International Consensus Conference

The Diamond Blackfan Anemia Foundation (DBAF) is a proud supporter of the Daniella Maria Arturi Foundation’s DBA International Consensus Conference. The DBA International Consensus Conference provides interaction with the international scientific and physician community from around the globe which has allowed them to become more directly involved in efforts to improve patient care. Coordination of the international experts in this field has resulted in a Clinical Care Consensus Document offering the latest opinions on how to diagnose and manage the care of patients with DBA.

Summary of the 2012 International Consensus Conference from DBAF’s Research Director, Steven Ellis, PhD:

The 12th Diamond Blackfan Anemia International Consensus Conference was held March 17-19th in Battery Park in New York City. The conference began with a kickoff dinner held in a restaurant club room which was actually an old vault in a former bank in lower Manhattan. The intimate setting set the stage for a meeting known for its blend of physicians, scientists and other interested parties who freely exchange ideas in a highly collaborative environment. The keynote speaker at the dinner was Jeff Bond, father of four-year old Angus Bond, who was diagnosed with DBA at 8 weeks of age. Like many, Mr. Bond told of the initial anguish he and his wife Jessica had in trying to understand his son’s diagnosis and how from this experience the seeds were sown for the Captain Courageous Foundation of Australia, one of a growing number of international foundations supporting research on Diamond Blackfan anemia. The Bonds were warmly welcomed into the broader DBA community.

Sunday, March 18th

Plenary Session “Assessment of iron loading in Diamond Blackfan anemia”.

This session was particularly timely given recent deaths in the DBA community from complications of iron overload in transfusion dependent patients.

Dr. Thomas Coates (Los Angeles) gave the first of two talks on iron loading relying on his considerable experience with thalassemia patients. He described studies indicating that certain tissues, like the heart, take up iron by mechanisms different from that in the bone marrow and the liver, and the rates at which tissues accumulate iron also differ. Consequently, a surrogate measure for tissue iron like serum ferritin is a totally unsatisfactory way to monitor iron content of different tissues. Instead, new imaging technologies are improving the way iron content in individual tissues can be monitored allowing much better assessment of the effectiveness of chelation therapies. Adherence to treatment regimes continues to be a major problem in older patients. Effective iron monitoring and close cooperation between patients, parents, and physicians is essential for reducing mortality.

His talk was followed by Dr. Ellis Neufeld (Boston) who spoke on the strengths and weaknesses of current chelation therapies. He indicated that there is still a need for improved chemical chelation therapies. He provided some encouraging data on a new chelator currently undergoing early phases of testing.

[Note: the ICC also had a session where research was presented in a poster format. I will not discuss the posters separately, but instead describe them briefly if they complement one of the session talks. Posters will be presented in italic.]

Dr. Josu de la Fuente (London) reiterated themes raised by Drs. Coates and Neufeld in his poster on iron loading in the UK DBA population. He showed data indicating a number of patients had clinically significant iron overload even though their ferritin measurements indicated adequate iron chelation. Again, these data indicate the need for more effective means of monitoring tissue iron content in DBA patients receiving transfusion therapy.

Developmental Biology

This session focused on the timing of DBA presentation during mammalian development.

Dr. Lydie Da Costa (Paris) gave a talk on DBA presentation in a developing fetus. One of the more puzzling aspects of DBA is why it typically presents in the first year of life, or in other words, why it doesn’t present in the developing fetus. Previously, published studies on fetal deaths thought to be as a result of DBA lacked a definitive genetic diagnosis. Dr. Da Costa’s study provided the first documented evidence of a ribosomal protein mutation associated with signs of anemia in the developing fetus. These studies indicate that DBA should be considered in cases where there is evidence of fetal anemia, but also raise the question of why many DBA patients escape anemia during fetal development and present after birth.

Dr. Johnson Liu (New York) spoke on work using mouse embryonic stem cell models of DBA comparing the differentiation of two cell lines each of which was mutated in a different mouse gene known to be affected in DBA. The results presented indicated that depending on the gene mutated there could be different effects on differentiation, providing a potential rationale for the heterogenous clinical presentation in humans affected in DBA. Trying to link clinical features of DBA with the underlying genetic defect has been a holy grail in DBA research. Dr. Liu’s presentation gave a very nice segue into the session on genetics which followed.

