BBS Translational Research and Clinical Practice

Clinical Registries

Registries collect and organize data from patients. This can include diagnostic information, genetic information, clinical data and longitudinal (over time) data. Registries are important for understanding prevalence, creating natural histories and enabling clinical research and improving clinical practice. 

The Clinical Registry Investigating Bardet Biedl Syndrome, or CRIBBS, is the largest clinical registry in the world currently, accepting anyone diagnosed with BBS from anywhere in the world. Currently over 1000 people, from more than a dozen countries, have enrolled in CRIBBS with 785 completing their initial interview. The BBS Foundation provides the majority of funding for CRIBBS, totaling about $750,000 since its creation in 2013.

The UK, with the oldest clinical practice specializing in BBS has the most complete registry of patients and clinical data. The UK’s clinical practice/registry is funded by the UK government. Prior to Brexit there was a pan-European effort to create a registry of several rare syndromes that included kidney disease (European Wolfram, Alstrom, and Bardet Biedl Registry, EuroWABB) coordinated from the University of Birmingham in England, but this is now defunct and it is unclear how many BBS patients were ever included. Other countries including the Netherlands, France and Norway also have centralized patient lists and records with some features of a registry; some are formalising these registries for clinical research and practice.

More on CRIBBS

Retinal Degeneration Gene Therapy

Three different groups are working on developing gene therapy for BBS genes: 

  • Dr. Phil Beales/Axovia working on BBS1

  • Dr. Martha Neuringer working on BBS7

  • Dr. Arlene Drack working on BBS10

Note that current work is limited to treatment of retinal degeneration, not any other symptoms of BBS and, based on results in animal models, these therapies will be most effective for young patients with substantial retinal function.

  • Dr. Beales has shown BBS1 gene therapy to be effective in stopping retinal degeneration in mice. Axovia, with investment from A Race Against Blindness, is planning to apply to begin a human trial of BBS1 gene therapy in the UK in 2025. 

  • “We identified a pedigree of rhesus monkeys at the Oregon National Primate Research Center with a mutation in the BBS7 gene. We have characterized the genotype in 9 cases, including 5 followed from birth, and shown that they replicate all the cardinal features of human BBS7, including retinal degeneration, kidney disease, brain abnormalities and obesity, but with the exception of polydactyly. The retinal degeneration progresses rapidly over the first two years, with the largest losses of structure and function in the macula and cone photoreceptors. A subretinal gene therapy slowed the retinal degeneration and significantly improved cone function, with the best results in younger animals with the least severe degeneration at the time of treatment.” - Dr. Martha Neuringer

    Dr. Neuringer’s lab is continuing to test gene therapy, but there is no current funding to move the work toward human trials. 

  • Dr. Drack has been testing BBS10 gene therapy in mice with support from InVision 2020 and initial funding from the BBS Foundation. Her lab is now in collaboration with Invision and MeiraGTx to further develop this work.

    “In mice with BBS10, subretinal gene therapy markedly slows down the loss of photoreceptor cells and markedly improves the function of cone photoreceptor cells which elicit fine vision. A BBS10 gene therapy vector has been manufactured in MeiraGTx’s GMP facilitymeaning it is appropriate for treating humans. It has been tested for safety and efficacy. MeiraGTx is in the process of obtaining approval for a Specials clinical study in the UK which will treat a small number of patients initially.” — Dr. Arlene Drack

 

Gene Agnostic Retinal Degeneration Therapies

There are a number of gene agnostic therapies for slowing, reversing or replacing retinal degeneration including NAC, NACA and optogenetics. However, the inclusion criteria for these trials almost certainly would lead to BBS patients being ruled out. 

If these trials are successful, the lack of inclusion of people with BBS does not mean they would not be eligible for treatment, but could complicate insurance approvals.

Centers of Excellence

The UK has the original “BBS Clinic” founded by Phil Beales, in operation since the 2010s. Netherlands, Norway, Germany and France have multidisciplinary care provided at one or more centers.

There is no official definition of what a “center of excellence” is in the United States. Some patient organizations create their own definitions, standards and certifications. Marshfield Clinic launched the first BBS Center of Excellence in 2014. With support and encouragement from Rhythm, a number of other health systems have started focused efforts to treat BBS patients. Some are using the terminology “Center of Excellence,” others are not.

These include:

 

Diagnostics

There are two published papers on clinical diagnosis of BBS: Beales et al 1999 and Dolfus et al 2024. Both have guidelines for diagnosing BBS based on primary and secondary clinical symptoms. Rhythm is supporting an effort to create a diagnostic algorithm based on input from clinicians and researchers with experience with BBS.

We are seeing many more people diagnosed at all ages because most BBS genes are now included in three common genetic testing panels: Uncovering Rare Obesity panel, the Renasight kidney disease gene panel and a ciliopathies panel. This includes many adults who were either never diagnosed or told they did not have BBS because their symptoms (especially retinal degeneration and cognitive impairment) were not severe enough. 

However, there are substantial questions about how the results of these tests are being interpreted for patients. We regularly see families post genetic testing results on social media which have been interpreted incorrectly: both families being told they do not have BBS when the results are likely (but not definitively) positive, and people being told they have BBS when the results do not support the diagnosis.

Standards of Care

Dolfus et al 2024 proposes some standards for follow-up clinical testing of patients diagnosed with or suspected to have BBS, but these are mostly suggestions for testing to uncover undiagnosed symptoms.

One of the recommendations from the BBS Research Summit held in conjunction with the BBS Conference this summer was to create a group of clinicians and researchers to publish standards of care for BBS.

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