Scruggs, Brittni A.

ABSTRACT 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.

Subretinal and intravitreal injection of retinal gene therapy is associated with serious adverse events and poor efficacy. We sought to improve retinal gene therapy delivery by developing fibrin hydrogel encapsulated adeno-associated virus (FE-AAV). Here we investigate conditions for storage and stability for FE-AAV. FE-AAV containing 1.9 × 109 genome copies of AAV2/2-CMV-GFP was manufactured using fibrinogen reconstituted in 0.01 M sodium citrate, pH 7 (NaC) or phosphate-buffered saline containing 0.001% (v/v) Pluronic F68 (F68). Samples were stored at either −80 °C or 4 °C for up to 16 weeks. Changes in transduction efficiency, and mechanical and physical properties were evaluated. In vitro transduction was significantly (p < 0.05) reduced for FE-AAV manufactured with NaC. In contrast, we observed no change in transduction through 16 weeks for FE-AAV made with F68. Physical changes occurred in FE-AAV stored at −80 °C. In contrast to FE-AAV formulated with NaC, FE-AAV formulated with F68 and stored at 4 °C for 16 weeks was essentially equivalent to freshly made FE-AAV and retained the ability to transduce retinal pigment epithelial (RPE) cells in the pig eye. We conclude that FE-AAV formulated with F68 and stored at 4 °C is stable and shows potential for retinal gene therapy for at least 4 months following manufacture.

ABSTRACT Considerable advances have been made in our understanding of Bardet–Biedl syndrome (BBS), particularly in its core clinical features and molecular genetics, warranting an update to the existing diagnostic criteria framework. Using a rigorous, evidence‐based, and consensus‐driven process, a multidisciplinary group of international experts and patient‐led organizations developed an updated diagnostic algorithm. This algorithm provides practical, updated guidance for clinicians, including a pathway for accurately incorporating genetic findings into the diagnostic process. We recommend that a clinical diagnosis requires either 4 major criteria or 3 major and 2 minor criteria. Revised major criteria are retinal dystrophy, obesity (or overweight in individuals < 2 years old), congenital anomalies of the kidney and urinary tract or chronic kidney disease, hypogonadism/genital anomalies, neurodevelopmental/neurocognitive manifestations, and postaxial polydactyly. The diagnosis can also be established with a positive genetic testing result in patients exhibiting ≥ 1 major criterion, provided that genetic findings should be interpreted in the context of the patient's clinical presentation, age, family history, and overlap with related ciliopathies. These consensus criteria offer a simple algorithm incorporating updated definitions for major and minor criteria and genetic testing to support a timely and accurate diagnosis of patients with BBS, inform genetic counseling, and potentially facilitate earlier access to treatment. Trial Registration: CRIBBS Registry; ClinicalTrials.gov : NCT02329210

Death or dysfunction of retinal pigment epithelium (RPE) cells occurs in age-related macular degeneration (AMD) and certain inherited retinal dystrophies (IRDs). Induced-pluripotent stem cell (iPSC) derived-RPE have been used in early-stage clinical trials to treat AMD and IRDs by injecting them as a cell suspension or monolayers. While RPE transplant shows therapeutic potential, issues ranging from failure to repopulate the entire treatment area, clumping and monolayer folding, and a foreign body response to the support have been reported. We’ve shown that RPE can be grown on high concentration (&gt;30 mg/mL) degradable fibrin hydrogels, and that cell free fibrin hydrogels implanted in the subretinal space degrade without causing inflammation. Here we describe manufacture and surgical implantation of degradable fibrin hydrogels carrying iPSC-RPE into a porcine model of geographic atrophy (GA). Large (15.25 × 58.42 × 0.2 mm) fibrin gel blanks were produced by injection molding, and iPSC-RPE were grown on their surface. Using a mechanical punch, the blank was subdivided into 1.5 × 5.0 × 0.2 mm doses, which fit a custom tool used for storage and surgical placement. Following aseptic packaging, RPE and gels were stable at 37 °C for at least 7 weeks. When transplanted into a pig model of GA, the fibrin scaffold degraded in &lt;1 month and the iPSC-RPE provided partial rescue from GA as assessed by preservation of photoreceptors and blood flow in the choriocapillaris. We conclude that iPSC-RPE delivered on degradable fibrin hydrogels represent a potentially safe and effective approach to RPE transplantation.

