United States Bone and Joint Initiative

A Synopsis of the 1^st Advances in Rare Bone Diseases Scientific Conference

Michael J. Econs, MD, and Craig B. Langman, MD, Meeting Co-Chairs

The 1st Advances in Rare Bone Disease meeting was held from October 23-24, 2008, in the Natcher Center on the NIH campus. Faculty from academic health centers, and representatives from patient support groups and foundations, the NIH and the FDA and industry were invited to attend. The meeting was organized by the United States Bone and Joint Decade and the Rare Bone Disease Patient Network. The overarching hypothesis of the meeting was that this unique grouping of individuals and organizations interested in rare bone diseases would be able to create new opportunities and understanding through common themes, but with specific applications to the unique diseases and conditions represented at the meeting. A measurable outcome for the meeting was to not only assess the current state of understanding for a given disease, but to determine the next steps in developing therapies for these disorders.

We were pleased to have the meeting begin with welcoming remarks from Dr. Stephen Katz and Dr. Ronald Margolis, representing NIAMS and NIDDK, respectively. These institutes have been instrumental in providing support to many of the rare bone diseases discussed at the meeting, including FOP, the hypophosphatemic rachitic disorders, hypophosphatasia, and the osteopetroses. Basic and translational research has progressed to partnering with industry to devise very promising treatments, two of which are now in clinical trials for hypophosphatasia and XLH, and others that are likely to be in trials in the next few years.

The format of the meeting had presentations of four plenary lectures of the highest quality science outside of traditional bone biology, but with applicability to problems encountered within rare bone diseases. We provide a brief précis of those presentations below. Following the outstanding learning experience provided by these preeminent plenary lecture scientists, we had brief presentations by outstanding junior scientists representing each of the component diseases of the meeting. Each was chosen by the meeting organizers with consultation from the Program Committee. These presentations helped to update all attendees about the current state of the science for each disease as well as showcase work done by some of the best young investigators in the world. This work is summarized in the meeting abstracts (on BoneKEy). At the lunch and dinner venues, which were important parts of the meeting, we had lectures from our federal agency and industry partners. A key goal of the meeting was to not only assess the current state of knowledge, but to outline the various pathways to develop therapies for these disorders. Representatives from NIH, the FDA, and industry made important presentations. Dr. Steve Groft, Director, Office of Rare Diseases, outlined mechanisms by which the Office of Rare Diseases serves to assist patient support groups and investigators. Dr. Matthew Thomas of the FDA outlined the process for getting a disease designated an orphan disease and presented information that is critical to getting approval for a new therapy or device for a rare disease. He also outlined potential future developments in this area. Dr. Edward Kaye from Genzyme, Inc. focused his presentation on the critical issue of academic and industry partnerships for rare diseases, a very necessary component for therapeutic advances that arise from the basic work of our scientists involved in rare bone diseases.

The first day closed with state-of-the-art presentations by three well-recognized bone scientists, Dr. Bjorn Olsen, Dr. Gerard Karsenty, and Dr. Lynda Bonewald, representing areas of bone development, neural control of bone formation, and the role of the osteocyte, respectively (the presentations are noted in the Abstracts for the meeting).

Plenary Lecture Summaries: Dr. Jeffrey Kelly discussed the emerging field of proteostasis, or the maintenance of protein folding in health and disease. This network acts beyond the intrinsic properties of protein structure, which supports its quaternary folding patterns through the extrinsic forces of the proteostasis network. The proteostasis network may play an important role in disorders, such as Alzheimers disease, where protein aggregation is likely important in the pathogenesis (too much protein folding) and loss of function diseases associated with excessive mutant protein misfolding and degradation, such as primary hyperoxaluria type I/oxalosis. Dr. Kelly also discussed approaches to treating diseases of the proteostasis network with small molecule proteostasis regulators, some of which are approved pharmaceuticals at present, and which enhance proper folding of mutant proteins through signaling pathways that control the proteostasis network. As an example a therapeutic approach to osteogenesis imperfecta was given as a target of successful modulation of the protestasis network.

Dr. Eddy Rubin described work by his group and others to identify tissue specific enhancers, which are regulators of spatiotemporal gene expression. Work to date has identified over 500 putative elements and demonstrated that at least 200 of them function as tissue-specific enhancers that effect gene expression. Moreover, over the next few years, his group plans to identify several thousand enhancers. Such work will have important implications for rare bone disorders as we seek to understand phenotypic variability among patients who have the same genetic basis for a disease.

Dr. Garry Cutting used Cystic Fibrosis as an example of complexity in Mendelian disorders. Most single gene genetic disorders display phenotypic variability that may be unrelated to variation in the disease causing gene. For example, approximately 50% of Cystic Fibrosis patients are homozygous for the D508 mutation. However, within this group, patients have extremely variable disease severity. Twin studies implicate both modifier genes and environmental exposure as playing a substantial role in this variability. Dr. Cutting reviewed approaches and recent successes from the Cystic Fibrosis Modifier Gene Consortium. These studies have identified TGFB1 as a genetic modifier and have established second hand smoke as a key environmental exposure. This work represents the next frontier in Mendelian genetics and a potential approach for many genetic rare bone diseases.

