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Molecules to Medicine

Molecules to Medicine

Demystifying drug development, clinical research, medicine, and the role ethics plays

Rare Diseases – in Honor of Sam Berns

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Sam Berns with Dr. Francis Collins at TEDMED2012

Two cases this week highlight some of the difficulties surrounding rare and orphan diseases.

First, Sam Berns, age 17, just died from his progressive genetic disease, progeria, which causes very rapid and premature aging. Progeria affects 1 in 4 - 8 million newborns; less than 250 kids in the world are alive, making research very difficult.

The second was the court-ordered release of Justina Pelletier, a 15 year old girl, from Boston Children’s Hospital (BCH), where she has been hospitalized for almost a full year against her parents wishes. Justina had been treated for a mitochondrial disease at Tufts Hospital, but BCH disputed the diagnosis.

Why care about these unusual cases?

Basic science is sometimes dismissed because it is not necessarily immediately translated into tangible results. Such rare diseases give us insights into basic cell functions and biochemistry that might be translated into clinical practice. As an NIH white paper notes, “mitochondrial function plays a central role in degenerative diseases and aging, making the understanding of this organelle important not only to patients with Primary Mitochondrial Diseases but also to patients with more common disorders, such as diabetes, Parkinson’s disease and age-related hearing loss among many others.” Similarly, progeria is thought by some to underly normal aging processes.

Let’s look at some of the problems in diagnosing and in developing treatments for rare diseases.

Mitochondrial diseases

Mitochondrial diseases were first described in 1963. They have only received more in-depth recognition in the past decade. I never saw them in my training or practice until the past 5 years. Even now, they are infrequently recognized. Mutations in over 100 genes have been identified so far, and are estimated to affect 1 ~5,000. Mitochondria are intracellular structures that fuel our cells via oxidative phosphorylation, in which food and oxygen are converted into ATP (adenosine triphosphate), which is required to maintain cell activities. We now know that mitochondrial DNA (mtDNA, or genetic material) is inherited differently from that of the rest of the cell (nuclear DNA, or nDNA), and is passed on by the mother. A mutation in the nDNA can also affect mitochondrial proteins and be transmitted by either parent. But because so many different genes are involved, manifestations vary widely making diagnosis difficult.

Justina’s case illustrates some of the problems of diagnosing and treating mitochondrial diseases, well described in the Boston Globe series. First, her symptoms were variable. Her parents took her to multiple physicians seeking a diagnosis and effective treatment plan. She, and her sister were under treatment by Dr. Mark Korson, Chief of Metabolism at Tufts. Unfortunately, her gastroenterologist, Dr. Alejandro Flores, transferred to BCH, so Dr. Korson suggested she go there when she became ill. BCH physicians not only reportedly disputed the diagnosis of mitochondrial disease, insisting she had a psychiatric problem, but did not allow either Dr. Korson or Dr. Flores to participate in Justina’s care, nor even to provide a second opinion.

Seeking multiple opinions was disparaged as “doctor shopping,” prompting concerns of Munchausen’s syndrome, or factitious illness (in this case created by the parents). Because of concerns over “medical child abuse,” Justina was put under the care of protective services and placed in a psychiatric unit, allowed only very limited contact with her family, and subjected to life in a very strict and regimented setting. Some of her medications were stopped. After a protracted battle, a court ordered Justina to be released from BCH and returned direction of her care to Dr. Korson.

Justina’s case caught my attention because I have helped care for a young patient with mitochondrial disease, who I will call “Rose,” since she is such a lovely person. I am sharing some of “Rose’s” story with her permission.

Rose has had a variety of vague symptoms “as long as she can remember,” including heat intolerance and dizziness. By the time she became a teen, she experience severe orthostatic hypotension (POTS) and fainting (syncopal) episodes. She then developed stroke-like episodes, with prolonged weakness and difficult recoveries, and severe migraines. Yet the diagnosis of POTS wasn’t made until she was 18, and mitochondrial disease was not the leading diagnostic consideration until she was 19. In the meantime she, like Justina, was “accused” of having a psychiatric rather than physical problem.