Genetics

his session focused on gene discovery, new approaches to gene discovery in DBA, and the identification of genes that may modify the manner in which DBA presents and responds to therapy in different patients.

Dr. Hanna Gazda (Boston) began this session by describing the first DBA gene that does not encode a ribosomal protein. As has been this case in all my meeting reports, I am unable to go into too much detail on the talks given as unpublished work is frequently presented. Suffice it to say, that this discovery raised quite a stir and set the stage for large scale projects interrogating the entire genomes of DBA patients for possible causative genes. One of the questions after Dr. Gazda’s talk was whether this new gene somehow links in to the ribosome defect in other DBA patients representing some type of biological continuum in disease pathophysiology or whether this represents a distinct subclass of DBA. The answer to these questions awaits further study.

Dr. Jason Farrar (Baltimore) presented his work on scanning the genomes of DBA patients for larger deletions containing genes whose loss would have been missed by traditional DNA sequencing technology. One of the more fascinating aspects of his study was finding that in some of these patients these deletions were found in mosaic cell populations where some of the cells had the deletion and others not. This mosaicism appears to be linked to remission in certain DBA patients.

Dr. Adrianna Vlachos (New York) presented another outgrowth of the deletion studies described by Dr. Farrar. One of the deletions indicated that a patient originally diagnosed with classic DBA in fact had a more non-classical form of DBA that can be effectively managed with a novel treatment. These studies illustrated the power of defining the underlying genes affected in all DBA patients, pointing out that gene discovery is not simply an academic exercise.

Dr. Paula Quarello (Turin) presented work on gene deletions in the Italian DBA population supporting the view that gene deletions are a relatively frequent occurrence in DBA patients.

Dr. Elizabeth Chao (Aliso Viejo) presented work on the diagnostic testing Ambry Genetics has begun offering to DBA patients in its CLIA (Clinical Laboratory Improvement Amendments) lab. Ambry Genetics currently offers testing for 11 possible DBA genes in a cost effective manner.

Dr. Annarita Migliaccio (New York) presented work on the tremendous amount of structural variation in the glucocortioid receptor in humans. Since this receptor mediates many of the biological and clinical effects of steroid hormones, their laboratory is currently investigating whether these sequence variants might somehow be linked to the different ways in which DBA patients respond to steroid therapy. Thus, it may be possible someday to be able to predict a patient’s response to steroids depending on the nature of their glucocorticoid receptor gene.

This session ended with a talk by Dr. Marcin Wlodarski (Freiburg) who described their studies on the genetics of DBA in the German DBA Registry. He, like others described above, is using various whole genome interrogation methods to identify genes affected in DBA patients. Clearly, these are very exciting times in the gene discovery field.

Basic Mechanisms and Translation

This session explored the molecular mechanisms whereby defects in ribosome synthesis influence cell death signaling pathways and how these pathways may be targeted in developing more effective therapies for DBA.

Dr. Teng Teng (Cincinnati) presented work on how reducing expression of the DBA protein Rpl11 influences how cells divide. Previous studies have reported that Rpl11 plays a central role in p53 activation in response to ribosome stress. Therefore, it came as somewhat of a surprise when RPL11 was identified as a DBA gene. The studies reported here indicate that alternative mechanisms may come into play in cells depleted of Rpl11.

Dr. Alan Warren (Cambridge) discussed what he feels may be a more primordial form of ribosome stress signaling in Drosophila which he plans to exploit in a strategy to identify therapeutics that target elements of this pathway.

Dr. Akiko Shimamura (Seattle) presented a poster that suggested additional complexity in signaling pathways responding to ribosome stress.

Dr. Pierre-Emmanuel Gleizes (Toulouse) outlined his studies on a newly identified DBA gene which appears to regulate p53 activity through various mechanisms. As I’m sure the reader is by now aware, there appear to be numerous mechanisms operating in terms of signaling ribosome stress to cell growth and death signaling pathways. This should come as no surprise however, given the ubiquitous and fundamental role the ribosome plays in all cell types.

Dr. Fabrizio Loreni (Rome) presented studies on one of these additional signaling pathways that appears to integrate aspects of cellular energy metabolism with ribosome stress and how it may be relevant to DBA.

Nadia Danilova (Palo Alto) presented work on how small molecule effectors of energy metabolism pathways influence phenotypes in their zebrafish model of DBA.

