New insights into the landscape of ALPL gene variants in patients with hypophosphatasia from the Global HPP Registry.

Hypophosphatasia (HPP) is a rare, inherited metabolic disease characterized by low tissue-nonspecific alkaline phosphatase activity due to ALPL gene variants. We describe ALPL variants from the observational, prospective, multinational Global HPP Registry. Inclusion in the analysis required a diagnosis of HPP, low serum ALP activity, and ≥1 ALPL variant. Of 1176 patients enrolled as of September 2022, 814 met inclusion criteria in Europe (48.9%), North America (36.7%), Japan (10.2%), Australia (2.6%), and elsewhere (1.6%). Most patients (74.7%) had 1 ALPL variant; 25.3% had ≥2 variants. Nearly all patients (95.6%) had known disease-causing variants; 4.4% had variants of uncertain significance. Disease-causing variants were predominantly missense (770/1556 alleles). The most common variants were c.571G>A (102/1628 alleles), c.1250A>G (66/1628 alleles), and c.1559del (61/1628 alleles). Variant profiles were generally consistent, except in Japan, where a higher proportion of patients (68.7%) had ≥2 ALPL variants, likely because more had disease onset before age 6 months (53.0% vs. 10.1%-23.1% elsewhere). Frameshift mutations (61/164 alleles) and inframe deletions (7/164 alleles) were more common in Japan. Twenty-three novel variants were discovered, each in a single geographic region, predominantly Europe. Analyses confirmed previously known ALPL variants, identified novel variants, and characterized geographic variation in frequency and type of ALPL variants in a large population.

Changes in forced vital capacity over ≤ 13 years among patients with late-onset Pompe disease treated with alglucosidase alfa: new modeling of real-world data from the Pompe Registry.

BACKGROUND: Chronic respiratory insufficiency from progressive muscle weakness causes morbidity and mortality in late-onset Pompe disease (LOPD). Previous Pompe Registry (NCT00231400) analyses for ≤ 5 years' alglucosidase alfa treatment showed a single linear time trend of stable forced vital capacity (FVC) % predicted. METHODS: To assess longer term Pompe Registry data, piecewise linear mixed model regression analyses estimated FVC% predicted trajectories in invasive-ventilator-free patients with LOPD aged ≥ 5 years. We estimated annual FVC change 0-6 months, > 6 months-5 years, and > 5-13 years from treatment initiation, adjusting for baseline age, sex, and non-invasive ventilation. FINDINGS: Among 485 patients (4612 FVC measurements; 8.3 years median follow-up), median ages at symptom onset, diagnosis, and alglucosidase alfa initiation were 34.3, 41.1, and 44.9 years, respectively. FVC% increased during the first 6 months' treatment (slope 1.83%/year; 95% confidence interval: 0.66, 3.01; P = 0.0023), then modestly declined -0.54%/year (-0.79, -0.30; P < 0.0001) during > 6 months-5 years, and -1.00%/year (-1.36, -0.63; P < 0.0001) during > 5-13 years. The latter two periods' slopes were not significantly different from each other (Pdifference = 0.0654) and were less steep than published natural history slopes (-1% to -4.6%/year). Estimated individual slopes were ≥ 0%/year in 96.1%, 30.3%, and 13.2% of patients during the 0-6 month, > 6 month-5 year, and > 5-13 year periods, respectively. CONCLUSION: These real-world data indicate an alglucosidase alfa benefit on FVC trajectory that persists at least 13 years compared with published natural history data. Nevertheless, unmet need remains since most individuals demonstrate lung function decline 5 years after initiating treatment. Whether altered FVC trajectory impacts respiratory failure incidence remains undetermined. TRIAL REGISTRATION: This study was registered (NCT00231400) on ClinicalTrials.gov on September 30, 2005, retrospectively registered.

Natural history study of hepatic glycogen storage disease type IV and comparison to Gbe1ys/ys model.

