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Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2.150), necessary for normal lysosomal degradation of the glycosaminoglycan heparan sulfate (HS). Tralesinidase alfa (TA), a fusion protein comprised of recombinant human NAGLU and a modified human insulin-like growth factor 2, is in development as an enzyme replacement therapy that is administered via intracerebroventricular (ICV) infusion, thus circumventing the blood brain barrier. Previous studies have confirmed ICV infusion results in widespread distribution of TA throughout the brains of mice and nonhuman primates. We assessed the long-term tolerability, pharmacology, and clinical efficacy of TA in a canine model of MPS IIIB over a 20-month study. Long-term administration of TA was well tolerated as compared with administration of vehicle. TA was widely distributed across brain regions, which was confirmed in a follow-up 8-week pharmacokinetic/pharmacodynamic study. MPS IIIB dogs treated for up to 20 months had near-normal levels of HS and nonreducing ends of HS in cerebrospinal fluid and central nervous system (CNS) tissues. TA-treated MPS IIIB dogs performed better on cognitive tests and had improved CNS pathology and decreased cerebellar volume loss relative to vehicle-treated MPS IIIB dogs. These findings demonstrate the ability of TA to prevent or limit the biochemical, pathologic, and cognitive manifestations of canine MPS IIIB disease, thus providing support of its potential long-term tolerability and efficacy in MPS IIIB subjects. SIGNIFICANCE STATEMENT: This work illustrates the efficacy and tolerability of tralesinidase alfa as a potential therapeutic for patients with mucopolysaccharidosis type IIIB (MPS IIIB) by documenting that administration to the central nervous system of MPS IIIB dogs prevents the accumulation of disease-associated glycosaminoglycans in lysosomes, hepatomegaly, cerebellar atrophy, and cognitive decline., (Copyright © 2022 by The Author(s).)

Objective: As prospective outcomes of septoplasty with or without turbinoplasty beyond the first year are few and have diverging results, this study evaluated later septoplasty results three to four years post-operatively., Methods: Patients undergoing septoplasty completed the Nasal Surgical Questionnaire pre-operatively, and at 6-12 months (early post-operative assessment) and 36-48 months (late post-operative assessment) after surgery. Primary outcome was visual analogue scale ratings for nasal obstruction (with a scale ranging from 0 to 100)., Results: In 604 patients with high response rates, the largest improvements in nasal obstruction were from pre-operative to early post-operative assessments (daytime score reduction = 33.9, night-time reduction 40.5). Nasal obstruction ratings worsened slightly between early and late post-operative assessments (daytime score increase = 5.3, night-time score increase = 9.7). Improvements were better in patients aged over 35 years and in those with pre-operative nasal obstruction scores of more than 62. There were no differences based on surgery type, septal deviation, allergy or smoking., Conclusion: Septoplasty improves nasal obstruction in both the first and the fourth year after surgery. Post-operative improvements decline slightly over time but remain significant.

Ataxia Telangiectasia (A-T) and Ataxia with Ocular Apraxia Type 1 (AOA1) are devastating neurological disorders caused by null mutations in the genome stability genes, A-T mutated ( ATM ) and Aprataxin ( APTX ), respectively. Our mechanistic understanding and therapeutic repertoire for treating these disorders are severely lacking, in large part due to the failure of prior animal models with similar null mutations to recapitulate the characteristic loss of motor coordination (i.e., ataxia) and associated cerebellar defects. By increasing genotoxic stress through the insertion of null mutations in both the Atm (nonsense) and Aptx (knockout) genes in the same animal, we have generated a novel mouse model that for the first time develops a progressively severe ataxic phenotype associated with atrophy of the cerebellar molecular layer. We find biophysical properties of cerebellar Purkinje neurons (PNs) are significantly perturbed (e.g., reduced membrane capacitance, lower action potential [AP] thresholds, etc.), while properties of synaptic inputs remain largely unchanged. These perturbations significantly alter PN neural activity, including a progressive reduction in spontaneous AP firing frequency that correlates with both cerebellar atrophy and ataxia over the animal's first year of life. Double mutant mice also exhibit a high predisposition to developing cancer (thymomas) and immune abnormalities (impaired early thymocyte development and T-cell maturation), symptoms characteristic of A-T. Finally, by inserting a clinically relevant nonsense-type null mutation in Atm , we demonstrate that S mall M olecule R ead- T hrough (SMRT) compounds can restore ATM production, indicating their potential as a future A-T therapeutic., Competing Interests: HP, MA, JC, AN, ME, KV, CB, VS, JK, MP, KN, GH, RG, JM, MI, PM, PM No competing interests declared, (© 2021, Perez et al.)

