Patient Advocacy Groups Band Together To Further Rare Disease Research

May 19, 2022 | The fast-growing Consortium for Outcome Measures and Biomarkers for Neurodevelopmental Disorders (COMBINEDBrain) represents patient advocacy organizations for individuals with rare, neurodevelopmental diseases who are disadvantaged by the small number of affected individuals and scientific brainpower to lead the way. Since its launch two years ago, right before the pandemic struck, COMBINEDBrain has been engaged in a multitude of projects—ranging from assisting with disorder identification and the development of disease-specific basic research models and experimental design to adapting outcome measures, identifying novel biomarkers, and interacting with the U.S. Food and Drug Administration (FDA), according to Terry Jo Bichell, MPH, Ph.D., the organization’s founder and director. 

Two initiatives of COMBINEDBrain have been particularly popular, she notes. One is development of a patient-centric biorepository, and the other a Rent-A-Neuroscientist program.   

After Bichell’s son was born with Angelman syndrome, she began working on finding treatments for his disorder, eventually going back to school to become a neuroscientist. She then began working for foundations to generate more and better research about the genetic condition. That quickly expanded to encompass organizations representing other similar disorders. 

COMBINEDBrain, based in Nashville, Tennessee, is now scaling those efforts across 501(c)3 patient advocacy groups representing over 35 distinct neurodevelopmental disorders, Bichell explains. The shared challenge in accessing patient samples for research—often turning into an unwieldy, cross-continental pursuit—was immediately recognized, making the biorepository for consolidating many of these samples in a single location a cornerstone of the new nonprofit. 

Samples in the biorepository get distributed to researchers and industry upon request and at the lowest possible cost, Bichell continues. Samples can be requested for a single disorder or several of them.  

The types of samples currently collected and stored at the biorepository include blood products, skin biopsies, cerebrospinal fluid (CSF), and various peripheral tissues. “We isolate peripheral blood mononuclear cells from blood, and fibroblasts from skin biopsies, says Anna Pfalzer, Ph.D., a COMBINEDBrain advisor and research assistant professor in the department of neurology at Vanderbilt University Medical Center. 

One focus currently is reprogramming many of these cell lines to generate induced pluripotent stem cells (iPSCs) for patient groups, Pfalzer says. The organization is also working on protocols around less invasively collected biofluids, such as saliva and urine, from which genomic material, or even generate cell lines, can be isolated, she adds.  

Demand is high for CSF samples that are being collected in conjunction with a diagnostic assay, Pfalzer says. “We are working on developing a method to collect CSF under more controlled conditions, but this is difficult given the invasiveness of the procedure to collect it [spinal tap].”  

The biorepository holds samples from over 100 donors, and many of the contributed samples can be used to produce iPSCs, she says. “Our groups are incredibly hopeful that gene therapy and gene editing technologies will be available for their kids in their lifetime, so they are particularly eager to provide their researchers with the tools [cell lines] necessary to investigate these emerging strategies.”  

Pfalzer anticipates that the biorepository will hand out five to 10 samples a year for each of the genetic conditions represented by COMBINEDBrain, some of which will be finite resources. Because of this limitation, she encourages groups to collect longitudinal samples.  

All biosamples are cataloged and stored at Sampled (formerly Infinity BiologiX) in Piscataway, New Jersey, which has over 20 years of biobanking experience. Whatever samples that might be needed by researchers or industry and are not currently in the biorepository can be solicited, Bichell notes, unlike other such laboratory facilities.  

COMBINEDBrain has obtained its own regulatory approval to actively recruit patients based upon advocacy group needs, says Bichell. The nonprofit also has a contract with a nationwide mobile phlebotomy service so blood samples can be collected in patients’ homes and shipped to the biorepository and then sent to requesters. Importantly, the service extends to the pediatric population.  

A second contract has been signed with Quest Diagnostics, which has thousands of lab locations around the country to collect blood in a clinical setting, she adds. 

Patient samples come in through efforts of the individual patient advocacy groups, explains Pfalzer. Typically, COMBINEDBrain hands over advertisements that have been approved by an institutional review board (IRB) for the groups to post on whatever social media platforms they use and the people in those communities happily respond to the invitation. 

The process starts when they email Taylor Morris, the biorepository manager, to set up a time to give their consent via Zoom, she says. The patient advocacy groups, being most familiar with their community, indicate exactly what should be collected and kept from each sample and how it should be stored, and these are the specifics for which consent is sought. 