BackgroundGlycogen storage disease type IV (GSD IV) is an ultrarare autosomal recessive disorder that causes deficiency of functional glycogen branching enzyme and formation of abnormally structured glycogen termed polyglucosan. GSD IV has traditionally been categorized based on primary hepatic or neuromuscular involvement, with hepatic GSD IV subclassified as discrete subtypes: classic (progressive) and nonprogressive.MethodsTo better understand the progression of liver disease in GSD IV, we present clinical and histopathology data from 23 patients from around the world and characterized the liver involvement in the Gbe1ys/ys knockin mouse model.ResultsWe propose an alternative to the established subtype-based terminology for characterizing liver disease in GSD IV and recognize 3 tiers of disease severity: (i) "severe progressive" liver disease, (ii) "intermediate progressive" liver disease, and (iii) "attenuated" liver disease. Analysis of liver pathology revealed that risk for liver failure cannot be predicted from liver biopsy findings alone in individuals affected by GSD IV. Moreover, analysis of postmortem liver pathology from an individual who died over 40 years after being diagnosed with nonprogressive hepatic GSD IV in childhood verified that liver fibrosis did not regress. Last, characterization of the liver involvement in a mouse model known to recapitulate the adult-onset neurodegenerative form of GSD IV (Gbe1ys/ys mouse model) demonstrated hepatic disease.ConclusionOur findings challenge the established subtype-based view of GSD IV and suggest that liver disease severity among patients with GSD IV represents a disease continuum.Trial registrationClinicalTrials.gov NCT02683512FundingNone.

Optimizing treatment outcomes: immune tolerance induction in Pompe disease patients undergoing enzyme replacement therapy.

Introduction: Pompe disease, a lysosomal storage disorder, is characterized by acid α-glucosidase (GAA) deficiency and categorized into two main subtypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The primary treatment, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), faces challenges due to immunogenic responses, including the production of anti-drug antibody (ADA), which can diminish therapeutic efficacy. This study aims to assess the effectiveness of immune tolerance induction (ITI) therapy in cross-reactive immunologic material (CRIM)-positive Pompe disease patients with established high ADA levels. Method: In a single-center, open-label prospective study, we assessed ITI therapy's efficacy in Pompe disease patients, both IOPD and LOPD, with persistently elevated ADA titers (≥1:12,800) and clinical decline. The ITI regimen comprised bortezomib, rituximab, methotrexate, and intravenous immunoglobulin. Biochemical data, biomarkers, ADA titers, immune status, and respiratory and motor function were monitored over six months before and after ITI. Results: This study enrolled eight patients (5 IOPD and 3 LOPD). After a 6-month ITI course, median ADA titers significantly decreased from 1:12,800 (range 1:12,800-1:51,200) to 1:1,600 (range 1:400-1:12,800), with sustained immune tolerance persisting up to 4.5 years in some cases. Serum CK levels were mostly stable or decreased, stable urinary glucose tetrasaccharide levels were maintained in four patients, and no notable deterioration in respiratory or ambulatory status was noted. Adverse events included two treatable infection episodes and transient symptoms like numbness and diarrhea. Conclusion: ITI therapy effectively reduces ADA levels in CRIM-positive Pompe disease patients with established high ADA titers, underscoring the importance of ADA monitoring and timely ITI initiation. The findings advocate for personalized immunogenicity risk assessments to enhance clinical outcomes. In some cases, prolonged immune suppression may be necessary, highlighting the need for further studies to optimize ITI strategies for Pompe disease treatment. ClinicalTrials.gov NCT02525172; https://clinicaltrials.gov/study/NCT02525172.

Long-term effectiveness of eliglustat treatment: A real-world analysis from the International Collaborative Gaucher Group Gaucher Registry.

