RARE DISEASE
Bardet-Biedl syndrome
Bardet-Biedl syndrome
Bardet-Biedl syndrome
Synonyms: BBS
Synonyms: BBS
Synonyms: BBS
Drug discovery
5
drugs
With orphan designations
Overview
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy characterized by rod-cone dystrophy, obesity, polydactyly, renal anomalies, learning disabilities, and hypogonadism. Caused by mutations in at least 24 genes affecting cilia function, it leads to multisystemic complications. Diagnosis relies on clinical criteria (four major features or three major plus two minor). Management requires a multidisciplinary approach addressing metabolic, renal, and visual impairments, with emerging therapies targeting underlying genetic mechanisms [1][5][12].
Burden
Leading morbidity: progressive vision loss, renal failure (30–50% develop chronic kidney disease), and obesity-related complications (e.g., type 2 diabetes) [1][5][12].
Caregiver burden: 53% of total costs stem from hyperphagia/obesity management, productivity loss, and emotional strain [4][9].
Lifetime societal cost: ~$5.2 million per patient, driven by medical care, reduced QALYs, and premature mortality [4][9].
Therapies
Categories: rare abdominal surgical diseases, rare developmental anomalies during embryogenesis, rare endocrine diseases, rare gastroenterological diseases, rare genetic diseases, rare gynecological and obstetric diseases, rare infertility disorders, rare neurological diseases, rare ophthalmic disorders, rare renal diseases, rare transplant-related disorders
Research Papers
243 drug discovery papers about Bardet-Biedl syndrome, with 1 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
243 drug discovery papers about Bardet-Biedl syndrome, with 1 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-14 | Clinical, Genetic, and Endocrine Features of Bardet-Biedl Syndrome in a Pediatric and Adult Cohort.
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by clinical and genetic heterogeneity. Data on the prevalence of clinical manifestations and comorbidities in BBS, particularly in pediatric patients, are limited. This study aimed to assess the prevalence and various manifestations of endocrine and other clinical comorbidities among pediatric and adult patients with BBS. This retrospective chart review included pediatric and adult patients with BBS evaluated at an academic tertiary care center in the United States between 2000 and 2024. The study included 31 patients (7 children and 24 adults) with seven identified pathogenic variants associated with BBS. The most common genetic etiology was biallelic variants in BBS1 (36%). Obesity was diagnosed in 86% of children and 100% of adults. No children had diabetes or prediabetes, whereas 46% of adults were affected. Dyslipidemia was identified in 29% of children and 46% of adults. No thyroid abnormalities were identified in children, whereas 25% of adults were affected. Retinal dystrophy was present in 71% of children and 96% of adults. Polydactyly was observed in 100% of children and 75% of adults. Chronic kidney disease was present in 29% of children and 63% of adults. This study highlights the clinical heterogeneity and substantial multisystem burden of BBS across pediatric and adult patients. The greater prevalence of diabetes/prediabetes, dyslipidemia, thyroid abnormalities, chronic kidney disease, and visual impairment among adults suggests that these complications may emerge or progress over time. Early recognition, proactive longitudinal surveillance, and comprehensive multidisciplinary care are essential to optimize management across the lifespan.
2026-08-01 | Melanocortin-4 Receptor Regulation of Endocrine Axes and Clinical Effects of Setmelanotide.
Bardet-Biedl syndrome (BBS) is a rare ciliopathy characterized by early-onset obesity and multisystem endocrine dysfunction. The melanocortin-4 receptor (MC4R) agonist setmelanotide is approved for hyperphagia-related obesity in BBS, but its endocrine effects remain incompletely understood. In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally. Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time. After 6 months, significant reductions in BMI and HbA1c were observed. Treatment was associated with increases in gonadotropins and testosterone and estradiol age-dependently. IGF-1 levels increased independently of weight change, while TSH decreased without corresponding changes in peripheral thyroid hormones. These effects were established within the first 6 months and remained stable thereafter. Setmelanotide exerts pleiotropic effects beyond weight reduction, modulating multiple endocrine axes in BBS. The observed changes highlight MC4R signaling pathway as a key integrator of metabolic and endocrine function and suggest partially weight-independent therapeutic effects. German Federal Ministry of Research and Education and Rhythm Pharmaceuticals.
