Network encourages close ties to patients

Organizations help with recruitment, study questions

Investigators working in a rare disease field often find that it's an uphill climb to recruit participants, obtain funding, and interest peers in the work.

Now, thanks to the work of the Rare Diseases Clinical Research Network (RDCRN), which is sponsored by the National Institutes of Health (NIH), some of these hurdles have become a little easier to jump.

For example, the RDCRN has helped with patient recruitment by encouraging clinical research sites and patient advocacy groups to work together to promote interest and funding for research.

"When it's clinical research in osteoporosis or hypertension, the recruitment is vastly different than it is in a rare disease," says Brendan Lee, MD, PhD, an investigator with the Howard Hughes Medical Institute and a professor in the department of molecular and human genetics at Baylor College of Medicine in Houston, TX. Lee studies urea cycle disorders as part of the network.

"But at the same time, we've found in our region some very motivated families," Lee says. "They are eager to help."

The families have assisted with a web site about the disorder and have supported a patient registry, Lee says.

"Interaction with families, and a partnership with them, is critical," Lee notes. "We work very closely with the primary family support organization, the National Urea Cycle Foundation."

Lee and other investigators describe how they have collaborated with patients, foundations, and families:

Rett Syndrome:

Investigators studying Rett Syndrome, which primarily impacts girls, developed satellite clinics across the country, in conjunction with the International Rett Syndrome Association (IRSA) of Clinton, MD, says Jane Lane, RN, BSN, a research nurse manager at the Civitan International Research Center at the University of Alabama, Birmingham.

"The two major centers for Rett Syndrome are in Houston, TX, and here in Birmingham, AL, so we had no problem in drawing patients from south of the Mason-Dixon line," Lane says. "But it's more difficult for families in other regions of the country."

Parents and family members of Rett Syndrome children have been very motivated to assist researchers, says Alan K. Percy, MD, professor in pediatrics, neurology, neurobiology, and genetics and associate director of the Civitan International Research Center and medical director of the Sparks Clinic at the University of Alabama.

"We have a very strong working relationship with the International Rett Syndrome Association, and I became scientific director with the association a year ago in January," Percy says.

In order to increase enrollment in Rett Syndrome clinical trials, investigators developed the novel strategy of bringing clinics to various regions of the country, he adds.

Investigators in the rare diseases network worked with the IRSA to establish satellite clinics for the purpose of increasing clinical research enrollment, but also to educate young physicians, therapists, and nurses about Rett Syndrome, in hopes they would start a Rett Syndrome clinic in their area, Lane explains.

For instance, one clinic was established two years ago in Oakland, CA, and it was named the Katie Clinic in honor of a Rett Syndrome patient. Its medical support comes from Oakland Children's Hospital, and the patient's family has been instrumental in supporting the clinic, Lane says.

"In New Jersey, there's a similar clinic in the works, but it's not established yet," Lane says.

The Katie Clinic is full service and provides all ancillary health and therapeutic services, Lane says.

The satellite clinics are held on weekends, and there are close to 70 patients enrolled and seen for follow-up every six months in various locations across the country, Lane says.

The clinic teams consist of physicians, nurses, genetic counselors, and nutritionists, she adds.

"We hope we will have between 75 and 100 children at each clinic," Percy says.

Urea cycle disorders:

Urea cycle disorder organizations are very well organized and have helped investigators with recruitment, Lee notes.

Also, representatives of family support organizations participate at RDCRN teleconferences and meetings, he says.

Urea cycle disorders are a group of genetic conditions that affect the body's ability to handle nitrogen, mostly from protein food intake, but also nitrogen created within the body, Lee explains.

"Patients with urea cycle disorders have a block in the enzymatic and transporter proteins that affect the ability to convert this nitrogen into urea," Lee says. "The excess nitrogen travels around as ammonia, and it can lead to coma and death."

One thing researchers are learning from the network involvement is that many patients present later in life in a nonclassical fashion, he notes.

"The classical presentation is often a newborn who becomes comatose, develops seizures, and dies, often with the diagnosis of Reye syndrome," Lee says.

Recent research suggests that patients sometimes have partial blockage in their ability to convert nitrogen from protein, and they could be asymptomatic clinically until following a stress event, such as eating too much protein or a viral illness, Lee explains.

Collaboration with patients, families and advocacy groups has been very helpful, he says.

"I'm a pediatrician and a geneticist, and I think we have more to learn from families than we do from each other," Lee says. "It's how families present with their own clinical problems that points us in the direction we need to take in research."

For example, in one urea cycle protocol, investigators became aware that patients were having significant liver disease, Lee explains.

Some patients had pediatric hypertension, and while the evidence was all anecdotal, it encouraged researchers to ask whether the excess argininosuccinic acid being made in patients with this specific urea cycle problem was toxic to the liver, Lee says.

"We give patients amino acids to make more precursors to get rid of the nitrogen that builds up in their bodies, and we think it's very effective," Lee says. "But we wondered whether the treatment itself could have the unwanted side effect of impacting the liver by making more of this acid."