Gaucher disease type 1 (GD1) is known for phenotypic heterogeneity and varied natural history. Registrational clinical trials enrolled narrowly defined phenotypes, but greater diversity is encountered in clinical practice. We report real-world outcomes with long-term eliglustat treatment in adults with GD1 in the International Collaborative Gaucher Group Gaucher Registry. Among 5985 GD1 patients in the Registry as of January 6, 2023, 872 started eliglustat at ≥18 years old; of these, 469 met inclusion criteria. We compared clinical parameters at eliglustat initiation (i.e., baseline) and follow-up in treatment-naïve patients and used linear mixed models to estimate annual change from baseline in parameters among patients who switched to eliglustat after ≥1 year on enzyme replacement therapy. Over 4 years of follow-up in non-splenectomized treatment-naïve patients, hemoglobin and platelet count increased, liver and spleen volume decreased, and total lumbar spine bone mineral density (BMD) Z-score decreased slightly. Among non-splenectomized switch patients, on average, hemoglobin decreased -0.030 (95% CI: -0.053, -0.008) g/dL (N = 272) and platelet count increased 2.229 (95% CI: 0.751, 3.706) × 103/mm3 (N = 262) annually up to 10 years; liver volume decreased (-0.009 [95% CI: -0.015, -0.003] MN) (N = 102) and spleen volume remained stable (-0.070 [95% CI: -0.150, 0.010] MN) (N = 106) annually up to 7 years; and total lumbar spine BMD Z-score increased 0.041 (95% CI: 0.015, 0.066) (N = 183) annually up to 8 years. Among splenectomized switch patients, clinical parameters were stable over time. These long-term, real-world outcomes are consistent with the eliglustat clinical trials and emerging real-world experience across the GD phenotypic spectrum.

Effectiveness of asfotase alfa for treatment of adults with hypophosphatasia: results from a global registry.

BACKGROUND: Hypophosphatasia (HPP) is a rare inherited disease caused by deficient activity of tissue-nonspecific alkaline phosphatase. Many adults with HPP have a high burden of disease, experiencing chronic pain, fatigue, limited mobility, and dental issues, contributing to decreased health-related quality of life (HRQoL). HPP may be treated with the enzyme replacement therapy asfotase alfa though real-world data in adults are limited. This analysis was conducted to assess the clinical effectiveness of asfotase alfa among adults in the Global HPP Registry. METHODS: The Global HPP Registry is an observational, prospective, multinational study. Adults ≥ 18 years of age were included in this analysis if they had serum alkaline phosphatase (ALP) activity below the age- and sex-adjusted reference ranges, and/or ALPL variant(s), and received asfotase alfa for ≥ 6 months. Mobility was assessed with the 6-Minute Walk Test (6MWT), and patient-reported outcomes tools were used to assess pain (Brief Pain Inventory-Short Form), quality of life (36-item Short Form Health Survey, version 2 [SF-36v2]), and disability (Health Assessment Questionnaire-Disability Index) at multiple time points from baseline through Month 36. Data were collected as per usual standard of care; patients may not have contributed data at all time points. RESULTS: A total of 190 patients met the inclusion criteria. For patients with ≥ 1 follow-up measurement, the mean distance achieved on 6MWT increased from 404 m (range 60-632 m) at baseline (n = 31) to 484 m at Month 12 (range 240-739 m; n = 18) and remained above baseline through Month 36 (n = 7). Improvements in mean self-reported pain severity scores ranged from - 0.72 (95% CI: - 1.23, - 0.21; n = 38) to - 1.13 (95% CI: - 1.76, - 0.51; n = 26) and were observed at all time points. Improvements in the Physical Component Summary score of SF-36v2 were achieved by Month 6 and sustained throughout follow-up. There was a trend toward improvement in the Mental Component Summary score of SF-36v2 at most time points, with considerable fluctuations from Months 12 (n = 28) through 36 (n = 21). The most frequent adverse events were injection site reactions. CONCLUSIONS: Adults with HPP who received asfotase alfa for ≥ 6 months experienced improvements in mobility, physical function, and HRQoL, which were maintained over 3 years of follow-up. REGISTRATION: NCT02306720; EUPAS13514.

Underrepresentation of Diverse Ancestries Drives Uncertainty in Genetic Variants Found in Cardiomyopathy-Associated Genes.