2026-07-22 | Regulation and adaption of adenylyl cyclases and cAMP signaling networks in brown and beige adipose tissue
β-adrenergic stimulation of brown adipose tissue (BAT) via G-protein coupled receptors (GPCRs) promotes BAT activity by increasing cellular cAMP levels through activating adenylyl cyclase 3 (AC3). We recently demonstrated that upon cold exposure, BAT expresses a truncated AC3 isoform (AC3-AT). Loss of Adcy3-at increases energy expenditure and protects from obesity and ensuing metabolic imbalances. I revealed that AC3-AT is retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and in turn interacts and sequesters AC3, thereby limiting cAMP synthesis. Thus, these findings reveal that AC3-AT acts as a cold-induced rheostat in BAT, limiting cAMP synthesis during chronic BAT activation. To preserve brown adipocyte function and tissue homeostasis, it is crucial to maintain a pool of adipocyte progenitor cells (APCs), which differentiate into mature brown adipocytes. Two distinct APC subpopulations in BAT are platelet-derived growth factor receptor α (PDGFRA)-expressing cells and highly thermogenic transient-receptor potential (TRP) vanilloid 1 (TRPV1) APCs derived from vascular smooth muscle (VSM) cells. One subcellular compartment, enriched with a unique receptor repertoire that has been proposed to play a key role during APC differentiation is the primary cilium. Increasing ciliary cAMP levels, has been shown to promote APC differentiation. Notably, AC3 is predominantly localized in primary cilia of APCs. However, how AC3 regulates ciliary cAMP signaling in brown APCs to control proliferation and differentiation is not known. I demonstrated that loss of AC3 in brown APCs reduces ciliary cAMP synthesis and in turn subpopulation expansion and differentiation. Furthermore, loss of AC3 in highly thermogenic APCs reduced BAT activity during an acute cold stimulus. In contrast increased ciliary AC3 abundance promoted expansion of brown APCs in BAT after cold exposure. My results reveal that AC3-mediated ciliary cAMP signaling is controlling brown APC differentiation and function and, therefore, a crucial regulator of BAT homeostasis. The ciliary dysfunction Bardet-Biedl syndrome (BBS) caused by mutations in one of the BBS genes leads to severe obesity and altered ciliary GPCR composition. Loss of BBS proteins has been associated with impaired thermogenesis and lipid metabolism, and on a cellular level a fate switch to a more fibrogenic phenotype in white APCs. However, whether BBS affects the function of brown APCs is not known. I demonstrated that loss of BBS8 reduces ciliary AC3 abundance in brown APCs and in turn subpopulation expansion and differentiation in BAT. These results reveal that BBS affects ciliary cAMP signaling in brown APCs and thereby alters subpopulation abundance and adipogenesis, and potentially BAT function.