Dr. Alison Taylor (Boston) backed into one of these alternative signaling pathways when she was screening chemicals that reversed a DBA-like phenotype in her zebrafish model of DBA. These studies have obvious implications for potential therapeutic development.

Dr. Lingbo Zhang (Boston) discussed his work on protein that is required for the ability of glucocorticorticoids to stimulate erythropoiesis. Identification of factors critical for the effects of glucocoroticoids may ultimately lead to alternative strategies to influence the activity of these factors with less toxic therapeutics.

Dr. Janice Abkowitz (Seattle) presented her work on the role of heme toxicity as a potential mediator of the erythroid selective nature of DBA clinical presentation. Her work is based on the DBA-like phenotypes in mouse where the heme exporter FLVCR is knocked out.

Two posters presented from the laboratory of Dr. Chetankumar Tailor linked ribosomal protein mutations to defective expression of FLVCR through an effect on RNA splicing. These studies again might relate to the continuum whereby defective ribosome synthesis can influence other cellular processes that ultimately give rise to the distinct clinical features of DBA.

Along these same lines, Dr. Marieke von Lindern (Rotterdam) presented her work on two genes that influence erythroid development whose expression is preferentially affected by ribosomal protein haploinsufficiency. Dr. Irma Dianzani (Novara) presented work on various transcriptional regulatory pathways that appear to be affected in cells expressing suboptimal amounts of ribosomal proteins.

Finally, Dr. Adrianna Vlachos (New York) closed out the session with her analysis of cancer incidence in the North American DBA Registry. While DBA appears to be a cancer predisposition syndrome, the cancer risk appears lower than with other bone marrow failure syndromes. While Dr. Vlachos’ talk at first blush may appear out of context with all the other talks in this session on different signaling mechanisms, it is worth pointing out that many of the signaling pathways that appear to be involved in DBA pathophysiology also play important roles in tumorigenesis.

Monday, March 19th

Clinical Treatment and Drug Development

This session focused on translating basic science discoveries into more effective treatments for DBA.

Dr. Anu Narla (Boston) presented her work on the effects of leucine in reversing phenotypes in zebrafish and human cellular models of DBA.

Dr. Dagmar Pospislova (Olomouc) presented a poster on her encouraging work on the effects of leucine in the Czech DBA population and Pekka Jakko (Lund) presented a poster on the effects of leucine in his mouse model of DBA.

Ms. Sara Sjögren (Lund) presented two high throughput strategies for DBA therapeutic development currently underway in the laboratory of Dr. Johan Flygare.

Dr. Johnson Liu (New York) described a new clinical trial for adult patients with DBA evaluating a drug initially developed for osteoporosis which had the undesirable side effect (at least in non-anemic patient populations) of stimulating red cell production. The safety and efficacy of this drug will be evaluated in this study. This fascinating drug is also undergoing clinical trials to stimulate red cell production in patients receiving cancer chemotherapy.

The last scientific talk of the meeting was given by Dr. Carol Mercer (Cincinnati) who discussed her work on the effects of a p53 inhibitor in a mouse model of DBA.

Summary

This was another outstanding DBA conference! I hope you can tell from the foregoing discussion that I think we have really turned the corner on potentially identifying genes affected in all DBA patients, which in turn will dramatically influence our ability to correlate clinical features of the disease with underlying genetic changes. The basic science discoveries of the past few years also appear to be leading to many different and novel approaches to therapeutic development. We hope that the fruits of the endeavors reported here will soon lead to improving the lives of patients and families affected by DBA.

Acknowledgements

Many thanks go out to Marie Arturi and Lauren Carroll for all the work they put into setting up the meeting and making sure everything ran smoothly. Thanks also go out to the Daniella Maria Arturi Foundation who sponsored the meeting and to Celgene, FerroKin BioSciences, Ambrey Genetics, and the Diamond Blackfan Anemia Foundation for their meeting support.

Summary of the 2010 International Consensus Conference from DBAF’s Research Director, Steven Ellis, PhD:

The Annual DBA International Consensus Conference is widely acknowledged as the premier showcase for clinical and basic research on Diamond Blackfan anemia. And the 2010 conference held in March in New York City was no exception. What struck me most about this year’s conference is the breath of DBA research drawing in more and more investigators of increasingly diverse backgrounds. The other thing that struck me about this meeting is the vital role that the DBAF plays in supporting research in these diverse areas and in supporting new investigators to the field. The DBAF logo was shown time and time again as speakers gratefully acknowledged the Foundation’s support for their research.