BACKGROUND: Thousands of genetic variants have been identified in cardiomyopathy-associated genes. Diagnostic genetic testing is key for evaluation of individuals with suspected cardiomyopathy. While accurate variant pathogenicity assignment is important for diagnosis, the frequency of and factors associated with clinically relevant assessment changes are unclear. OBJECTIVES: The authors aimed to characterize pathogenicity assignment change in cardiomyopathy-associated genes and to identify factors associated with this change. METHODS: We identified 10 sarcomeric and 6 desmosomal genetic cardiomyopathy-associated genes along with comparison gene sets. We analyzed clinically meaningful changes in pathogenicity assignment between any of the following: pathogenic/likely pathogenic (P/LP), conflicting interpretations of pathogenicity or variant of unknown significance (C/VUS), and benign/likely benign. We explored association of minor allele frequency (MAF) differences between well, and traditionally poorly, represented ancestries in genetic studies with assessment stability. Analyses were performed using ClinVar and GnomAD data. RESULTS: Of the 30,975 cardiomyopathy-associated gene variants in ClinVar, 2,276 of them (7.3%) had a clinically meaningful change in pathogenicity assignment over the study period, 2011 to 2021. Sixty-seven percent of variants that underwent a clinically significant change moved from P/LP or benign/likely benign to C/VUS. Among cardiomyopathy variants downgraded from P/LP, 35% had a MAF above 1 × 10 -4 in non-Europeans and below 1 × 10 -4 in Europeans. CONCLUSIONS: Over the past 10 years, 7.3% of cardiomyopathy gene variants underwent a clinically meaningful change in pathogenicity assignment. Over 30% of downgrades from P/LP may be attributable to higher MAF in Non-Europeans than Europeans. This finding suggests that low ancestral diversity in genetic studies has increased diagnostic uncertainty in cardiomyopathy gene variants.

An updated management approach of Pompe disease patients with high-sustained anti-rhGAA IgG antibody titers: experience with bortezomib-based immunomodulation.

Introduction: High sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT. Methods: Here, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment. Results: In total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week. Discussion: These case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.

104-week efficacy and safety of cipaglucosidase alfa plus miglustat in adults with late-onset Pompe disease: a phase III open-label extension study (ATB200-07).

The phase III double-blind PROPEL study compared the novel two-component therapy cipaglucosidase alfa + miglustat (cipa + mig) with alglucosidase alfa + placebo (alg + pbo) in adults with late-onset Pompe disease (LOPD). This ongoing open-label extension (OLE; NCT04138277) evaluates long-term safety and efficacy of cipa + mig. Outcomes include 6-min walk distance (6MWD), forced vital capacity (FVC), creatine kinase (CK) and hexose tetrasaccharide (Hex4) levels, patient-reported outcomes and safety. Data are reported as change from PROPEL baseline to OLE week 52 (104 weeks post-PROPEL baseline). Of 118 patients treated in the OLE, 81 continued cipa + mig treatment from PROPEL (cipa + mig group; 61 enzyme replacement therapy [ERT] experienced prior to PROPEL; 20 ERT naïve) and 37 switched from alg + pbo to cipa + mig (switch group; 29 ERT experienced; 8 ERT naive). Mean (standard deviation [SD]) change in % predicted 6MWD from baseline to week 104 was + 3.1 (8.1) for cipa + mig and - 0.5 (7.8) for the ERT-experienced switch group, and + 8.6 (8.6) for cipa + mig and + 8.9 (11.7) for the ERT-naïve switch group. Mean (SD) change in % predicted FVC was - 0.6 (7.5) for cipa + mig and - 3.8 (6.2) for the ERT-experienced switch group, and - 4.8 (6.5) and - 3.1 (6.7), respectively, in ERT-naïve patients. CK and Hex4 levels improved in both treatment groups by week 104 with cipa + mig treatment. Three patients discontinued the OLE due to infusion-associated reactions. No new safety signals were identified. Cipa + mig treatment up to 104 weeks was associated with overall maintained improvements (6MWD, biomarkers) or stabilization (FVC) from baseline with continued durability, and was well tolerated, supporting long-term benefits for patients with LOPD.Trial registration number: NCT04138277; trial start date: December 18, 2019.

Effect of avalglucosidase alfa on disease-specific and general patient-reported outcomes in treatment-naïve adults with late-onset Pompe disease compared with alglucosidase alfa: Meaningful change analyses from the Phase 3 COMET trial.