2026-05-20 | Primary Cilia-Mediated GPCR Signaling in Neuroendocrine Physiology
Primary cilia are important signaling organelles found on most cell types in the human body, including neurons and endocrine cells where they are responsible for coordinating diverse signaling pathways for cell-cell communication. Yet, despite their ubiquitous nature, how cilia composition and signaling are regulated across development, physiological inputs, and disease is not fully understood; an overview of cilia function in signaling and disease is provided in Chapter 1. I propose that the primary cilium serves as a dynamic signaling hub whose molecular composition and function are actively remodeled throughout development and under different physiological constraints and that their dysfunction leads to neuroendocrine disease features observed in syndromic ciliopathies.In Chapter 2, I provide results that specifically demonstrate that primary cilia and the BBSome component BBS4 are required for postnatal pituitary development, with loss of ciliary signaling resulting in pituitary hypoplasia, altered gonadotroph fate, and impaired Hedgehog (Hh) signaling.Chapter 3 results focus on cilia within the hypothalamus, where I show that neuronal cilia undergo postnatal remodeling of specific ciliary proteins in an age, sex, and physiological state-dependent manner. This is assessed via changes in ciliary length and frequency and protein composition, including a development associated transition f of proteins enriched in hypothalamic cilia from one (Arl13b) to another (Adcy3). Moreover, I identify physiological condition and receptor specific changes in the localization and morphology of neuronal cilia suggesting that they dynamically adapt to metabolic state.Studies investigating the cellular origins of the ciliopathy Bardet–Biedl syndrome (BBS)–associated hyperphagia are the focus of Chapter 4. Specifically, we uncover a surprising mechanism between receptor cilia localization and signaling efficacy in brain feeding centers of the mouse. BBSome disruption selectively reduces ciliary localization of the downstream effector Adcy3 in MC4R-expressing neurons, despite preserved receptor localization. We next identify PKA-mediated negative feedback as a key regulator of ciliary Adcy3 levels, linking GPCR activity to dynamic control of signaling capacity. Notably, loss of ciliary Adcy3 is age dependent and temporally coincides with the onset of hyperphagia and obesity in BBS models.Inhibition of PKA activity in the hypothalamus also leads to obesity and altered ciliary Adcy3 levels. Thus, across different genetic and physiological obesity paradigms, reduced PKA activity, specifically in MC4R-expressing neurons, emerges as a common theme, suggesting ciliary PKA signaling as a central mediator of anorexigenic control.Together, these studies redefine neuronal primary cilia as adaptive signaling compartments whose function depends on coordinated regulation of receptors, effectors, and feedback mechanisms and their implications and future directions are discussed in Chapter 5. They reveal how disruption of ciliary signaling, not simply GPCR mislocalization, drives neuroendocrine disease and obesity, providing new insight into the pathogenesis of ciliopathies and energy balance disorders. A comprehensive understanding of these processes and mechanisms will reveal additional roles for cilia in other behaviors and how their disruption potentially contributes to other neuroendocrine disorders.
2026-04-21 | A systematic literature review of economic evaluations of setmelanotide.
PURPOSE: This systematic literature review (SLR) aimed to assess the economic value of setmelanotide, a selective melanocortin-4 receptor agonist, in the treatment of rare genetic diseases of obesity (RGDOs), specifically Bardet-Biedl syndrome (BBS), pro-opiomelanocortin (POMC) deficiency, and leptin receptor (LEPR) deficiency. METHODS: The SLR was conducted according to PRISMA guidelines and registered on PROSPERO. Systematic searches were performed in Embase, MEDLINE/PubMed, and Global Health, supplemented by manual searches and reference screening. Inclusion criteria included full economic evaluations (cost-effectiveness and cost-utility analyses) published in English since 2019. Data extraction and quality assessment followed established checklists (BMJ, CHEERS 2022), with findings synthesised descriptively due to heterogeneity in study designs and settings. RESULTS: Four studies (one CEA, three CUAs) met inclusion criteria, all employing model-based frameworks from a healthcare payer perspective with a lifetime horizon. Incremental cost-effectiveness ratios (ICERs) varied: NICE appraisals in the UK suggested potentially favorable or even negative ICERs, while the Canadian CADTH review reported ICERs exceeding CAD $2 million/QALY, far above conventional willingness-to-pay thresholds. Key drivers included drug acquisition cost, severity of hyperphagia, and caregiver burden. All studies noted significant uncertainty due to limited long-term data and small patient populations. CONCLUSIONS: While setmelanotide demonstrates clinical benefit in RGDOs, its high cost poses substantial challenges to conventional pharmacoeconomic evaluations. Adoption may require significant price reductions or alternative value assessment frameworks, particularly for rare diseases. Further research is needed to address long-term effectiveness and ethical considerations in economic evaluations.