A surgeon, consulted to place a feeding tube, decided in that single visit that she had bulimia. For Rose, this isn't surprising; doctors diagnosing her after a single visit, or even sight unseen, happens all the time. (In her own case, Rose had been given several incorrect diagnoses of psychiatric disorders before doctors correctly diagnosed her with a mitochondrial disease—after a delay of many months). Rose goes on to note that not only is a delay in treatment harmful, "but it causes mental anguish, worry, and distrust. Every other mito, POTS, or chronic illness person I meet has had this happen. Every single one. And they all have some level of fear meeting a new doctor, opening up about their symptoms, and constantly worry it is going to happen again.

Complications worsened, with inability to swallow and with bowel dysmotility, requiring multiple surgeries and, ultimately, years of intravenous feeding (hyperalimentation). Through this, Rose has remained as active as possible, enjoying family, friends, and school.

Rose states, “Insurance is a constant battle. We've payed thousands out of pocket each year in past years. I've been denied medications that could improve my motility and aid me in staying off of TPN, which in turn would help prevent [my life-threatening] central line infections/sepsis. It has gratefully improved but only by stressful and constant fighting...”

“I've been refused inpatient physical and occupational therapy multiple times, including kicked out of the program twice. Once I was unable to walk on my own, making it a very dangerous situation in my multilevel home that was not set up for me. I didn't even have a proper wheelchair, and had to drag my feet and was constantly running them over. …I was also denied further studies for mito diagnostics.” This was because a diagnosis would not likely change the progressive decline in her condition.

Frankly, in caring for Rose, I have at times wondered if her insurance carrier hoped to hasten her death in order to save money.

Rose has had to travel far from home for her care, but now has a team she trusts. “Things since have been very good. All my doctors are wonderful, caring, understanding, and fight for me every day. My disease has progressed to the point of total TPN dependence, chronic respiratory failure, and general progression of other organ systems either becoming involved or worsening. However, I'm very much at peace and so grateful for my life.”

Progeria

Even if a syndrome is recognized, like progeria, there are huge barriers to research, illustrated by Sam Berns’ case. Sam was born in 1996, and diagnosed with progeria at 22 months. His parents, Drs. Scott Berns and Leslie Gordon, both physicians, formed the Progeria Research Foundation (PRF) in 1999, in response to his illness. Gordon subsequently completed an MD-PhD program and has since devoted herself to research on her son’s disease, working closely with NIH, through it's director, Dr. Francis Collins.

Molecular basis of nuclear defects in progeria

The Progeria Foundation has made remarkable progress since then, through this collaborative process. In 2002, the PRF Genetics Consortium was formed; they succeeded in identifying the gene for progeria, in part through their development of a PRF Cell and Tissue Bank, just 10 months later. This single gene mutation leads to an inner nuclear membrane protein, called Lamin A, to be produced abnormally, and a farnesyl group can’t be cleaved. The resultant abnormal protein, called progerin, causes persistent farenesylation, or accumulation of this protein on the nuclear rim.

This leads to distortion of the nucleus of cells and abnormal development, resulting in cells being unable to divide normally and to the cell’s premature aging.

Normal and progeria-distorted nuclei of cell

Astonishingly, PRF funded and coordinated the first clinical trial of a treatment for progeria, using a drug called lonafarnib, a farnesyltransferase inhibitor (FTI), which inhibits this process. FTI had been shown to prevent cardiovascular disease —the major cause of death in children with progeria—in young mice and to reverse disease somewhat in older ones.

The trial included 28 children—75% of the world’s population with the disease at that time, including Sam Berns. His mother, Leslie Gordon, was the lead author on the report announcing the first potential treatment of progeria, with some patients showing modest improvement in weight gain, cardiovascular, and bone disease.

Target sites for drugs for progeria

Since then, other targets for treatment are under study. A triple drug trial is in progress, combining drugs for the targets shown: lonafarnib (FTI inhibitor, pravastatin, and zoledronic acid, a bisphosphonate. (The latter drugs have been marketed for some years for treatment of elevated cholesterol and osteoporosis, respectively). Rapamycin (sirolimus), a macrolide antibiotic used as an immunosuppressant, is also being explored, as it removes progerin from the cell’s nuclear membrane.

