend

by Sydney Lupkin (@slupkin)

Every morning at 3 a.m. Lora Pournazarian is awake to feed her 8-year-old son Jonah a mixture of corn starch and water through a tube in his stomach.

If she doesn’t, Jonah could die because he has a rare form of glycogen storage disease, a hereditary disorder that means his liver can store sugar but can’t release it, causing him to have dangerously low blood sugar levels that can result in seizures or even death.

“That’s huge anxiety every night,” his mother Lora Pournazarian told ABC News. “We go to sleep going, ‘We hope we don’t miss an alarm clock because he could die.’“

But Jonah’s parents aren’t the only ones looking out for him. His best friend from preschool, Dylan Siegel has his back, too.

Dr. David Weinstein, who studies and treats patients with glycogen storage disease at the University of Florida, was almost out of funding when he heard that Dylan wanted to help raise money to find a cure for the disease. Dylan was only 6 years old at the time, so Weinstein mostly just thought he was cute.

But Dylan had other plans. He wrote a book called “Chocolate Bar,” and explained to his parents “chocolate bar” means “awesome” to him. “Disneyland is so chocolate bar,” the book starts out. The last page says, “I like to help my friends. That is the biggest chocolate bar.”

Dylan’s project raised more than $750,000 in a little more than a year by selling the books for $20 each in all 50 states and 42 countries. Every cent goes to Weinstein’s lab.

“Boy, have I been shocked,” Weinstein told ABC News in September, when the book had crossed the $400,000 mark. “He’s raised more money for this disease than all the medical foundations and all the grants combined. Ever.”

When this story aired on ABC World News Wednesday night, “Chocolate Bar” had raised more than $500,000. Fewer than 24 hours later, it had raised an additional $250,000.

When asked where the two boys will be in 10 or 15 years, Dylan said, “High school, and probably his disease would be cured ’cause it’s not going to take like 15 years to be cured.”

That would be so chocolate bar.

Charlotte Jordan, 6, (left) with her sister Alexis Jordan, 10.

Gift of Hope

by Melanie Stawicki Azam

Florida Physician

For Lindsay Jordan, it was a mixed blessing when her daughter Charlotte was diagnosed with glycogen storage disease type 1a.

On one hand, the California mother finally knew why her 3-year-old little girl had been struggling to thrive since birth. At the same time, she faced the sobering reality that Charlotte had a rare genetic disease that could be fatal if not properly treated.

“It was a surreal experience, but I knew she’d been sick,” Jordan said.

Little did she know that Charlotte’s condition would take her to the other side of the U.S. for treatment and inspire her family to donate $1 million to UF to help find a cure for glycogen storage disease type 1a, also known as GSD 1a.

The Fry Foundation, which Lindsay Jordan’s parents, Stephen T. and Cynthia Fry, created, donated the money to establish The Charlotte’s Cure for Type 1a GSD fund. The money will support research geared toward finding a cure for the disease.

“Their gift is the biggest in the history of the program,” said David Weinstein, MD, MMSc, a professor of pediatrics and director of the UF Glycogen Storage Disease Program. “It allows me to focus on some of the programs we’re working on, including gene therapy.”

The UF GSD program is the largest of its kind in the world for care and research for the liver forms of GSD, such as type 1a. It follows more than 425 patients from 37 countries and all U.S. states.

GSD type 1, which affects about one in 100,000 children, impacts the body’s ability to correctly store and use sugar between meals.

After Charlotte was diagnosed with GSD 1a at her local hospital in California, she still struggled from complications related to the disease.

Charlotte met with Weinstein in November 2011 and thrived under his care. Now 6 years old, she visits him annually.

“He could have dedicated himself to anything and for him to pick this little–known disease and try to make a difference for these kids is amazing,” Jordan said.

Photo Credit:  Jordan Family Photo

A boy’s serious ailment required only a simple fix once it was diagnosed.

By Sandra G. Boodman

When she heard her younger son’s quavery cry of “M-o-o-o-m-m-m” drifting down the hall in the middle of the night, Jocelyn Mathiasen stiffened, braced for what lay ahead.