BACKGROUND: The Phase 3 COMET trial (NCT02782741) comparing avalglucosidase alfa and alglucosidase alfa included health-related quality of life (HRQoL) assessments in treatment-naïve patients with late-onset Pompe disease (LOPD). Here, we further characterize results from disease-specific and general patient-reported outcome (PRO) measures. METHODS: Adults who participated in the COMET trial receiving avalglucosidase alfa or alglucosidase alfa (both 20 mg/kg biweekly) during the 49-week double-blind treatment period were included in the analysis. Proportions of patients exceeding meaningful change thresholds at Week 49 were compared post hoc between treatment groups. PROs and their meaningful change thresholds included: Pompe Disease Severity Scale (PDSS; decrease 1.0-1.5 points), Pompe Disease Impact Scale (PDIS; decrease 1.0-1.5 points), Rasch-built Pompe-specific Activity Scale (R-PAct; change from unable to able to complete activity), 12-item Short Form Health Survey (SF-12; physical component summary [PCS] score: increase ≥6 points, mental component summary [MCS] score: increase ≥7 points), EuroQol 5 Dimension 5 Level (EQ-5D-5L; improvement of ≥1 category), and Patient Global Impression of Change (PGIC; any improvement). RESULTS: The analysis included 99 adult patients (avalglucosidase alfa n = 50; alglucosidase alfa n = 49). Patients who received avalglucosidase alfa had significantly greater odds of achieving a meaningful change versus alglucosidase alfa for the PDSS Shortness of Breath (OR [95% CI] 11.79 [2.24; 62.18]), Fatigue/Pain (6.24 [1.20; 32.54]), Morning Headache (13.98 [1.71; 114.18]), and Overall Fatigue (5.88 [1.37; 25.11]) domains, and were significantly more likely to meet meaningful change thresholds across multiple PDSS domains (all nominal p < 0.05). A numerically greater proportion of patients in the avalglucosidase alfa group were able to complete selected activities of the R-PAct compared with the alglucosidase alfa group. Significantly greater proportions of patients who received avalglucosidase alfa achieved meaningful improvements for EQ-5D-5L usual activities dimension, EQ visual analog scale, and all four PGIC domains. The proportion of patients with improvements in SF-12 PCS and MCS was greater in the avalglucosidase alfa group versus alglucosidase alfa group, but was not significant (p > 0.05). CONCLUSIONS: These analyses show that avalglucosidase alfa improves multiple symptoms and aspects of daily functioning, including breathing and mobility. This supports the clinical relevance of the effects of avalglucosidase alfa on HRQoL for patients with LOPD.

Severe CNS involvement in a subset of long-term treated children with infantile-onset Pompe disease.

INTRODUCTION: The standard of care for patients with infantile-onset Pompe disease (IOPD) is enzyme replacement therapy (ERT), which does not cross the blood brain barrier. While neuromuscular manifestations of IOPD are well-described, central nervous system (CNS) manifestations of this disorder are far less characterized. Here we describe severe CNS-related neurological manifestations including seizures and encephalopathy in six individuals with IOPD. METHOD: We identified six children with IOPD who developed CNS manifestations such as seizures and/or encephalopathy. We studied their brain magnetic resonance imaging scans (MRIs) and graded the severity of white matter hyperintensities (WMHI) using the Fazekas scale scoring system as previously published. Longitudinal cognitive measures were available from 4/6 children. RESULTS: All six IOPD patients (4 males/2 females) had been treated with ERT for 12-15 years. Seizures and/or encephalopathy were noted at a median age at onset of 11.9 years (range 9-15 years). All were noted to have extensive WMHI in the brain MRIs and very high Fazekas scores which preceded the onset of neurological symptoms. Longitudinal IQ scores from four of these children suggested developmental plateauing. DISCUSSION: Among a subset of IOPD patients on long-term ERT, CNS manifestations including hyperreflexia, encephalopathy and seizures may become prominent, and there is likely an association between these symptoms and significant WMHI on MRI. Further study is needed to identify risk factors for CNS deterioration among children with IOPD and develop interventions to prevent neurological decline.

Validation of the Patient-Reported Outcomes Measurement Information System (PROMIS®) physical function questionnaire in late-onset Pompe disease using PROPEL phase 3 data.

