Frederick Ashby

Sanfilippo syndrome is a rare disease and fatal genetic disorder with no FDA-approved treatment in the United States (US), and no comprehensive assessment of economic disease burden is available. To develop a model to project the economic burden associated with Sanfilippo syndrome in the US using direct costs, indirect costs and valued intangibles (disability-adjusted life years, or DALYs) from 2023 onward. A multistage comorbidity model was generated based on Sanfilippo syndrome symptoms, and disability weights from the 2010 Global Burden of Disease Study. Attributable increase in caregiver mental health burden was estimated using data from the CDC National Comorbidity Survey and retrospective studies on caregiver burden. Direct costs were approximated from the 2019 EveryLife Foundation survey, and indirect costs were estimated from Federal income data. Monetary valuations were adjusted to USD 2023 and given a 3% discount rate from 2023 onward. Incidence of Sanfilippo syndrome was calculated for each age group in each year, and year-over-year DALYs due to patient years lived with disability (YLDs) and years life lost (YLLs) were calculated by comparing to the health-adjusted life expectancy (HALE) in the US. From 2023 to 2043, overall economic burden in the US attributable to Sanfilippo syndrome was estimated to be $2.19 billion USD present value (2023) with current standard of care. The burden to individual families exceeded millions of dollars in present value from time of birth per child born with Sanfilippo syndrome. Sanfilippo syndrome is a rare lysosomal storage disease, however the severe burden associated with the disease for individual families suggests a possible cumulative impact. Our model represents the first disease burden value estimate associated with Sanfilippo syndrome, and underscores the substantial morbidity and mortality burden of Sanfilippo syndrome. • This analysis incorporates direct and indirect costs, while also considering the intangible value losses associated with the disease burden of Sanfilippo syndrome. • This analysis not only considers disease burden (DALYs) for Sanfilippo syndrome patients, but also the parents. • The disability weights used reflect the progressive nature of the disease based on disease course. Intangible valuation in this analysis presumes willingness-to-pay for one DALY averted is on parity with the cost of the US healthcare system to avert one DALY. DALY quantification relied on comorbidity of disease symptoms, which may differ from the true disability burden of the disease. Direct costs rely on previous work that generalizes all lysosomal storage disorders, and will not take into account nuances of MPS III. Thus much of these costs are speculative. As with any estimate, these rely on many presumptions which may or may not apply to the current US system or in the future.

In the original publication [...].

Background: Behavioral, social, and physical characteristics are posited to distinguish the sexes, yet research on transcription-level sexual differences in the brain is limited. Here, we investigated sexually divergent brain transcriptomics in pre-pubertal cynomolgus macaques, a commonly used surrogate species to humans. Methods: A transcriptomic profile using RNA sequencing was generated for the temporal lobe, ventral midbrain, and cerebellum of three female and three male cynomolgus macaques previously treated with an adeno-associated virus vector mix. Statistical analyses to determine differentially expressed protein-coding genes in all three lobes were conducted using DeSeq2 with a false-discovery-rate-corrected p-value of 0.05. Results: We identified target genes in the temporal lobe, ventral midbrain, and cerebellum with functions in translation, immunity, behavior, and neurological disorders that exhibited statistically significant sexually divergent expression. Conclusions: We provide potential mechanistic insights into the epidemiological differences observed between the sexes with regard to mental health and infectious diseases, such as COVID-19. Our results provide pre-pubertal information on sexual differences in non-human primate brain transcriptomics and may provide insight into health disparities between the biological sexes in humans.

Introduction: Sanfilippo syndrome is a rare disease and fatal genetic disorder with no FDA-approved treatment in the United States (US), and no comprehensive assessment of economic disease burden is available. Objectives: To develop a model to estimate the economic burden associated with Sanfilippo syndrome in the US using direct costs, indirect costs and valued intangibles (disability-adjusted life years, or DALYs) from 2023 onward. Design and Setting: A multistage comorbidity model was generated based on Sanfilippo syndrome symptoms, and disability weights from the 2010 Global Burden of Disease Study. Attributable increase in caregiver mental health burden were estimated using data from the CDC National Comorbidity Survey and retrospective studies on caregiver burden. Direct costs were approximated from the 2019 EveryLife Foundation survey, and indirect costs were estimated from Federal income data. Monetary valuations were adjusted to USD 2023 and given a 3% discount rate from 2023 onward. Main Outcome Measures: Incidence of Sanfilippo syndrome was calculated for each year, and year-over-year DALYs due to patient years lived with disability (YLDs) and years life lost (YLLs) were calculated by comparing to the health-adjusted life expectancy (HALE) in the US. Direct and indirect costs were calculated for each simulated patient from onset of symptoms to death. Results: From 2023-2043, overall economic burden in the US attributable to Sanfilippo syndrome was estimated to be $2.04 billion USD present value (2023) with current standard of care. The burden to individual families exceeded $8 million present value from time of birth per child born with Sanfilippo syndrome. Conclusion: Sanfilippo syndrome is a rare lysosomal storage disease, however the severe burden associated with the disease for individual families demonstrates a considerable cumulative impact. Our model represents the first disease burden value estimate associated with Sanfilippo syndrome, and underscores the substantial morbidity and mortality burden of Sanfilippo syndrome.