Sometimes the little boy would awaken just before dawn shaky and weak, complaining of hunger or thirst; after consuming something he would quickly recover. But on the bad nights Peter Dawson would spend hours lying on the floor of the bathroom clutching his stomach, vomiting intermittently and refusing to drink anything. It took him hours to rebound — and it was never clear what had made him so sick.

Mathiasen did not know what to make of these episodes, which at first were only mild and infrequent, blips in the life of her otherwise healthy child. But when Peter turned 5 in 2006 and the family moved to Easton, Conn., from Seattle, Mathiasen asked her new pediatrician whether the episodes were normal. Leveling a hard look at her, he told her that what she was describing was definitely not normal — and might signify a serious problem, such as juvenile, or Type 1, diabetes. But after tests for diabetes were negative, the search for the underlying cause of Peter’s odd problem floundered.

It would take nearly five years for a specialist eight states away to figure out what was wrong. The solution was a surprisingly cheap and prosaic remedy — but one that recently drew attention in an airport security line.

As an infant, Peter would periodically wake up in the morning in obvious distress, grabbing his bottle and sucking down the contents “in one gulp, like he was desperate,” his mother recalled.

“I didn’t worry too much about it because it didn’t happen often, and after he ate he seemed fine,” Mathiasen said. For some reason the episodes were worse when the family traveled. Mathiasen said she refrained from mentioning them to his doctor, not wanting to seem alarmist. “I was trying to be this relaxed mother,” she said.

After the test for diabetes was negative, the pediatrician referred Peter to a pediatric endocrinologist in New Haven. Once a tumor and several other disorders had been ruled out, the doctor settled on a diagnosis of reactive hypoglycemia: severely low blood sugar that occurs several hours after eating. She predicted that Peter would outgrow the problem when he hit puberty and recommended that he eat yogurt at bedtime: The protein would be slowly digested and would prevent his blood sugar from plummeting.

By 2007 Mathiasen had become increasingly uneasy. Despite the yogurt, Peter kept having episodes. She began keeping lollipops or Skittles in the house: A rapid hit of sugar seemed to help him recover faster.

After four incidents in four weeks, Mathiasen consulted a second pediatric endocrinologist. He admitted the first-grader to a hospital overnight, hoping to catch an episode, which could provide important clues. Peter underwent hourly checks; although his blood sugar dropped, the readings were not alarming.

When he was discharged the following morning, Mathiasen was told to continue the yogurt regimen; by now he was eating two heaping bowls at bedtime.

“It was a very, very disconcerting experience,” recalled Mathiasen, who had become increasingly convinced that waiting for the problem to disappear was not a solution. In the spring of 2008, Peter had a scary episode on a trip. The family had forgotten his bedtime yogurt, and he awoke shaky and incoherent. His parents gave him a lollipop and bundled him into the car; at the airport he vomited several times, reluctantly ate a cookie and then fell into a deep sleep on the plane. After he woke up he drank six glasses of milk, then seemed fine.

“At that point, I said we really need to figure out what’s going on here,” Mathiasen recalled.

In December 2008, Peter underwent a complete workup with the second endocrinologist, which provided no answers. Mathiasen had been monitoring Peter’s blood sugar when he woke; she found that readings on some days were very high, not low. Because nothing else seemed to fit, the endocrinologist suggested that Peter might have a rare condition: glycogen storage disease (GSD).

The inherited metabolic problem is a constellation of 14 disorders, ranging from mild to life-threatening, that result from the impaired regulation of glycogen, the stored form of glucose, which the body uses for fuel. DNA testing for the disease, which afffects about one in 20,000 people, according to Cincinnati Children’s Hospital, had recently become available. The doctor suggested that Peter undergo a test for a mild form of GSD that seemed to fit his symptoms. After several months, the family’s insurance company agreed to pay for it.

Months went by — genetic tests often take a long time — and Mathiasen, who had heard nothing, began calling the doctor. In October 2009, he sent her an apologetic e-mail: The lab had lost the sample before the DNA test could be performed.