BACKGROUND: The construct validity and interpretation of the Patient-Reported Outcome Measurement Information System (PROMIS®) Physical Function short form 20a (PF20a) questionnaire were evaluated for patients with late-onset Pompe disease (LOPD), a rare, autosomal recessive, progressive neuromuscular disorder treatable by enzyme replacement therapy (ERT). METHODS: In the phase 3 PROPEL study, adults with LOPD underwent testing of physical functioning and had PRO measurements at baseline and at weeks 12, 26, 38, and 52 while receiving experimental or standard-of-care ERT. All patients were pooled for analyses, without comparisons between treatment groups. Associations and correlations between PROMIS PF20a scores and the 6-minute walk distance (6MWD), % predicted forced vital capacity (FVC), manual muscle test (MMT) of the lower extremities, Gait, Stairs, Gowers' maneuver, Chair (GSGC) score, and Rasch-built Pompe-specific Activity (R-PAct) scale were evaluated by calculating regression coefficients in linear regression models and Pearson correlation coefficients (R); patients' age, sex, race, ERT prior to study, body mass index, and study treatment were included as covariables. The minimal clinically important difference (MCID) of PROMIS PF20a was determined using distribution- and anchor-based methods. RESULTS: 123 patients received at least 1 dose of ERT. In multivariable analyses, PROMIS PF20a scores had strong correlations with R-PAct scores (R = 0.83 at baseline and R = 0.67 when evaluating changes between baseline and 52 weeks) and moderate correlations with the 6MWD (R = 0.57 at baseline and R = 0.48 when evaluating changes between baseline and 52 weeks). Moderate correlations were also observed between PROMIS PF20a and MMT (R = 0.54), GSGC (R=-0.51), and FVC (R = 0.48) at baseline. In multivariable linear regression models, associations were significant between PROMIS PF20a and 6MWD (P = 0.0006), MMT (P = 0.0034), GSGC (P = 0.0278), and R-PAct (P < 0.0001) at baseline, between PROMIS PF20a and 6MWD (P < 0.0001), FVC (P = 0.0490), and R-PAct (P < 0.0001) when combining all measurements, and between PF20a and 6MWD (P = 0.0016) and R-PAct (P = 0.0001) when evaluating changes in scores between baseline and 52 weeks. The anchor-based and distribution-based MCID for a clinically important improvement for PROMIS PF20a were 2.4 and 4.2, respectively. CONCLUSIONS: PROMIS PF20a has validity as an instrument both to measure and to longitudinally follow physical function in patients with LOPD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03729362. Registered 2 November 2018, https://www. CLINICALTRIALS: gov/search?term=NCT03729362 .

Gene therapy for glycogen storage diseases.

Glycogen storage disorders (GSDs) are inherited disorders of metabolism resulting from the deficiency of individual enzymes involved in the synthesis, transport, and degradation of glycogen. This literature review summarizes the development of gene therapy for the GSDs. The abnormal accumulation of glycogen and deficiency of glucose production in GSDs lead to unique symptoms based upon the enzyme step and tissues involved, such as liver and kidney involvement associated with severe hypoglycemia during fasting and the risk of long-term complications including hepatic adenoma/carcinoma and end stage kidney disease in GSD Ia from glucose-6-phosphatase deficiency, and cardiac/skeletal/smooth muscle involvement associated with myopathy +/- cardiomyopathy and the risk for cardiorespiratory failure in Pompe disease. These symptoms are present to a variable degree in animal models for the GSDs, which have been utilized to evaluate new therapies including gene therapy and genome editing. Gene therapy for Pompe disease and GSD Ia has progressed to Phase I and Phase III clinical trials, respectively, and are evaluating the safety and bioactivity of adeno-associated virus vectors. Clinical research to understand the natural history and progression of the GSDs provides invaluable outcome measures that serve as endpoints to evaluate benefits in clinical trials. While promising, gene therapy and genome editing face challenges with regard to clinical implementation, including immune responses and toxicities that have been revealed during clinical trials of gene therapy that are underway. Gene therapy for the glycogen storage diseases is under development, addressing an unmet need for specific, stable therapy for these conditions.

Long-term safety and efficacy of cipaglucosidase alfa plus miglustat in individuals living with Pompe disease: an open-label phase I/II study (ATB200-02).

Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2-6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL - 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; - 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016.

The Global ALPL gene variant classification project: Dedicated to deciphering variants.

