Translational Research Program in Pediatric Orthopaedics, The Children's Hospital of Philadelphia (CHOP)




Dr. Pacifici, can you please share your titles at Children’s Hospital of Philadelphia (CHOP) and the University of Pennsylvania and provide some background on your work history leading up to your current work on FOP?

I am the Director of Orthopaedic Research at CHOP, Professor of Orthopaedic Surgery at the University of Pennsylvania, and Associate Director of the Penn Center for Musculoskeletal Diseases (PCMD). My biomedical research work spans over three decades and has been directed at deciphering the cellular, signaling and molecular mechanisms by which the skeleton forms and grows during fetal and postnatal life and acquires its organization and structure.

Areas of particular research attention include: the origin, lineage commitment and determination of embryonic skeletal progenitor cells; differentiation of commitment cells into cartilage and associated musculoskeletal tissues; mechanisms of assembly of the initial cartilaginous skeleton and its distinct elements including joints; and maturation and hypertrophy of growth plate chondrocytes and progression and transition to endochondral bone and marrow. We’ve been investigating a number of possible mechanisms and factors regulating those processes, including the bone morphogenetic protein (BMP) and hedgehog protein signaling pathways, the nuclear retinoic acid receptor (RAR) transcription factors and associated proteins, and cell surface receptor-ligand interactions and co-receptor function. My lab members and I have used the information and insights deriving from these and related research projects to predict and decipher the pathogenesis of congenital pediatric musculoskeletal disorders.

In addition to FOP, rare disorders under study in my lab are Multiple Osteochondroma (aka Hereditary Multiple Exostoses) and Ankylosing Spondylitis. FOP is characterized by formation and accumulation of extraskeletal endochondral bone - collectively termed heterotopic ossification (HO) - that is caused by germline mutations in the BMP cell surface receptor ACVR1/ALK2 and excessive BMP signaling. We also study forms of non-congenital HO caused by serious injuries, invasive surgeries and deep burns that can occur in any individual and are particularly common among severely injured soldiers. 

Can you please introduce your team and provide a description of the current FOP research being done in your lab? 

Many lab and group members have contributed to our biomedical research studies over the years. In particular, Dr. E. Koyama and I have long worked together to study the roles of RARs in early skeletal development and also test effects of different industry-made synthetic retinoid analogs that stimulate retinoid signaling action (retinoid agonists) or block it (retinoid antagonists). These lines of investigation were further expanded and tested in greater depth after Dr. M. Iwamoto joined our group. Currently, key lab members carrying out HO/FOP research include Dr. C. Mundy, Research Associate; Ms. Juliet Chung, Research Assistant; and my colleague Dr. Koyama. We continue our long-standing and fruitful collaborations with members of the PCMD and in particular Dr. E. Shore as well as with researchers at other institutions.

Current studies aim to further illuminate: how the ACVR1/ALK2 mutations trigger HO, in what manner congenital HO in FOP differs from non-congenital HO caused by injury or trauma, what other possible targets of therapeutic intervention may exist to block HO including combination therapy, and whether pre-existing HO bone masses in FOP patients could be removed surgically and prevented from reforming.

What precipitated your interest in working to find treatments and a cure for FOP?

Rare diseases such as FOP and MO are not “rare” for the individuals suffering from them and their families, and it is this fact that has long inspired me to focus my research work in this field. I became familiar with FOP through the activities of the University of Pennsylvania Center for Research in FOP and Related Disorders directed by Drs. F. Kaplan and E. Shore. It became amply and sorely clear that there was an urgent need to find a treatment but also figure out changes in cellular and molecular mechanisms triggering HO formation. In my lab, we exploited our findings and insights into the mechanisms of normal cartilage induction and growth to identify vulnerable and druggable cellular, biochemical or molecular targets that could serve as therapeutics against HO. It is this type of approach and reasoning that led us to zero in on the retinoid/RAR pathway. Thus, contrasting normal developmental biology and physiology with pathology has provided fertile ground for inquiry and identification of possible therapeutic solutions.

Can you discuss why you’re so passionate about FOP research?

Undoubtedly, meeting patients and their families has propelled my efforts to work on FOP and find a treatment. It’s both humbling and painful to meet patients and not be able to conclusively reassure them that things will be fine and treatments are on their way. The FOP Italia organization has used a motto in their brochures that says: “Rare, but no longer alone.” Indeed, it used to be that patients with rare and ultra-rare diseases and their families felt alone and isolated when there was little if any research work on their diseases and no hope for a treatment. When I first learned about FOP years ago, it immediately became my mission to contribute to FOP research and identify a treatment. I remain determined to bring this goal to full fruition.

What do you anticipate for the next 5-10 years of FOP research?

Given our efforts and those of others, it is possible and quite likely that FOP will become a manageable chronic disease treatable pharmacologically. It is important to note that current research activities on other genetic diseases are testing different and novel therapeutic modalities and approaches. Thus, those studies could inspire additional ways to treat FOP, including genetic means to stop the expression of mutant ACVR1 while allowing the wild type second ACVR1 copy that patients have to take over and restore normality. Also, research on rare diseases such as FOP and MO can - and does - provide insights and a better understanding of common diseases. I mention above the very common non-congenital HO caused by injury and trauma that affects many thousands of patients annually. In sum, the future is bright and I trust it will produce ever-improved treatments and provide renewed hope and relief to patients and families alike.

Make a Difference

Donate Connect Fundraise

Already a Member? Sign In

Sign Up for FOP Connection, Our Monthly eNewsletter