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Updates From the ICHG/ASHG 61st Annual Meeting

	The treatment of Gaucher disease is poised to enter a new era as a result of advances in the understanding of the cellular pathways at work in the disorder, according to Pramod Kumar Mistry, MBBS, PhD, whose research is helping to chart the future.

	Mistry said researchers have been exploring the reasons that patients with Gaucher disease face an increased risk of multiple myeloma and other cancers, osteoporosis, and Parkinson disease. Neurodegenerative disorders are particularly pronounced in patients with type II and type III Gaucher disease.

	He said enzyme replacement therapy (ERT ), introduced approximately 20 years ago, has made a dramatic difference for patients once consigned to disabling diseases and premature death, but that they still face a high-risk burden.

	“The new generation of patients are doing extremely well, but they do carry ongoing risks. Those observations have prompted us to go back to the bench to do investigations into mechanisms of Gaucher disease,” Mistry said in an interview during ICHG/ASHG 2011. “We want to understand how these pathways intersect.”

	Mistry is chief of Pediatric Gastroenterology & Hepatology, medical director of the Pediatric Liver Transplant Program, and a professor of Pediatrics and Internal Medicine at Yale University School of Medicine, New Haven, Conneticut. He also is the director of the National Gaucher Disease Treatment Center.

	The center is playing a major role in the development of eliglustat tartrate, a novel oral therapy for type I Gaucher disease that is aimed at reducing levels of lipids before they can build to harmful elevations.

	Last year, Mistry’s team announced the development of a new mouse model after nearly 2 decades of work. The glucocerebrosidase gene, GBA1, was deleted from the mouse, giving researchers a powerful tool to explore the cellular pathways of the disease (

	Mutations in the GBA1 gene cause enzyme deficiencies that result in a lipid buildup in the liver, spleen, bone marrow, and nervous system.

	“We were among the first groups in the world to develop a mouse model that faithfully replicates human disease, and the advantage of having a model like that is that we can really begin to define the molecular steps from the buildup of the lipids to the clinical manifestations,” said Mistry.

	He said researchers no longer believe that Gaucher disease affects only the macrophage cell type (white blood cells within tissue). Instead, he said, it affects all cells in the body.

	“Gaucher disease is not just a passive buildup of this fatty substance in cells. It’s not as if the cells are constipated with this fatty material,” said Mistry. “Once the fatty material begins to accumulate, it alters—dramatically&mdash;the entire genetic program of the cell.”

	Mistry is particularly optimistic about the prospects for eliglustat to improve treatment. He said the small molecule nature of the drug would make it easier to produce than the biologic, injectable ERT , and that it would be more accessible for patients, particularly those in lessdeveloped countries.

	Eliglustat also employs a mechanism of action that differs from ERT , he explained. “Enzyme replacement therapy is targeted just to the macrophage, and it goes to the macrophage and breaks down the lipid that has accumulated,” he said. “Eliglustat works by reducing the level of this lipid that builds up in macrophages, but it also reduces the level of lipid that builds up in other cell types.”

	Mistry believes eliglustat eventually may prove to be therapeutic not only for Gaucher disease, but also for other LSD s such as Fabry disease, and perhaps even in certain cancers.

	“What is really exciting about this particular molecule is that it is already being engineered in a form that may be able to cross the blood—brain barrier, and the biggest burden of lysosomal disease are the diseases that affect the brain and cause neurodegenerative disease,” he said.

	“I think that the next era is going to see us not only being able to treat all of the disease in patients suffering from Gaucher disease, but we also will be able to use some of these molecules in a subset of patients with cancers,” said Mistry.

The treatment of Gaucher disease is poised to enter a new era as a result of advances in the understanding of the cellular pathways at work in the disorder.

Noted Researcher Sees ERT as Remarkable Beginning

	Rogério Vivaldi, MD, has vivid memories of the first patient with Gaucher disease ever treated in Brazil with enzyme replacement therapy (ERT ). The patient was a shy 14-year-old boy struggling to play soccer, even though he had bone pain, an enlarged spleen, and bleeding events due to low platelet levels.

	After several months of ERT, the patient had grown nearly 22 inches, his spleen and platelets were normal, and he was no longer hesitant to speak.

	Today, that patient is in his early 30s, is healthy, and recently was married.