One of the Foundation’s philosophies is to support as much research as possible with the limited funds available with an emphasis on new and innovative research and supporting new investigators to the field. What this means in practical terms is that the Foundation’s awards are typically much smaller than those from the Federal Government, but play vital roles in testing new ideas and allowing these investigators to generate preliminary data that will make them competitive for larger awards. What I think is evident from listening to awardees speak at this year’s conference is how much they appreciate these funds and how important they have been to making progress in the field.

As a consequence of this funding philosophy, the DBAF’s Research Portfolio is fairly broad from gene discovery to drug development, from zebrafish to mice, from the USA to the world, and from young investigators to established investigators. Thus, DBAF support continues to be a significant driving force for progress in the field. Researchers supported through the DBAF presenting at this year’s meeting included:

  • Dr. Hanna Gazda, Boston’s Children’s Hospital, Gene discovery efforts in DBA
  • Dr. Johan Flygare, Whitehead Institute of Biomedical Research, DBA drug development
  • Dr. Shuo Lin, UCLA, zebrafish model of DBA
  • Dr. David Bodine, National Human Genome Research Institute, mouse models of DBA
  • Dr. Fabrizio Loreni, Universita di Roma Tor Vergata, cellular models of DBA
  • Dr. Irma Dianzani, Eastern Piedmont University, DBA mutation database

One of the major developments in the past few years in the field has been the development of animal models for DBA. There were five talks this year on different mouse models of DBA (Flygare, Mason, Bodine, Abkowitz, and Jaako) and two on zebrafish models (Taylor and Lin). Animal models with their complex physiology allow investigators to begin to address the fundamental question of how defects in ribosome synthesis affect erythropoiesis and other developmental pathways. These animal models are also crucial for drug development studies (Flygare). Cellular models of DBA continue to provide interesting insights into features of ribosome synthesis and pathways through which defects in ribosome synthesis trigger signaling pathways that lead to critical cell fate decisions. Numerous talks dealt with this fascinating topic (Fumagalli, Goldberg, Du, Moniz, Caywood, Horos, Loreni, Gleizes). There was even a talk on the prospect of using ribosome synthesis as a tool in DBA diagnosis (Leblanc). Gene discovery continues to play a vital role in our understanding of the basic biology of DBA. Two large scale sequencing efforts were reported by Gazda and Farrar, where it is hoped that the majority of genes giving rise to DBA in patients in North American will soon be identified. Genetic analysis will play an increasingly important role in DBA diagnosis as more genes are identified. It is also hoped that the genes affected may give insights into how patients may respond to various treatment and potentially also provide insights into other clinical parameters like cancer predisposition. In this regard, Alter gave a talk on cancer predisposition in DBA, while Ball discussed the need for regular updates to the DBA clinical consensus document. These topics were also front and center at a poster session where information from many DBA registries throughout the world was presented. Finally, Pospisilova, Vlachos, and Glader gave updates on clinical trials either beginning or underway to carefully analyze the value of leucine and lenalidomide as potential treatments for DBA.

As noted above, the DBA International Consensus Conference continues to be the premier venue for DBA research. The conference was hosted by the Daniella Maria Arturi Foundation, and supported by the Diamond Blackfan Anemia Foundation, the Office of Rare Diseases at the National Institutes of Health, the National Heart Lung and Blood Institute, and Jack’s Fight for a Cure. In addition to clinicians and scientists in attendance, the conference also includes various other interested constituencies included representatives from various Institutes within the National Institutes of Health and other National agencies. I hope the reader will get a sense from this brief summary of the 2010 conference that progress continues to be made on numerous research fronts giving us a better understanding of DBA pathophysiology. The quest now is to exploit this understanding to improve clinical care for DBA patients and identify more effective treatments for this disorder.

Summary of the 2009 International Consensus Conference from DBAF’s Research Director, Steven Ellis, PhD

This year represents the 10th anniversary of the Diamond Blackfan Anemia International Consensus Conference. I have been attending these conferences since 2004. From my viewpoint this year’s conference was one of the most far reaching and important conferences from both the clinical and scientific perspectives.

