Highlights of the XIIIth International Symposium on Amyloidosis

University Medical Center Groningen, The Netherlands
May 6-10, 2012

The XIIIth International Symposium on Amyloidosis took place in Groningen, The Netherlands from May 6-10, 2012, hosted by Dr. Bouke P. C. Hazenberg and his colleagues.  The Symposium was entitled From Misfolded Proteins to Well-Designed Treatment and focused on research on amyloid fibril formation, diagnostic techniques, and treatments for light chain (AL) and familial (AF) amyloidoses, including new treatments and gene therapies.  It was a busy four days packed full of talks, posters, and panel discussions.  There were a record number of participants, more than 400, of which almost 25% were students, trainees, or young investigators. All of the major medical centers involved in amyloidosis research in the United States were represented, including scientists from the Mayo Clinic in Minnesota; Karmanos Cancer Center in Michigan; Indiana University; Memorial Sloan Kettering Cancer Center, NYU, and Einstein in New York; Tufts; University of Tennessee; University of Pennsylvania; City of Hope, Stanford, UCSF, UCLA, and the Scripps Research Institute in California; Cleveland Clinic in Ohio, Loyola Medical Center in Chicago; the National Institutes of Health; and others. It was truly an international meeting with participants from many other countries including The Netherlands, Italy, UK, Spain, Portugal, Japan, France, Germany, Belgium, Canada, Israel, Sweden, Norway, Bulgaria, Slovenia, Poland, Romania, Switzerland, Brazil, New Zealand, Denmark, Australia, South Korea, Cyprus, Argentina, Lithuania, Turkey, Mexico, Malaysia, Ukraine, and the Czech Republic.  It was inspiring to see the interest in amyloid research extending around the world.  We benefited greatly from the exchange of basic and clinical research information with other scientists, and importantly, developed new collaborations that have potential to enhance the pace of discovery.

The Boston University Amyloid Treatment and Research Program was well-represented with 15 scientists and trainees, who made a total of 20 presentations.  In addition several of our group chaired sessions and gave “state of the art” and “perspective” lectures.  On Monday morning Dr. David Seldin chaired the opening session on “Fibril and Amyloid Formation” which featured talks by investigators from Germany, England, Denmark, United Stated, and Sweden on amyloid protein aggregation, fibril formation, and fibril toxicity.  In the next session Dr. Amy Leung, a post-doctoral fellow in Dr. George Murphy’s laboratory in the BU Section of Hematology and Center for Regenerative Medicine, presented her work that showed pluripotent stem cells could be made from fibroblasts taken from a patient with TTR amyloidosis and reprogrammed to make liver, heart, and nerve cells. Furthermore, the TTR amyloid protein produced by the new liver cells showed a toxic effect on the heart and nerve cells, which could be abrogated by small molecule stabilizers of TTR such as diflunisal.  This system provides a “patient-specific” model that will help us understand the diversity of ATTR disease. This outstanding work was given an award for best presentation by a young investigator.  Also on Monday Dr. Jennifer Ward had a presentation on research that showed that treatment with the antibiotic doxycycline can disrupt amyloid fibrils in vitro, and prevent amyloid fibril formation in transgenic mice.  This work is the basis for a new clinical trial for our patients.

Clarissa Koch
Clarissa Koch

In the plenary session on TTR amyloidosis, Dr. Lawreen Connors presented the clinical features, laboratory results and survival in the largest group of patients ever studied with age-related amyloidosis.  These patients are part of her NIH-sponsored study to investigate the natural history of the disease and to identify biochemical markers and prognostic factors.  Michael Greene and Clarissa Koch, both doctoral students of Dr. Connors’, had poster presentations on studies of normal and mutant type transthyretin protein.  Michael Greene reported on the interaction of transthyretin with the chaperone protein, clusterin, that added to the understanding of why the two proteins deposit together.  Clarissa Koch reported on her research showing the toxic effect of mutant and wild type transthyretin on cultured cardiac cells, and the beneficial effect of adding doxycycline to the cell culture. 

Dr. Flora Sam, one of the Amyloid Program cardiologists, presented results of cardiac pulmonary exercise testing in patients with the age-related type of transthyretin amyloidosis that suggested similarities between patients with TTR amyloidosis and patients with cardiomyopathy due to other causes.  In a second presentation, Dr. Sam showed that using new cardiac biomarkers, metalloproteimases, she could differentiate cardiomyopathy due to TTR amyloidosis and AL amyloidosis.

