Early this fall, Deanna Portero, FDF’s Executive Director, and Amanda Konradi PhD, FDF President-Emeritus attended a Service Learning fair at Loyola University Maryland in Baltimore, MD, where Dr. Konradi is also a professor. Community engagement is central to Loyola’s commitment to transformative student learning, and FDF is always looking to engage more energy in the fight against FD/MAS. The fair, organized by Jean Lee Cole of Loyola’s Center for Community Service, helps connect undergraduate and graduate students to academic projects with community-focused outcomes. There, Portero was lucky enough to connect with Dr. Lisa Scheifele, an Assistant Professor in the Department of Biology with an interest in molecular biology and genomics. Dr. Scheifele and her undergraduate student Ryan O’Donnell spoke to Portero about the top questions she receives from the FD/MAS community, and volunteered to complete a literature review on bisphosphonates and the potential for new therapeutic technologies like gene therapy.
“The FDF often hears about medications and new technologies that could be harnessed toward treating FD/MAS and its symptoms, but it’s difficult to understand which current approaches have the most merit, or which future approaches are most realistic to achieve in the near-future without a close look at published research,” explained Portero.
O’Donnell, a biology major from Toms River, NJ, signed on to the project because of his interest in healthcare. He’s currently a junior and hopes attend medical school after he graduates. “It seemed like a research opportunity that would allow me to have a direct impact on fibrous dysplasia patients and how they understand the condition, the efficacy of current treatment options, and new developments in the field,” said O’Donnell. Under Dr. Scheifele’s guidance, O’Donnell took the time to read through published research on the basic biology of FD/MAS, as well as published case studies and clinical trials. After his semester was complete he shared some of his analysis and conclusions with FDF.
O’Donnell’s review of existing treatments focused in particular on bisphosphonates, a class of drugs that can prevent the loss of bone density in patients with conditions like osteoporosis. There are several different bisphosphonates on the market including alendronate (Fosamax), pamidronate (Aredia), zoledronic acid (Reclast), and risedronate (Actonel). Doctors sometimes prescribe bisphosphonates for FD patients because some believe that bisphosphonates might reduce bone pain or slow lesion activity. Unfortunately, it’s not clear from published research whether any bisphosphonates provide those benefits. While published studies have documented the potential side effects of bisphosphonates such as osteonecrosis of the jaw, the published research studies on the drug’s benefits are still limited.
“There is a clear divide between the results of the only clinical trial and prior case studies,” explains O’Donnell. Case studies are studies that look at the results of a handful of patients who are given the drug. Many of the published case studies examined pamidronate, and reported clinical benefits from that bisphosphonate. In particular, many of the case studies of pamidronate reported reductions in pain. However, the only published double-blind placebo-controlled clinical trial, which examined alendronate, found that that bisphosphonate didn’t have an effect on bone pain. A double-blind placebo study is a type of study where neither the patient nor the clinical researcher administering the treatment knows whether the patient is receiving the bisphosphonate or if they are receiving a fake drug that should have no effect.
“Patients may feel better after receiving an intervention because they expect it to be helpful, this is known as a placebo effect,” explains O’Donnell, this is part of why “clinical trial experimental designs are time-proven for determining efficacy across all drugs.”
O’Donnell and Scheifele note another type of bias that readers should be suspicious of: publishing bias. Authors are more likely to submit papers where a drug makes a difference, and editors of scientific journals are more likely to publish a paper where a difference is found. So, even though most of the published case studies on pamidronate state that there was a positive impact on pain, a savvy reader might also consider that case studies where authors found the opposite conclusion are less likely to be published.
Of course, it’s also possible that the difference between the unfavorable results of the alendronate clinical trial and the more favorable results of the pamidronate case studies can be explained by something other than the placebo effect or a bias toward publishing positive results. For example, the two types of bisphosphonates are delivered differently, and some researchers speculate that delivery could explain the difference. Alendronate, the drug from the clinical trial, is delivered by oral tablet, and pamidronate, the drug from the case studies, is given by IV. There is some suggestion that “intravenous bisphosphonates, as used in the case studies, may be more effective for bone pain management,” said O’Donnell. “This is an area for future research that would have near immediate impact in clinical outcomes of fibrous dysplasia,” concluded O’Donnell.
There remains much to be studied about FD/MAS and bisphosphonates, with many unknowns. Patients and families should make decisions about their care in consultation with their doctors.
In addition to his literature review on bisphosphonates studies, O’Donnell also looked at other developing technologies that could help treat FD patients. Gene therapy has been a promising new field for treating genetic conditions, but the nature of FD presents some significant challenges.One type of gene therapy is “germline editing,” where mutations are fixed in the genetic code by editing the DNA of the sperm, egg or zygote prior to in vitro fertilization, so that none of the cells of the carry the genetic mutation in the first place. “Gene therapy has seen great success for inherited genetic disorders,” explains O’Donnell, but “germ line therapy will not be an option for the treatment of FD, because it is not inheritable.” In FD/MAS, the mutation develops post-zygotically, or as an embryo’s cells are dividing and developing, so you can’t prevent FD/MAS through germline gene editing, because the mutation isn’t present in the sperm or egg in the first place.
FD also challenges the limits of current “in vivo” gene therapy technology, the name for gene therapies that are designed to be delivered to human patients who are born with genetic defects. Unlike most genetic illnesses, “the mutation that causes FD only affects a portion of the cells, this is known as a mosaic mutation,” continued O’Donnell. While some cells in the bodies of FD/MAS patients carry the GNAS mutation, many other cells do not. To treat this mutation without causing more negative side effects to other, unaffected cells, the gene therapy has to be able to systematically target the mutant cells without negatively affecting the functioning of other cells and organs. O’Donnell believes that mosaicism is a challenge in developing a therapy for FD/MAS, whether a genetic therapy or a more conventional drug.
O’Donnell also did a review of new tools that could help scientists advance towards a treatment or cure. “New animal models of FD will better our understanding of the disease,” said O’Donnell, as new mouse models express the GNAS gene mutations in ways that are more similar to the expression present in FD patients. Additionally, “better gene sequencing technologies could help identify patterns in the mosaic nature of the disease mutation, and therefore increase our understanding of FD.” While it’s unclear if genetic therapy can provide a treatment for FD/MAS in the near future, gene editing tools like CRISPR-Cas9 are already being used to create a stem cell model of FD, which could be used to find new targets for drugs.
FDF is grateful to O’Donnell, Dr. Scheifele, and the Loyola University’s Center for Civic Engagement and Justice for their work and for making this review possible. “Not only is it useful to have this kind of analysis available for patients and families, it’s also really exciting to have students become interested in FD/MAS during their undergraduate experience,” said Portero, “More research and collaboration are key tenets of our strategic plan to beat FD/MAS, and working with students at all stages of their careers helps us work towards those aims.”
We asked O’Donnell what field of medicine he’s interested in focusing on, and he hasn’t decided. Of course, he has plenty of time to make a decision, but we’d like to be the first to say that FD/MAS could use knowledgeable clinicians in so many different specialities. Since patients see endocrinologists, ENTs, orthopaedic surgeons, maxillofacial surgeons, neurologists, opthomologists, and more, there are many fields for O’Donnell to choose between if he’d like to support the complex needs of FD/MAS patients.