“My clinical impression [is] that this glycogen storage disease diagnosis is highly unlikely,” he wrote. He proposed that Peter undergo a procedure to implant a device that continuously monitors glucose levels to see if he might have a rare condition called exercise-
induced hyperinsulinism, or low blood sugar after exercise, because some episodes had occurred after skiing.

Mathiasen, who was then spending hours online researching Peter’s symptoms, assisted by a friend who is an endocrinologist in Baltimore, decided that maybe GSD wasn’t so unlikely. The name of one expert kept popping up: pediatric endocrinologist David A. Weinstein, who heads the Glycogen Storage Disease Program at the University of Florida College of Medicine.

One evening in February 2010, Mathiasen sent Weinstein an e-mail. She described Peter’s case and said she’d hit a brick wall. Did Weinstein have any suggestions?

Soon afterward Weinstein called Mathiasen back. He agreed that Peter might have GSD and recommended the family buy a monitor that could check the level of ketones, potentially dangerous substances that can cause nausea and vomiting and, at sustained high levels, death. Ketones, produced when the body uses fat rather than glucose for energy, would be an important clue to a diagnosis; ketotic hypoglycemia is a symptom of some forms of GSD. Testing over the next few months showed that Peter’s ketone levels were sometimes dangerously elevated; his body was literally starving for energy.

A cheap treatment

Weinstein agreed to accept Peter as a patient and to perform DNA testing. He advised Mathiasen to replace the bedtime yogurt with a drink containing several tablespoons of cornstarch. One of the cheapest ingredients in a supermarket at less than $2 per box, cornstarch provides slow-release glucose. Within weeks, Peter’s episodes largely disappeared.

In June 2011, after the first DNA test proved to be negative, Peter and his mother flew to Florida to see Weinstein, who observed Peter having an episode in the hospital. Peter was then tested for two other generally mild forms. Six months later, just as the family was departing for a holiday trip, Weinstein called with the diagnosis that had taken five years: Peter’s DNA test revealed he had a type of GSD that is caused by a deficiency in the liver enzyme phosphorylase kinase.

GSD has received scant attention and is, in Weinstein’s view, underdiagnosed; in part, this is because there is little incentive to develop sophisticated treatments, since cornstarch has proven effective for certain forms of the disease if detected early enough. “One of the problems we’ve had is that treatments are not fancy — cornstarch is a gravy thickener,” observed Weinstein, who said his program has treated 400 children from 31 countries and nearly every state. “Most people feel that if we’re not treating it with a fancy medication, it’s not a real medical condition,” and in some cases schools don’t take it seriously.

Although Peter’s type of GSD tends to be mild and can be controlled with a combination of careful monitoring, a high-protein diet and cornstarch, Weinstein said he has seen babies who needed liver transplants. “There’s a variability we don’t quite understand” in the severity of the disease.

Peter, who will soon turn 11, has been told that when he is older he must completely abstain from alcohol, because it could damage his liver. He takes cornstarch dissolved in a drink at bedtime every night and also during the day if he is especially active. And he always travels with several boxes of the cheap white powder and a scale to measure it. For children who travel by air, the cornstarch regimen can raise questions. Recently, Mathiasen said, her family was stopped at a New York airport, where airline security guards tested Peter’s cornstarch. (Weinstein said he offers patients a letter explaining the therapy.)

The strange, shaky episodes are a thing of the past, and Peter is living a normal life. “Now I know what’s wrong, how to treat it, what’s going to happen next and I have a doctor to call,” Mathiasen said. “It’s such a relief.”

Photo Credit:  Family Photo

Every Minute Counts.

Please visit Crazy Days Designs to purchase your very own “Every Minute Counts” pendant and chain.

The hand stamped washer and 24" ball chain necklace are made of stainless steel and the alarm clock is sterling silver.  The price is $30.00 plus $5.00 s/h and all proceeds from the sale of these pendants will be used for Glycogen Storage Disease research.  These pendants are “hand made with love, just for you!” by a mother of two little GSD boys, so she definitely knows the meaning of Every Minute Counts.