2026-08-14 | Clinical, Genetic, and Endocrine Features of Bardet-Biedl Syndrome in a Pediatric and Adult Cohort.
Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder characterized by clinical and genetic heterogeneity. Data on the prevalence of clinical manifestations and comorbidities in BBS, particularly in pediatric patients, are limited. This study aimed to assess the prevalence and various manifestations of endocrine and other clinical comorbidities among pediatric and adult patients with BBS. This retrospective chart review included pediatric and adult patients with BBS evaluated at an academic tertiary care center in the United States between 2000 and 2024. The study included 31 patients (7 children and 24 adults) with seven identified pathogenic variants associated with BBS. The most common genetic etiology was biallelic variants in BBS1 (36%). Obesity was diagnosed in 86% of children and 100% of adults. No children had diabetes or prediabetes, whereas 46% of adults were affected. Dyslipidemia was identified in 29% of children and 46% of adults. No thyroid abnormalities were identified in children, whereas 25% of adults were affected. Retinal dystrophy was present in 71% of children and 96% of adults. Polydactyly was observed in 100% of children and 75% of adults. Chronic kidney disease was present in 29% of children and 63% of adults. This study highlights the clinical heterogeneity and substantial multisystem burden of BBS across pediatric and adult patients. The greater prevalence of diabetes/prediabetes, dyslipidemia, thyroid abnormalities, chronic kidney disease, and visual impairment among adults suggests that these complications may emerge or progress over time. Early recognition, proactive longitudinal surveillance, and comprehensive multidisciplinary care are essential to optimize management across the lifespan.
2026-08-01 | Melanocortin-4 Receptor Regulation of Endocrine Axes and Clinical Effects of Setmelanotide.
Bardet-Biedl syndrome (BBS) is a rare ciliopathy characterized by early-onset obesity and multisystem endocrine dysfunction. The melanocortin-4 receptor (MC4R) agonist setmelanotide is approved for hyperphagia-related obesity in BBS, but its endocrine effects remain incompletely understood. In this prospective single-centre observational cohort study, 58 genetically confirmed BBS patients initiating setmelanotide therapy were followed longitudinally. Linear mixed-effects models adjusted for age, sex, and BMI z-score were used to evaluate changes over time. After 6 months, significant reductions in BMI and HbA1c were observed. Treatment was associated with increases in gonadotropins and testosterone and estradiol age-dependently. IGF-1 levels increased independently of weight change, while TSH decreased without corresponding changes in peripheral thyroid hormones. These effects were established within the first 6 months and remained stable thereafter. Setmelanotide exerts pleiotropic effects beyond weight reduction, modulating multiple endocrine axes in BBS. The observed changes highlight MC4R signaling pathway as a key integrator of metabolic and endocrine function and suggest partially weight-independent therapeutic effects. German Federal Ministry of Research and Education and Rhythm Pharmaceuticals.