Where once there were few treatment options for DBA, novel therapies are moving forward into clinical trials with others in various stages of development. We heard from Dr. Adrianna Vlachos (New York) who is coordinating the North American clinical trial for the efficacy of leucine as treatment for DBA. While there have been published reports of small trials where DBA patients have been given leucine and anecdotal reports from sporadic families trying leucine, a carefully controlled clinical trial is necessary to truly address its efficacy and address any potential adverse side effects. Plans for this trial are nearing completion and patient accrual should begin soon! Dr. Vlachos also reported on a clinical trial being considered for the use of lenalidomide as a therapeutic option for DBA. This trial will be led by Dr. Bertil Glader (Palo Alto). Initially this trial will be limited to a small number of adult patients because of the potential for serious adverse side effects. Dr. Monica Bessler (St. Louis) presented a novel idea for using a drug currently under clinical trials for a number of different genetic diseases that may be efficacious in ~ 20% of DBA patients with a particular class of mutations. What is interesting about this drug is that it doesn’t matter which gene the mutation is in, it just targets the type of mutation. Thus, we could have designer drugs specific for some DBA patients and not others. Drs. Narla (Boston) and Johan Flygare (Boston/Lund) presented work on the mechanisms by which steroids promote erythropoiesis in DBA patients. These studies are yielding fascinating new insights. Dr. Flygare wants to use this insight to create a method for screening thousands of chemicals for properties similar to steroids. Compounds identified in this manner would be lead compounds for drug development with the hope that drugs could be found that act like steroids but have fewer side effects. As I hope you can tell, there was considerable excitement at this meeting relating to possible new treatments for DBA.

Where once there were none, we now have several animal models for DBA. In the past most laboratory studies on DBA relied on tissue culture cells and yes, even Brewer’s yeast. As you might expect, these cell based models lack the complex physiology of a complete organism and, so while valuable, are limited especially for matters like drug testing and understanding factors like why mutations in ribosomal protein genes selectively affect the production of red blood cells. We heard reports on three mouse models of DBA from Drs. David Bodine (Washington D.C.), Kelly McGowan (Palo Alto), and Stefan Karlsson (Lund). We also heard about zebrafish models for DBA from Drs. Sakamoto (Los Angeles) and Taylor (Boston). Recent technological developments have allowed scientists to create embryonic stem cell-like cells from adult cells. These cells, called induced pluripotent stem cells, allow investigators to study complex developmental questions in cell based models. Drs Warren (Cambridge, England) and Lensch (Boston) described studies using this class of cells, whereas Dr. Singh (New York) spoke on similar studies using mouse embryonic stem cells. Again, with so many possible models to choose from, progress on the translational research front should move forward rapidly.

Where once there was RPS19, we now have a total of six genes known to be affected in DBA. Dr. Gazda (Boston) reported on the identification of two new DBA genes, with other genes identified, but not as yet confirmed. Dr. Vlachos (New York) reported studies trying to correlate the gene affected in DBA patients with various clinical parameters associated with the disease. Interesting relationships are being found. One of the goals of this type of study would be to determine if knowledge of gene affected could give physicians insight into how well a patient might respond to therapy or perhaps even go into remission. Dr. Moniz (Paris) reported that cells from patients with different types of mutations behaved differently in cell culture adding fuel to the fire that the nature of the gene affected will likely influence clinical presentation. I could go on and on about remarkable new insight being uncovered at the basic science level pertaining to the underlying molecular basis for DBA. As this is my own research area, I am hoping all remaining investigators focusing their time and energies in this area will forgive my cutting this discussion short. Let me just close by saying without the foundations laid by these studies on the basic science side of DBA: Drs. Gleizes (Toulouse, France), Fumagalli (Cincinnati), Dianzani (Novara, Italy), Meerpohl (Freiburg, Germany), Pospisilova (Czech Republic), Keel (Seattle), Dahl (Uppsala, Sweden) Mason (St. Louis), Tailor (Toronto), Loreni (Rome), Caywood (Baltimore), and Sieff (Boston), I doubt we would have seen all the progress discussed above.

In closing, let me reiterate my view that the 10th annual Diamond Blackfan Anemia International Consensus Conference sponsored by the Daniella Maria Arturi Foundation and co-sponsored by the Diamond Blackfan Anemia Foundation was a smashing success, with outcomes that should transform the lives of patients and families affected by DBA in the near future.