Since patients raised questions about the liver disease, researchers were able to address this issue with possible research projects, he says.

Angelman, Rett & Prader-Willi Syndromes:

Other researchers involved in the rare diseases network noted ways patients and families have impacted their research and, occasionally, even study design.

For example, investigators working in the Angelman, Rett & Prader-Willi Syndrome Consortium have discovered new areas of investigation because of the input from families, says Steve Skinner, MD, a senior clinical geneticist and associate director, and director of clinical services at the Greenwood Genetic Center in Greenwood, SC.

"I think it's important to have families involved in designing research," Skinner says. "The trials are going to benefit them and help them."

While researchers have a scientific interest in the rare diseases, the families live with the conditions and know what's most important to their own lives, he notes.

"They're also very powerful advocates for fundraising, awareness, and political organization," Skinner says. "They can do a lot more than we can as individual investigators, so it's a very good partnership."

Rett Syndrome families convinced researchers to investigate the seemingly high incidence of gall bladder disease among young patients, Skinner says.

"We didn't know about this until families pointed it out to us, and so we did an incidence study and confirmed it," he says.

While basic science and animal studies are very important, one of the goals of the NIH is to do translational research from basic science to what will benefit patients, Skinner says.

"One of the NIH's goals with these grants is to do something that will benefit patients and their lives," Skinner explains. "So we're starting out with natural history studies because many of these diseases don't have a good baseline of what is the norm and what you can expect to see developmentally, as well as what problems you can expect."

Once these natural histories are complete, investigators will design an intervention trial to see if they can make a difference in patients' lives through better quality of life or survival rates, he adds.

Lung Diseases:

The Lung Disease Consortium has worked closely with the Alpha-1 Foundation of Miami, FL, which is named after the disease of Alpha-1 Antitrypsin Deficiency, says Charlie Strange, MD, professor of pulmonary and critical care medicine at the Medical University of South Carolina in Charleston.

"The Alpha-1 Foundation has set up significant infrastructure to support research and run the Alpha-1 registry of more than 3,000 individuals," Strange says.

All 3,000 people have agreed to be involved in research if the right protocol comes their way.

"In this way, new drugs and new therapies that may have had a hard time enrolling patients with a rare disease have an almost instant way of enrolling people," Strange explains. "We can enroll a clinical trial in a heartbeat, and there are significant advantages to come to the FDA with a shorter review time."

The Alpha-1 Foundation has also set up an infrastructure of clinical resource centers, as well as a DNA and tissue bank. When a new patient is diagnosed, they are invited to donate blood/tissue to the DNA tissue bank, Strange says.

Alpha-1 patients sit at research meetings and discuss options of investigation, he adds.

The Lung Disease Consortium also works with other foundations and advocacy groups, and some of these have been established by the consortium and Alpha-1 in recent years, Strange says.

Alpha-1 Foundation also has a health care arm called Alpha Net, which is a foundation that has spun off large amounts of money to support Alpha-1 research, including $28 million in research over the past few years, Strange says.

"With this rare disease, that amount is rather significant, and it helps tide over seasoned and young investigators," he adds.

Neurologic channelopathies:

Investigators working in the area of neurologic channelopathies have sat at meetings with the president of the Periodic Paralysis Association of Tracy, CA, says Richard J. Barohn, MD, chair and professor in the department of neurology at the University of Kansas Medical Center in Kansas City, KS.

"The association's president has been at RDCRN meetings twice a year, and he's had significant input in these protocols," Barohn says. "We've had more patients' input for this research than we have through other research studies I've been involved in."

Some of the patient input has helped investigators decide how much testing patients can tolerate, Barohn says.

"At one time, we thought about having patients spend a night in the hospital, and we decided not to do that based on input from patient groups," Barohn says. "We decided to do all of the testing in an outpatient clinic and squeeze as much [information] as we can in one day."

Genetic diseases of mucociliary clearance:

Research sites studying genetic diseases of mucociliary clearance have worked closely with the Primary Ciliary Dyskinesia (PCD) Foundation of Phoenix, AZ, which has served as a sounding board, says Susan Minnix, RN, BSN, a research nurse coordinator at the University of North Carolina at Chapel Hill.

"Some investigators have presented at the PCD Foundation, and we keep them abreast of what we're doing," Minnix says. "We've listened to their input and questions."

Patients with PCD have a genetic sinus pulmonary disease, characterized by chronic otitis media and a history of neonatal respiratory distress, Minnix explains.

Half of the patients have reversed organs with their heart and stomach reversed, and most of them are born full term with lungs full of fluid, resulting in pneumonia or collapsed lungs, she adds.

The clinical research site opened a year ago, and so far more than 100 patients have been recruited, Minnix says.

"We have two studies going on, including the rare diseases of the airways, which is a cross-sectional comparison of clinical features," Minnix says. "And another study is a longitudinal study of participants, seeing what happens to their lungs over five years."