2026-07-22 | Regulation and adaption of adenylyl cyclases and cAMP signaling networks in brown and beige adipose tissue
β-adrenergic stimulation of brown adipose tissue (BAT) via G-protein coupled receptors (GPCRs) promotes BAT activity by increasing cellular cAMP levels through activating adenylyl cyclase 3 (AC3). We recently demonstrated that upon cold exposure, BAT expresses a truncated AC3 isoform (AC3-AT). Loss of Adcy3-at increases energy expenditure and protects from obesity and ensuing metabolic imbalances. I revealed that AC3-AT is retained in the endoplasmic reticulum, unable to translocate to the plasma membrane and in turn interacts and sequesters AC3, thereby limiting cAMP synthesis. Thus, these findings reveal that AC3-AT acts as a cold-induced rheostat in BAT, limiting cAMP synthesis during chronic BAT activation. To preserve brown adipocyte function and tissue homeostasis, it is crucial to maintain a pool of adipocyte progenitor cells (APCs), which differentiate into mature brown adipocytes. Two distinct APC subpopulations in BAT are platelet-derived growth factor receptor α (PDGFRA)-expressing cells and highly thermogenic transient-receptor potential (TRP) vanilloid 1 (TRPV1) APCs derived from vascular smooth muscle (VSM) cells. One subcellular compartment, enriched with a unique receptor repertoire that has been proposed to play a key role during APC differentiation is the primary cilium. Increasing ciliary cAMP levels, has been shown to promote APC differentiation. Notably, AC3 is predominantly localized in primary cilia of APCs. However, how AC3 regulates ciliary cAMP signaling in brown APCs to control proliferation and differentiation is not known. I demonstrated that loss of AC3 in brown APCs reduces ciliary cAMP synthesis and in turn subpopulation expansion and differentiation. Furthermore, loss of AC3 in highly thermogenic APCs reduced BAT activity during an acute cold stimulus. In contrast increased ciliary AC3 abundance promoted expansion of brown APCs in BAT after cold exposure. My results reveal that AC3-mediated ciliary cAMP signaling is controlling brown APC differentiation and function and, therefore, a crucial regulator of BAT homeostasis. The ciliary dysfunction Bardet-Biedl syndrome (BBS) caused by mutations in one of the BBS genes leads to severe obesity and altered ciliary GPCR composition. Loss of BBS proteins has been associated with impaired thermogenesis and lipid metabolism, and on a cellular level a fate switch to a more fibrogenic phenotype in white APCs. However, whether BBS affects the function of brown APCs is not known. I demonstrated that loss of BBS8 reduces ciliary AC3 abundance in brown APCs and in turn subpopulation expansion and differentiation in BAT. These results reveal that BBS affects ciliary cAMP signaling in brown APCs and thereby alters subpopulation abundance and adipogenesis, and potentially BAT function.
2026-05-20 | Primary Cilia-Mediated GPCR Signaling in Neuroendocrine Physiology
Primary cilia are important signaling organelles found on most cell types in the human body, including neurons and endocrine cells where they are responsible for coordinating diverse signaling pathways for cell-cell communication. Yet, despite their ubiquitous nature, how cilia composition and signaling are regulated across development, physiological inputs, and disease is not fully understood; an overview of cilia function in signaling and disease is provided in Chapter 1. I propose that the primary cilium serves as a dynamic signaling hub whose molecular composition and function are actively remodeled throughout development and under different physiological constraints and that their dysfunction leads to neuroendocrine disease features observed in syndromic ciliopathies.In Chapter 2, I provide results that specifically demonstrate that primary cilia and the BBSome component BBS4 are required for postnatal pituitary development, with loss of ciliary signaling resulting in pituitary hypoplasia, altered gonadotroph fate, and impaired Hedgehog (Hh) signaling.Chapter 3 results focus on cilia within the hypothalamus, where I show that neuronal cilia undergo postnatal remodeling of specific ciliary proteins in an age, sex, and physiological state-dependent manner. This is assessed via changes in ciliary length and frequency and protein composition, including a development associated transition f of proteins enriched in hypothalamic cilia from one (Arl13b) to another (Adcy3). Moreover, I identify physiological condition and receptor specific changes in the localization and morphology of neuronal cilia suggesting that they dynamically adapt to metabolic state.Studies investigating the cellular origins of the ciliopathy Bardet–Biedl syndrome (BBS)–associated hyperphagia are the focus of Chapter 4. Specifically, we uncover a surprising mechanism between receptor cilia localization and signaling efficacy in brain feeding centers of the mouse. BBSome disruption selectively reduces ciliary localization of the downstream effector Adcy3 in MC4R-expressing neurons, despite preserved receptor localization. We next identify PKA-mediated negative feedback as a key regulator of ciliary Adcy3 levels, linking GPCR activity to dynamic control of signaling capacity. Notably, loss of ciliary Adcy3 is age dependent and temporally coincides with the onset of hyperphagia and obesity in BBS models.Inhibition of PKA activity in the hypothalamus also leads to obesity and altered ciliary Adcy3 levels. Thus, across different genetic and physiological obesity paradigms, reduced PKA activity, specifically in MC4R-expressing neurons, emerges as a common theme, suggesting ciliary PKA signaling as a central mediator of anorexigenic control.Together, these studies redefine neuronal primary cilia as adaptive signaling compartments whose function depends on coordinated regulation of receptors, effectors, and feedback mechanisms and their implications and future directions are discussed in Chapter 5. They reveal how disruption of ciliary signaling, not simply GPCR mislocalization, drives neuroendocrine disease and obesity, providing new insight into the pathogenesis of ciliopathies and energy balance disorders. A comprehensive understanding of these processes and mechanisms will reveal additional roles for cilia in other behaviors and how their disruption potentially contributes to other neuroendocrine disorders.