Sanfilippo syndrome Type-B, also known as mucopolysaccharidosis IIIB (MPS IIIB), accounts for approximately one-third of all Sanfilippo syndrome patients and is characterized by a similar natural history as Type-A. Patients suffer from developmental regression, bone malformation, organomegaly, GI distress, and profound neurological deficits. Despite human trials of enzyme replacement therapy (ERT) (SBC-103, AX250) in MPS IIIB, there is currently no FDA approved treatment and a few palliative options. The major concerns of ERT and gene therapy for the treatment of bone malformation are the inadequate biodistribution of the missing enzyme, N-acetyl-α-glucosaminidase (NAGLU), and that the skeleton is a poorly hit target tissue in ERT and gene therapy. Each of the four known human types of MPS III (A, B, C, and D) is usually regarded as having mild bone manifestations, yet it remains poorly characterized. This study aimed to determine bone mineral content (BMC), volumetric bone mineral density (vBMD), and biomechanical properties in femurs MPS IIIB C57BL/6 mice compared to phenotypic control C57BL/6 mice. Significant differences were observed in MPS IIIB mice within various cortical and cancellous bone parameters for both males and females (p < 0.05). Here, we establish some osteogenic manifestations of MPS IIIB within the mouse model by radiographic and biomechanical tests, which are also differentially affected by age and sex. This suggests that some skeletal features of the MPS IIIB mouse model may be used as biomarkers of peripheral disease correction for preclinical treatment of MPS IIIB.

Background: Physician burnout is increasingly recognized as a problem in physician well-being and may negatively affect patient care outcomes. Burnout can begin at any point of training or practice, potentially as early as the first year of medical school. Thus, there is a need to characterize possible burnout in medical students as the first step to optimizing strategies for mitigation. Traditionally, burnout has been studied using survey-based variables; however, identifying novel physiological and molecular biomarkers could allow for the expansion of screening and intervention strategies. Methods: In this pilot prospective cohort study, we followed a group of preclinical 1st and 2nd year medical students (n = 9) at the University of Florida over one academic year of medical school. We collected survey responses (Maslach Burnout Inventory [MBI], Patient Health Questionnaire-9 [PHQ-9], and Perceived Stress Scale [PSS]) and measured a panel of candidate physiological biomarkers of burnout (Inflammatory Cytokine Panel, Heart Rate Variability [HRV], and Leukocyte Telomere Length). Results: In the study participants, MBI composite scores and PHQ-9 scores showed a statistically significant increase over the course of an academic year, indicating higher levels of medical student burnout. Additionally, respondents reported a statistically significant decrease in time devoted to exercise, and we measured a significant increase in body mass index (BMI) during the academic year. PSS scores showed an upward trend which was not statistically significant. Likewise, average leukocyte telomere length trended downward, but the change was not statistically significant. There were no measured changes in the serum concentration of pro-inflammatory cytokines, and time-domain heart rate variability metrics did not differ significantly between timepoints. Conclusions: This pilot study supports the notion that burnout can begin early in medical school and is detectable via survey instruments in first-year and second-year medical students even with a small sample size. Additionally, leukocyte telomere length could potentially be a useful biomarker of burnout with supporting data, but we did not observe any statistically significant changes in inflammatory cytokines or heart rate variability. Further investigation into these potential biomarkers with larger cohort sizes is required to fully characterize their clinical utility.

Mucopolysaccharidosis type IIIB (MPS IIIB) is an autosomal recessive lysosomal storage disease caused by mutations in the gene that encodes the protein N-acetyl-glucosaminidase (NAGLU). Defective NAGLU activity results in aberrant retention of heparan sulfate within lysosomes leading to progressive central nervous system (CNS) degeneration. Intravenous treatment options are limited by the need to overcome the blood–brain barrier and gain successful entry into the CNS. Additionally, we have demonstrated that AAV8 provides a broader transduction area in the MPS IIIB mouse brain compared with AAV5, 9 or rh10. A triple-capsid mutant (tcm) modification of AAV8 further enhanced GFP reporter expression and distribution. Using the MPS IIIB mouse model, we performed a study using either intracranial six site or intracisterna magna injection of AAVtcm8-codon-optimized (co)-NAGLU using untreated MPS IIIB mice as controls to assess disease correction. Disease correction was evaluated based on enzyme activity, heparan sulfate storage levels, CNS lysosomal signal intensity, coordination, activity level, hearing and survival. Both histologic and enzymatic assessments show that each injection method results in supranormal levels of NAGLU expression in the brain. In this study, we have shown correction of lifespan and auditory deficits, increased CNS NAGLU activity and reduced lysosomal storage levels of heparan sulfate following AAVtcm8-coNAGLU administration and partial correction of NAGLU activity in several peripheral organs in the murine model of MPS IIIB.