As part of the consenting process, which is handled by Deputy Director Kristin Hatcher, donors provide their mailing address where the corresponding collection kit (skin biopsy, blood, or CSF) should go, says Pfalzer. If individuals are due for a clinic visit anyway, the sample might be collected at that time as a matter of convenience. 

If not, a mobile phlebotomist can be dispatched to their home. For biopsies, parents make an appointment with a local clinician to have the sample taken with the kit, she says. Most of the patient advocacy groups partially or fully reimburse community members for any out-of-pocket costs associated with these sample donations.    

The nonprofit currently serves only the United States, owing to the difficulty of finding an IRB that works across multiple countries, says Bichell. It is likely COMBINEDBrain will end up using three different IRBs, one each for the UK, Europe, and North America. If so, consent forms will indicate that deidentified samples can be shipped to other biorepositories and as needed, to the host biorepository in New Jersey. The newly branded Sampled just bought a UK biorepository where donations from that region of the world can be stored. 

On the year of launch, the nonprofit spent eight months hashing out with 55 different stakeholders how best to tie the samples in the biorepository to patients’ data in clinical studies as well as with natural history and potentially pilot clinical trial data from industry, Bichell notes. Individuals from Europe and the U.S. had strikingly different sentiments stemming from regulations on privacy, but, in the end, the group settled on The CRID, a service enabling research participants (patients and parents) to create their own unique universal identifier and decide for themselves where to share it. The CRID is actively being used by studies at Lurie Children’s Hospital and Baylor College of Medicine as well as COMBINEDBrain. 

“It’s so simple it is bizarre,” says Bichell. “It becomes sort of like a social security number for research.” In providing that identifier, individuals are giving permission for their data to be shared in a deidentified fashion. “As long as we collect The CRID, health data can be connected to [donated] biosamples, and it is free.” 

The nonprofit was initially funded primarily by Bichell, who continues to donate her time, according to Hatcher. The Nashville-based Hays Foundation also provided a startup grant. 

It is now receiving funding from annual membership dues of between $50 and $900 paid by the 35 patient advocacy groups as well as dues of between $1,000 to $20,000 paid by members of a newly launched industry advisory board—a group that includes Novartis, UCB, Encoded Therapeutics, and Ambit Biosciences—using the sliding scale of the National Organization for Rare Disorders. Those industry groups are typically treating multiple disorders represented by COMBINEDBrain. 

Dues are used primarily to pay the salaries of postdoctoral fellows, graduate student interns, staff scientists (now including an epidemiologist), and the biorepository administrator, Hatcher says. Currently, 13 people are on payroll and another six are under contract, up from four a year ago, she adds. 

In partnership with a team at Duke University, COMBINEDBrain has more recently secured a five-year grant from the FDA for a study to develop the Observer-Reported Communication Ability Measure (ORCA), Bichell notes. The caregiver-reported questionnaire, originally validated for Angelman syndrome, is being expanded to capture communication abilities in 12 additional COMBINEDBrain patient communities. 

Bichell and Pfalzer lead the Rent-A-Neuroscientist program, and one of the many roles of this brain trust is to fill the gaps in research for COMBINEDBrain disorders and to draft grant applications to “get the ball rolling,” Bichell says. To find these gaps, the neuroscientists must become familiar with the literature for the disease as well as have a good understanding of the current state of the field for therapeutics strategies. They also develop strategic research plans, assist in conceptual model development, and draft manuscripts from data that has been collected in their community, although the complete project list is broad.  

Recently, a small foundation focused on a disorder identified only eight years ago “rented” postdoctoral fellow Kyle Horning, Ph.D., as a part-time scientific officer to serve as its resident expert. Horning surveyed the landscape and helped the organization produce a research plan. “When he was going through the literature, he stumbled on a compound that might be really helpful, and so we were able to help them cobble together a collaborative network with the scientists who were in the field already,” says Bichell. 

It came to light that a particular mouse model was needed for proof of concept on the compound, she continues. The Rent-A-Neuroscientist program secured a grant for that mouse model to be developed through Jackson Labs and scientists previously unknown to one another are now trying out the drug in a clinical trial. “Even if this compound isn’t effective, the collaboration probably will endure, and maybe find a better one.”  

The COMBINEDBrain team now juggles many projects for its individual member groups based on the needs of the foundation and the state of research for each disease. The demand for COMBINEDBrain membership and services is high, with a long waitlist for joining, says Bichell. 

But she is hopeful the organization will have the financial resources to hire several more scientists in the immediate future, she quickly adds. This would help COMBINEDBrain fulfill its mission to “speed the path to clinical treatments for people with severe rare, genetic, non-verbal neurodevelopmental disorders by pooling efforts, studies, and data.”