Subretinal injection of adeno-associated virus (AAV) is generally more efficacious and less inflammatory than intravitreal injection for retinal gene therapy. However, adverse events (e.g., chorioretinal atrophy) have been reported in many patients receiving subretinal injection of Luxturna (voretigene neparvovec-rzyl) and experimental gene therapies. Subretinal injection confines transduction to the treated area. To address this, we manufactured high-concentration fibrin hydrogels encapsulating AAV2–green fluorescent protein (AAV2- GFP ). Gels had homogeneous AAV distribution, desired mechanical properties, and retained infectivity. Epiretinal placement of fibrin–AAV2- GFP ( n = 11) was compared to subretinal ( n = 5) and intravitreal AAV2- GFP injection ( n = 3). The subretinal group exhibited inconsistent retinal pigment epithelium (RPE) transduction restricted to the injection region with severe atrophy in two cases. The intravitreal group had weak transduction and inflammation. In contrast, epiretinal hydrogels degraded within days and led to broad transduction of RPE without atrophy or inflammation. This technology could advance gene therapy for retinal degenerations and other ocular or systemic disorders.

ABSTRACT Background To explore the prevalence of serious adverse events ( SAEs ) associated with retinal viral gene therapy and to examine trends influencing SAE occurrences in human gene therapy surgeries and pre‐clinical animal trials. Methods Literature review was performed to identify peer‐reviewed human and animal studies relevant to viral gene therapy, subretinal injections, and intravitreal injections. For clinical trials and post‐approval LUXTURNA studies, only those that examined SAEs were included. Results Of included clinical trial studies ( n = 31), SAEs were recorded in 51 out of 438 eyes (11.6%) that received subretinal injections and in 11 out of 348 eyes (3.2%) that received intravitreal injections. There were fewer intravitreal‐related SAEs and less vision loss compared to subretinal gene therapy. Inflammation was the predominant SAE following intravitreal injections, whereas unexplained vision loss was the most common for subretinal injections. Clinical trials utilising subretinal injections met primary or secondary efficacy endpoints more than intravitreal trials. Eighteen studies (429 eyes) of post‐approval LUXTURNA were reviewed, and SAEs were reported in 24.7% of eyes, retinal degeneration being most common (20.7%). For 58 animal studies, SAEs were recorded in 17.3% of eyes that received subretinal injections and 8.7% of eyes that received intravitreal injections. Conclusions Subretinal injections show higher efficacy than intravitreal injections but are associated with more serious adverse events. Consistent adverse event patterns in humans and large animals highlight their predictive value for safety. There is a need for optimised delivery methods, refined dosing protocols, and improved post‐treatment monitoring to improve safety and effectiveness in gene therapy.

Purpose: We describe a case of nontraumatic macular hole in a pediatric patient associated with numerous epiretinal lesions throughout the macula. Methods: A healthy 9-year-old girl presented to retina clinic with several months of blurry vision in the right eye. Clinically, there was a full-thickness macular hole with serous detachment and white epiretinal tufts. Spectral-domain optical coherence tomography confirmed the presence of the full-thickness macular hole with hyperreflective epiretinal proliferations in the right eye and an unremarkable left eye. Systemic workup was negative. After a short period of observation, the patient underwent vitrectomy with internal limiting membrane peel and 14% C3F8 gas tamponade in the right eye. Multiple intraoperative samples were sent for further testing, which were also negative. Results: At 1- and 12 months/1 year postoperative visits, examination showed successful closure of the full-thickness macular hole with resolution of the subretinal fluid and improved VA. Conclusion: Nontraumatic macular holes in pediatric patients warrant systemic and ocular workup, including fluorescein angiography and laboratory testing. Good anatomic and visual outcomes are generally seen with spontaneous and surgical closures of macular holes in this age group. Early vitrectomy with histologic analysis of ocular samples should be considered in pediatric macular hole cases associated with vitreoretinal traction, especially those with epiretinal abnormalities.

Purpose: To report the rare clinical, optical coherence tomography, and optical coherence tomography-angiography (OCT-A) findings of a visually significant choroidal neovascular membrane in the setting of focal choroidal excavation in a child. Methods: Case report and literature review. Results: A 9-year-old girl with focal choroidal excavation–related central choroidal neovascular membrane based on clinical findings and multimodal imaging. Patient's visual acuity and retinal findings progressed, and bevacizumab intravitreal therapy (off label) was started with resultant stepwise improvement in visual acuity and retinal imaging findings, including regression of a neovascular complex on OCT-angiography. Conclusion: This case highlights the successful use of bevacizumab for a rare choroidal neovascular complex associated with focal choroidal excavation in a child.

A full-term female was admitted at 3 days of life with a worsening rash since birth, concerning for infection. She developed clinical seizures and was transferred to our facility. She was admitted to the pediatric hospital medicine service and diagnostic workup was expanded with several specialists consulted. Presumptive diagnosis was made clinically, with definitive diagnosis established thereafter.