	And Vivaldi, the physician who treated him, is now Head of Rare Diseases at Genzyme Corporation, which developed the drug that altered the lives of both the patient and his doctor.

	“He had his life transformed by therapy, but at the same time that transformed my life because it showed me that good medicines could really transform and change the natural history of a disease,” said Vivaldi in an interview during ISGH/ASHG 2011, where Genzyme commemorated its 30-year history with a dinner symposium.

	“After 20 years, it’s amazing how people sometimes even forget what the disease was,” he said. “I still remember the very difficult days when I was accompanying people to funerals because not everybody was succeeding, or because not everybody had therapy.”

	Vivaldi, who launched and built Genzyme Brazil, is focused these days on the next chapter in the company’s history. He has been with Genzyme for 16 years, attaining his current executive team position in November.

	Since its founding in 1981, the Cambridge, Massachusetts- based company has grown from a fledgling biopharmaceutical start-up with 21 employees to a company with a worldwide workforce of approximately 10,000 people and $4.05 billion in revenues. Sanofi-aventis acquired Genzyme in April.

One priority facing Vivaldi is remedying manufacturing issues that have affected the supplies of 2 drugs in its product line for patients with lysosomal storage disorders: Cerezyme® (imiglucerase for injection), the foremost ERT for type I Gaucher disease, and Fabrazyme® (agalsidase beta), used to treat Fabry disease.

	The company has informed healthcare providers that Cerezyme supplies will be tight through January, with dosing schedules affected for some patients, and that supplies of Fabrazyme will be “significantly restricted” while the company works to get a new manufacturing facility in Framingham, Massachusetts, operational.

	The plant is expected to begin producing Fabrazyme during the first quarter of 2012, enabling the company to improve production of Cerezyme, which now shares a facility with Fabrazyme.

	The production process for ERT s is challenging, Vivaldi noted. Cerezyme, for instance, is produced in bioreactors containing Chinese hamster ovary cells that express the needed enzymes from amplified human DNA (

	“It is very complex when you do biologic manufacturing because (the output) depends on the cell,” said Vivaldi. “The cells are the ones that are producing the proteins. You never know exactly how much will be produced.”

	Vivaldi said Genzyme remains committed to developing drugs for patients with rare genetic diseases, and that the company maintains charitable programs for those who cannot afford the therapeutics.

	“This is a commitment beyond the supplies, a commitment that we will continue to do what we did for years,” said Vivaldi.

	Although the number of patients with such disorders is minuscule compared with those whose diseases are broad public health problems, their needs are pressing and deserve attention, Vivaldi indicated.

	“Someone who has a rare disease has the same right as someone who has malaria or tuberculosis,” he said. “…These patients deserve to be treated.”

Rogerio Vivaldi, MD, has vivid memories of the first patient with Gaucher disease ever treated in Brazil with enzyme replacement therapy.

Same Mission, New Role for Genzyme Executive: Head of Rare Diseases Committed to Patients

	The 12th International Congress of Human Genetics attracted approximately 7500 people this year, including scientists, clinicians, and industry representatives, a turnout that organizers said constituted the largest-ever gathering in the field. The American Society of Human Genetics hosted the congress in partnership with the International Federation of Human Genetics Societies. ICHG/ASHG 2011 was held at the Palais des Congrès de Montréal, Canada, October 11-15.

	The mood of the congress often seemed buoyant as researchers discussed the doors that technology is helping to open in the study of inherited disorders.

	“This is an extremely exciting time for human genetics,” said Evan Eichler, PhD, a professor of Genome Sciences at the University of Washington in Seattle, during a press briefing. “It is arguably one of the most transformative moments that we’re facing right now, with the ability to actually sequence the complete spectrum of genetic variation from common to rare, irrespective of class, type, and frequency, systematically across different genomes.”

	Such enthusiasm was shared during discussions of lysosomal storage disorders (LSDs), a category of more than 40 rare metabolic conditions. Most LSDs are inherited conditions, such as Tay-Sachs disease, Gaucher disease, and Fabry disease.

	LSDs occur when a particular enzyme or component in the lysosome organelle is deficient or malfunctions, causing the accumulation of undigested or partially digested macromolecules.

Nearly every bodily system can be affected, including a variety of hematologic functions.