Barriers in diagnosing and caring for patients with rare diseases

These two cases illustrate some of the difficulties families face in caring for children with rare diseases. First, symptoms may be subtle or unusual and therefore not be readily recognized by physicians. Many of us may not ever encounter patients with recognized disease in our careers and thus lack the opportunity to learn from them.

Time and knowledge constraints limit physicians, too. For example, patients with complaints of “chronic fatigue” syndrome are enormously time-consuming and frustrating to attempt to diagnose. Their complaints simply cannot be addressed in the 15-20 minutes often allotted for a visit. The same is true with mitochondrial diseases, where symptoms might affect a variety of organs, with varying degrees of severity, and therefore with widely different symptoms.

Similarly, not all believe in a physiologic basis for some syndromes—reportedly a problem in Justina’s care, as well as people with “chronic fatigue,” “chronic Lyme,” or PANDAS (pediatric autoimmune neuropsychiatric disease associated with Strep).

There are huge obstacles to diagnosis imposed by insurance. Barriers may be from people lacking the necessary insurance coverage to obtain testing. But insurers have also denied testing to make a diagnosis, given that there is no specific treatment for many rare diseases.

Lack of funding is a growing problem. In Canada, the cbc notes, “In the past five years the federal government has dismissed more than 2,000 scientists, and hundreds of programs and world-renowned research facilities have lost their funding. Programs that monitored things such as smoke stack emissions, food inspections, oil spills, water quality and climate change have been drastically cut or shut down.” In the U.S., the sequester imposed by Congress imposed an initial 5% cut in research spending. NIH has lost 25% of its funding since 2003. In a survey last fall, 1/3 of scientists said they had laid off researchers. This is not just an immediate problem, but is likely to decimate US research, persuading aspiring young basic science researchers to seek alternative careers.

Difficulties in designing studies for rare diseases

The progeria trial also illustrates the difficulty in designing studies and getting them accepted for publication. The first trial has been criticized for being inconclusive, though some patients showed improvement. Clearly, it is not possible to amass large numbers of patients to demonstrate efficacy definitively. Nor is it possible to do a randomized controlled trial, so observational studies were done, comparing the children to their pre-treatment growth and studies. [Note: It would have been unethical to do a clinical trial comparing treatment to placebo, since progeria is a progressive and universally fatal disease, with children generally dying by their early teens.]

Getting small trials like this accepted for publication may also be more difficult, noted Dr. Mark Kieran, Director of Pediatric Medical Neuro-oncology at the Dana-Farber/Children’s Hospital Cancer Center, who headed the progeria trial. This may be because of their non-traditional design, and because some journals may perhaps be more interested in blockbuster stories with immediate and broad economic impact.

An excellent overview of other barriers to research for rare diseases is available here and for mitochondrial disease is here.

Advocacy

As government funding for research is cut, private advocacy groups like the Progeria Foundation assume a greater role. Obtaining funding for progeria has been easier, perhaps, than for some other rare diseases because understanding progeria help lead to finding drugs to slow aging, with great commercial potential. Having bright, articulate, well-educated and committed activist parents like Gordon is an enormous boost. And so is having a child like Sam, who educated the public about his disease so passionately, as he did at TEDMED in 2012, when I heard him with Dr. Francis Collins. Sam subsequently shared his inspiring philosophy for life in TEDxMidAtlantic 2013 and Life According to Sam. In an NPR interview, “Sam says the most important thing people should know about him is that he has a great family and a very happy life.” Rose would say the same.

Credits

"Molecules to Medicine" banner © Michelle Banks

Photo of Dr. Collins and Sam Berns from Dr. Collins moving tribute to Sam, Director's Blog

Molecular basis of progeria - PLOS Biology

Medications that inhibit farnesylation - AlbetaPons, Wikipedia

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The views expressed are those of the author and are not necessarily those of Scientific American.

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