2026-04-21 | A systematic literature review of economic evaluations of setmelanotide.
PURPOSE: This systematic literature review (SLR) aimed to assess the economic value of setmelanotide, a selective melanocortin-4 receptor agonist, in the treatment of rare genetic diseases of obesity (RGDOs), specifically Bardet-Biedl syndrome (BBS), pro-opiomelanocortin (POMC) deficiency, and leptin receptor (LEPR) deficiency. METHODS: The SLR was conducted according to PRISMA guidelines and registered on PROSPERO. Systematic searches were performed in Embase, MEDLINE/PubMed, and Global Health, supplemented by manual searches and reference screening. Inclusion criteria included full economic evaluations (cost-effectiveness and cost-utility analyses) published in English since 2019. Data extraction and quality assessment followed established checklists (BMJ, CHEERS 2022), with findings synthesised descriptively due to heterogeneity in study designs and settings. RESULTS: Four studies (one CEA, three CUAs) met inclusion criteria, all employing model-based frameworks from a healthcare payer perspective with a lifetime horizon. Incremental cost-effectiveness ratios (ICERs) varied: NICE appraisals in the UK suggested potentially favorable or even negative ICERs, while the Canadian CADTH review reported ICERs exceeding CAD $2 million/QALY, far above conventional willingness-to-pay thresholds. Key drivers included drug acquisition cost, severity of hyperphagia, and caregiver burden. All studies noted significant uncertainty due to limited long-term data and small patient populations. CONCLUSIONS: While setmelanotide demonstrates clinical benefit in RGDOs, its high cost poses substantial challenges to conventional pharmacoeconomic evaluations. Adoption may require significant price reductions or alternative value assessment frameworks, particularly for rare diseases. Further research is needed to address long-term effectiveness and ethical considerations in economic evaluations.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
5 orphan drug designations for Bardet-Biedl syndrome, including 2 approved therapies.
5 orphan drug designations for Bardet-Biedl syndrome, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant, replication incompetent adeno-associated virus viral vector platform with a serotype 8 capsid and a cDNA encoding the human BBS10 gene (AAV8-RK-BBS10) | gene therapies | FDA | 2024-10-11 | — | MeiraGTx UK II Ltd |
adeno-associated virus 2/8 expressing human BBS1 gene | gene therapies | FDA | 2020-10-16 | — | Axovia Therapeutics |
adeno-associated virus 2/9 expressing human BBS1 gene | gene therapies | FDA | 2020-10-16 | — | Axovia Therapeutics |
setmelanotide [Imcivree] | small molecules | FDA | 2019-09-19 | 2022-06-16 | Rhythm Pharmaceuticals, Inc |
Setmelanotide [Imcivree] | small molecules | EMA | 2019-08-21 | 2022-09-05 | Rhythm Pharmaceuticals Netherlands B.V. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.