	As a result, hematologists often treat patients with LSDs, particularly those with Gaucher disease, whose symptoms can include bone disease, chronic thrombocytopenia, and coagulation deficiencies.

 Initially, clinicians may suspect the patient has an oncologic condition such as leukemia or lymphoma.

	Major changes have occurred in the past 20 years for patients with Gaucher disease, however, according to Richard Moscicki, MD, head of Clinical Development, Genzyme Corporation.

	“It has been a real journey, not just for myself personally, but for the entire field. When we entered this area with the first enzyme replacement therapy, we didn’t know what to expect long term, and over this 20 years, since the first one was approved in 1991, we have seen that it has made a huge difference in patients’ lives.” Moscicki said that when he goes to a patient meeting today, as opposed to when he started 19 years ago with Genzyme, he no longer sees patients in wheelchairs.

	Therapies for other conditions that are similar to Gaucher disease have since been developed, and despite the challenges of treating such complex conditions, researchers at the congress reported making strides in the understanding of LSDs, as well as in screening and treatment of patients.

			Fong C. Lysosomal storage disorders. In The Merck Manual Online. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2010. Updated February 2010. Accessed November 18, 2011.

			Kruer MC, Steiner RD. Lysosomal storage disease. In Kao A, ed. Medscape Reference. New York, NY: WebMD LLC; 2011. 

http://emedicine.medscape.com/article/1182830-overview

. Updated June 28, 2011. Accessed November 18, 2011.

			About lysosomal storage disorders: presentation and progression. Lysosomal Learning Website. 

http://www.lysosomallearning.com/healthcare/about/lsd_hc_abt_presentation.asp

			Making a diagnosis. Gaucher Care Website. 

http://www.gauchercare.com/en/healthcare/diagnosing/MakingADiagnosis.aspx#P56_2114

The mood of the ICHG/ASHG 2011 congress often seemed buoyant as researchers discussed the doors that technology is helping to open.

Lysosomal Storage Disorders: Marking Milestones and Moving Forward

Gregory A. Grabowski, MD, professor, University Cincinnati, Department of Pediatrics, director, Division of Human Genetics, director, Medical Genetics Training Program, Cincinnati Children's Hospital Medical Center, discusses the immense benefit that enzyme therapy provides to patients with Gaucher disease, a debilitating lysosomal storage disease.

Dr. Grabowski Explains the Effects of Enzyme Therapy

Dr. Gregory Grabowski, from the University Cincinnati, Explains the Effects of Enzyme Therapy

Pramod Kumar Mistry, MBBS, PhD, is chief of Pediatric Gastroenterology & Hepatology, medical director of the Pediatric Liver Transplant Program, and a professor of Pediatrics and Internal Medicine at Yale University School of Medicine, New Haven, Conneticut. He also is the director of the National Gaucher Disease Treatment Center.

Pramod K. Mistry, MD, PhD, from Yale University, discusses Gaucher disease

Dr. Mistry Discusses His Experience With Gaucher Disease

The dramatic benefits of enzyme therapy became increasingly evident 5 years after the therapy came into the market. While delivering a talk at a patient conference Grabowski recalls noticing the shift in the appearance of the patients; they no longer carried crutches and looked healthy. The way patients looked before enzyme therapy was gone and would remain gone.

Although the costs are a concern the benefits of the treatment is remarkable. He heralds the Gaucher disease enzyme treatment as amazing with very few problems associated with the treatment.

Grabowski remarks that it is an amazing experience to see patients get better. In the past 20 years he’s witnessed 1200-1300 patients become healthy after receiving the treatment. The comparison of benefits between the enzyme therapy and the supportive therapies used before is remarkable and is a total transformation in healthcare.

Dr. Gregory A. Grabowski from Cincinnati Children's Hospital Medical Center Explains the Effects of Enzyme Therapy

Updates From the ICHG/ASHG 61st Annual Meeting | Conference

Noted Researcher Sees ERT as Remarkable Beginning

Same Mission, New Role for Genzyme Executive: Head of Rare Diseases Committed to Patients

Lysosomal Storage Disorders: Marking Milestones and Moving Forward

Dr. Grabowski Explains the Effects of Enzyme Therapy

Dr. Mistry Discusses His Experience With Gaucher Disease

Dr. Grabowski Explains the Effects of Enzyme Therapy