The collaborative network approach: a new framework to accelerate Castleman's disease and other rare disease research.

Despite technological advances and substantial investments of time and funding, many challenges exist for rare disease research and drug development. Basic disease mechanisms are often poorly understood, selection of suitable research participants can be diffi cult, and endpoints for clinical trial registration might not be established. Progress is further impeded by limited collaboration and data coordination, misaligned incentives, funding decisions made in isolation from community consensus, and inter-institutional barriers to tissue sharing. Although frequently used, off -label treatments are infrequently tracked, and thus valuable opportunities to build on observations are lost. One coauthor (DCF) comments, “Despite being a physician, I didn’t fully understand the barriers that slowed down life-saving progress until I was dying from a rare illness. I received my last rites in 2010 while battling idiopathic multicentric Castleman’s disease and found that [the disease] had no Food and Drug Administration [FDA]-approved therapies, a poorly understood model of pathogenesis, and a 65% 5-year survival rate”. After surviving three life-threatening episodes, DCF began to assess how non-profi t research funding was allocated for rare diseases, for which 95% of conditions do not have an FDA-approved therapy. Disease research organisations (DROs) make important contributions by funding research. However, the framework through which many (but not all) DROs traditionally distribute funding can present challenges (fi gure). DROs typically fundraise fi rst and then invite researchers to apply through a request for proposals (RFP) to use the funding for their specifi c purposes. In parallel, these organisations often provide patients with supportive resources and facilitate referrals to experts, who collect and store clinical data and biomaterials at their respective institutions. This model can in some cases result in organisations funding studies targeted at questions proposed by a small selection of researchers with requisite tissue samples rather than the studies that may have the highest impact on the fi eld, which might require collaboration and sample sharing. A more effi cient, collaborative, and consensus-driven framework than exists at present is needed to fully harness the opportunities aff orded by technological advances for the approximately 7000 rare diseases and 350 million individuals affl icted globally. One such neglected rare condition is Castleman’s disease, which describes a heterogeneous group of lymphoproliferative disorders straddling the fi elds of immunology, oncology, and virology. Castleman’s disease ranges from a single region of enlarged lymph nodes (unicentric Castleman’s disease) to multicentric lymphadenopathy with systemic infl ammation and multiple organ system dysfunction (multicentric Castleman’s disease) caused by immune activation and proinfl ammatory hypercytokinaemia, often including interleukin 6. Multicentric Castleman’s disease is either caused by human herpesvirus 8 (HHV8) infection, which is called HHV8-associated multicentric Castleman’s disease, or is idiopathic in HHV8-negative patients and called idiopathic multicentric Castleman’s disease. The absence of a unique international classifi cation of disease (ICD) code for Castleman’s disease has made epidemiological studies diffi cult. The estimated incidence of all forms of Castleman’s disease is 6500–7700 individuals of all ages every year in the USA or about 2·2 per 100 000.