Dr. Samuel Stupp presented the rationale and several applications for the formation and delivery of self-assembling bio-nanostructures to human disease. Such structures allow precise, often repetitive delivery of growth factors, supporting frameworks, and critical enzymes to groups of cells, a given organ, or even to the whole body through the bloodstream, in order to correct genetic and structural defects. Dr. Stupp provided examples that included regeneration of axonal structures in neural cord injury and fracture healing.

Following the daytime presentations on October 23, attendees divided themselves into disease-specific sessions. Members of these groups consisted of patients, members of the patient support groups and foundations, industry representatives, and clinical and basic researchers. Each group was asked to address the question what is needed to move your disease area to where it needs to go? Specifically, what basic and clinical research is needed to assist in the development of new therapies? These groups then reported their findings on the second day of the meeting. These individual disease-based meetings pointed out the vast diversity in the state of knowledge among the rare bone diseases, and could be divided into three groupings. The first group of diseases was represented by diseases where there was substantial knowledge about the disease and its pathogenesis and new therapies are starting to emerge. In the second group there is some knowledge about the disease and pathophysiology, but, as of yet, no emerging therapy.

Our third grouping, however, is not so fortunate in that many of the cases have an incomplete picture of the disease manifestations and there is little to no information about their pathogenesis. With little knowledge about the disease and even less about the pathogenesis, the hope for development of therapy is limited, at best. Of note, the single biggest predictor of which category a disease fell into was whether there was a dedicated research group working on the disease and, in the case of emerging therapies, if those groups partnered successfully with industry.

Another critical need that arose for those diseases in one of the first two groupings was the absence of sufficient clinical research to advance drug testing, should it be available. As but one example, there is no generally accepted severity score for X-linked hypophosphatemic rickets and absence of such a way to grade and monitor its severity may hamper Phase 2 and Phase 3 trials of new investigational therapies. This becomes even more apparent when considering diseases for which much less is known. In several breakout groups, participants felt that a patient registry with detailed clinical information was critical to gaining the phenotypic information that is required to better to push the field forward. Realistically, without a reasonably complete understanding of disease manifestations it will be difficult to pursue further research with either animal models or in vitro studies. Additionally, for some disorders, such as melorheostosis (OMIM 155950), it is not clear in all cases as to whether the disease is a genetic or environmentally induced disorder. Development of patient registries may be another area for collaboration between academic physician scientists and patient support groups/foundations. Patient groups may be able to mobilize patients to participate in clinical research studies. Additionally, they may be able to provide critical early funding of registries. It will be important for these groups to work with the NIH Office of Rare Diseases, which has substantial experience in initiating registries for rare diseases, to ensure that the registries are set up to maximize their usefulness to researchers.

On some level the distinction between rare and common disease is somewhat artificial because research into rare diseases frequently benefits common diseases. There are numerous examples of research into a rare disorder enlightening the pathophysiology of a more common disorder. One of the more recent examples is research into the very rare disorder autosomal dominant hypophosphatemic rickets, which led to the identification of FGF23. Further research has established that FGF23 is a hormone that controls normal phosphate and vitamin D metabolism and that FGF23 is markedly elevated in chronic kidney disease (CKD), and is emerging as its most useful biomarker for mortality related to CKD induced bone and mineral disturbances. Other examples include research on osteopetrosis, which has enlightened osteoclast biology and work in familial Pagets disease, which has provided insight into the RANK, RANKL, OPG system. Thus, it may be very important to have representative investigators at forums where more common bone disorders are discussed.

The 1^st meeting on Advances in Rare Bone Diseases thus represented a partnership of exploration, discourse, and discovery between academic scientists, industry, government and patient groups. We learned of new science outside of traditional bone research that may be very useful, of the current best bone research into processes common to those rare diseases, of the creative aspects of our junior investigators for the diseases, and of the many arenas, both federal and through industry-partnerships, for pathways to drug discovery and development. We learned of the mutual needs for dialogue between patient groups and scientists and how important patient support groups are to the successful development of new therapies not only in providing access to potential study subjects, but in informing both industry and academic researchers what the needs of patients with the disease really are. The attendees left with renewed vigor and capacity to influence the course of research into rare bone diseases. In the future it will be important to have regular Advances in Rare Bone Diseases meetings to highlight those successes, and provide a forum for new, creative venues for understanding mechanisms of disease, and achievement of novel diagnostics and therapeutics.

Click here for links to the conference program, program committee list, abstracts on BoneKEy, and for conference supporter information.