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B) is an autosomal recessive lysosomal storage disorder caused by the deficiency of alpha-N-acetylglucosaminidase activity, leading to increased levels of nondegraded heparan sulfate (HS). A mouse model has been useful to evaluate novel treatments for MPS IIIB, but has limitations. In this study, we evaluated the naturally occurring canine model of MPS IIIB for the onset and progression of biochemical and neuropathological changes during the preclinical stages (onset approximately 24-30 months of age) of canine MPS IIIB disease. Even by 1 month of age, MPS IIIB dogs had elevated HS levels in brain and cerebrospinal fluid. Analysis of histopathology of several disease-relevant regions of the forebrain demonstrated progressive lysosomal storage and microglial activation despite a lack of cerebrocortical atrophy in the oldest animals studied. More pronounced histopathology changes were detected in the cerebellum, where progressive lysosomal storage, astrocytosis and microglial activation were observed. Microglial activation was particularly prominent in cerebellar white matter and within the deep cerebellar nuclei, where neuron loss also occurred. The findings in this study will form the basis of future assessments of therapeutic efficacy in this large animal disease model.

Objective: This study evaluated the effect of mail non-response on the validity of the results of nasal septal surgery., Method: Six months post-operatively, questionnaires with both prospective and retrospective ratings were mailed to patients. Patients who did not respond (non-responders) were contacted by telephone. This study compared two cohorts of patients using different interviewers (a nurse and a surgeon). Cohort one consisted of 182 patients (with 67 per cent mail response), and cohort two consisted of 454 patients (with 64.8 per cent mail response)., Results: In both cohorts, the improvement in obstruction scores was significantly better among mail responders than among non-responders (telephone interviewees) using prospective ratings, but worse using retrospective ratings., Conclusion: Mail responders had better improvement in nasal obstruction after septoplasty than non-responders. Therefore, low response rates may cause an overestimation of the results. The retrospective ratings obtained through telephone interviews are less reliable because they are influenced by memory and the patients' tendency to give socially acceptable answers.

Background: Postal questionnaires are often used to assess the results of nasal septoplasty, but response rates vary widely. This study assesses strategies designed to increase the response rate., Methods: Postoperative questionnaires using visual analogue scales (VAS) for nasal obstruction were mailed to 160 consecutive patients alternately allocated to one of two groups. Group A received the questionnaire in the usual manner and group B received a modified cover letter with hand-written name and signature and a hand-stamped return envelope., Results: Of the 80 patients in each group, 47 (58.8%) in group A and 54 (67.5%) in group B returned the questionnaire (p = 0.25). There were no age or gender differences between the groups, nor did the pre- and postoperative VAS scores differ between the groups., Conclusion: The strategies used in this study increased the response rate to postal questionnaires by 8.7% points, but this was not a statistically significant or clinically meaningful improvement.

Objective: Questionnaires are often used to assess the results of nasal septoplasty, but response rates vary widely. The possible bias caused by non-responders was evaluated to determine the validity of questionnaire results., Methods: Post-operative questionnaires employing visual analogue scales for nasal obstruction were mailed to 182 patients. The 62 non-responders (34.1 per cent) were contacted by telephone, 58 (93.5 per cent) of whom were contactable and responded orally to the questionnaire., Results: Non-responders were younger, but no different from responders with regard to gender, smoking habits or allergies. Post-operative visual analogue scale obstruction scores were slightly, but not statistically, higher in non-responders. However, because non-responders' pre-operative scores were lower, obstruction scores improved less than in responders. The main reason for not responding was forgetfulness. Some would have preferred an electronic version of the questionnaire., Conclusion: Although post-operative obstruction scores did not differ between the groups, nasal obstruction scores improved more among responders than non-responders. Thus, low response rates may cause bias.