Dr. Seldin gave the state of the art lecture in the session on design of targeted molecules and innovative drugs.  He reviewed the progress of amyloid research laboratories and pharmaceutical companies towards designing targeted therapies for amyloidosis of all types; the rapid pace of drug discovery in recent years gives new hope for treatment of all types of amyloidosis.  Targeted therapies are those that are designed specifically to inhibit the fibril formation of an amyloid precursor protein, examples are diflunisal or tafamidis for TTR amyloidosis and eprodisate for AA amyloidosis.  In this session Dr. John Berk presented the Diflunisal Trial and compared the demographics, baseline neurologic staging, and adverse events with those of the Tafamidis Trial (Pfizer).  Final results of the Diflunisal Trial must await the study’s completion at the end of this year. Dr. Berk also masterly summarized the challenges of developing new therapies for ATTR in a perspectives talk on Wednesday.

In a plenary session Dr. Vaishali Sanchorawala presented data demonstrating that the risk of a second malignancy in patients with AL amyloidosis treated with lenalidomide is very low. In poster sessions, Dr. Sanchorawala presented the results incorporating bortezomib into high dose melphalan chemotherapy and stem cell transplantation as a highly effective treatment for AL amyloidosis.  In a third presentation, Dr. Sanchorawala, on behalf of an international group of investigators, reported the early phase results of MLN9708, an investigational oral proteasome inhibitor, from a trial which is still recruiting patients to evaluate the drug’s efficacy and toxicity.

Our amyloid internist Dr. Andrew Cowan reported on a series of patients with AL amyloidosis who presented with gastrointestinal involvement.  Twenty percent of the patients had localized disease only, and although they did not have any major therapy, none progressed to systemic amyloidosis.  Dr Cowan also presented data showing that the presence of amyloid deposits in the bone marrow did not impact on stem cell collection or on bone marrow blood cell engraftment after high dose chemotherapy. 

Graduate student Yanyan Lu, using mass spectrometry, presented structural data on the light chains in fat deposits.  She identified the precise amino acid changes and chemical modifications in the light chains  which are linked to the amyloid forming potential of the proteins.  Biophysicist Dr. Elena Klimtchuk analyzed the thermal stability of light chains, and demonstrated how changes in the structure of the amyloid light chain lead to misfolding and amyloid fibril formation.

Drs. Olga Gursky and Tatiana Prokaeva reported research studies on rare forms of amyloidosis. Dr. Gursky, a biophysicist, described the crystal structure of human apolipoprotein A-I and proposed how amyloidogenic mutations lead to amyloid formation.  Dr. Prokaeva reported on the clinical findings in three cases of a newly discovered type of amyloidosis due to deposition of apolipoprotein A-IV.

Dr. Martha Skinner completed her term as the President of the International Society of Amyloidosis (ISA).  She turned over the presidency of the society to Dr. Merrill Benson, leaving the society in excellent shape, with a 50% increase in membership, new electronic initiatives, and a flourishing journal under the Editorship-in-Chief of Dr. Per Westermark.  Dr. Skinner continues on the ISA Board as Immediate Past President.  Dr. Seldin was re-elected to a position on the ISA Board and appointed by Dr. Benson to Chair the new Membership Committee.

The meeting concluded with a half-day session for patients and their families, attended by approximately 200 Dutch patients and family members, and representatives of the Amyloidosis Support Groups in the U.S., Muriel Finkel and Paula Schmitt.  There, Dr. Skinner gave a talk on newer forms of amyloidosis, with her slides and summary translated into Dutch.

We are very grateful to Mr. and Mrs. Samuel Finkielsztein, the family of Mary Miliano, Mr. and Mrs. Peter Wellington, Mr. Charles Young, Mrs. Christine Wright, Mr. Robert Trotter, and the Amyloidosis Foundation for providing travel support.  We also thank Mr. and Mrs. Stephen Finkel and Mr. Howard Weitzman for “best clinical research” awards given to young investigators.  It is so important for the future of amyloidosis research to have support that allows students, fellows, and junior investigators to participate in the International Symposium and to receive recognition for their work.

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