BACKGROUND: Hypophosphatasia (HPP) is an inherited multisystem disorder predominantly affecting the mineralization of bones and teeth. HPP is caused by pathogenic variants in ALPL, which encodes tissue non-specific alkaline phosphatase (TNSALP). Variants of uncertain significance (VUS) cause diagnostic delay and uncertainty amongst patients and health care providers. RESULTS: The ALPL gene variant database (https://alplmutationdatabase.jku.at/) is an open-access archive for interpretation of the clinical significance of variants reported in ALPL. The database contains coding and non-coding variants, including single nucleotide variants, insertions/deletions and structural variants affecting coding or non-coding sequences of ALPL. Each variant in the database is displayed with details explaining the corresponding pathogenicity, and all reported genotypes and phenotypes, including references. In 2021, the ALPL gene variant classification project was established to reclassify VUS and continuously assess and update genetic, phenotypic, and functional variant information in the database. For this purpose, the database provides a unique submission system for clinicians, geneticists, genetic counselors, and researchers to submit VUS within ALPL for classification. An international, multidisciplinary consortium of HPP experts has been established to reclassify the submitted VUS using a multi-step process adhering to the stringent ACMG/AMP variant classification guidelines. These steps include a clinical phenotype assessment, deep literature research including artificial intelligence technology, molecular genetic assessment, and in-vitro functional testing of variants in a co-transfection model to measure ALP residual activity. CONCLUSION: This classification project and the ALPL gene variant database will serve the global medical community, widen the genotypic and phenotypic HPP spectrum by reporting and characterizing new ALPL variants based on ACMG/AMP criteria and thus facilitate improved genetic counseling and medical decision-making for affected patients and families. The project may also serve as a gold standard framework for multidisciplinary collaboration for variant interpretation in other rare diseases.

Higher dose alglucosidase alfa is associated with improved overall survival in infantile-onset Pompe disease (IOPD): data from the Pompe Registry.

BACKGROUND: Studies indicate that doses of alglucosidase alfa (ALGLU) higher than label dose (20 mg/kg every other week) improve clinical outcomes in infantile-onset Pompe disease (IOPD). We investigated data from the Pompe Registry to determine the association between ALGLU dose and survival in IOPD. RESULTS: We included 332 IOPD patients from the Registry as of January 2022 who had cardiomyopathy and were first treated at age < 1 year. We used Cox proportional hazards models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between ALGLU as a time-varying exposure and survival, adjusting for age at first treatment, sex, and cross-reactive immunologic material (CRIM)/immune tolerance induction (ITI) status. Dose was measured as average relative dose received over time (in multiples of label dose, range > 0 to 4 times label dose), current dose, and lagged dose. 81% patients received label dose at treatment initiation. Over time, 52% received a higher dose. Higher ALGLU dose over time was associated with improved survival: adjusted HR 0.40 (95% CI 0.22-0.73, p = 0.003) per 1-unit increase in average relative dose, with similar results for invasive ventilation-free survival (adjusted HR 0.48, 95% CI 0.28-0.84; p = 0.010). The association was consistent in patients first treated before or after 3 months of age and did not vary significantly by CRIM status. Results for current and lagged dose were similar to average dose. CONCLUSIONS: Higher ALGLU doses were associated with significantly improved overall and invasive ventilator-free survival in IOPD. Results were consistent across sensitivity analyses.

Intrauterine enzyme replacement therapies for lysosomal storage disorders: Current developments and promising future prospects.

Lysosomal storage disorders (LSDs) are a group of monogenic condition, with many characterized by an enzyme deficiency leading to the accumulation of an undegraded substrate within the lysosomes. For those LSDs, postnatal enzyme replacement therapy (ERT) represents the standard of care, but this treatment has limitations when administered only postnatally because, at that point, prenatal disease sequelae may be irreversible. Furthermore, most forms of ERT, specifically those administered systemically, are currently unable to access certain tissues, such as the central nervous system (CNS), and furthermore, may initiate an immune response. In utero enzyme replacement therapy (IUERT) is a novel approach to address these challenges evaluated in a first-in-human clinical trial for IUERT in LSDs (NCT04532047). IUERT has numerous advantages: in-utero intervention may prevent early pathology; the CNS can be accessed before the blood-brain barrier forms; and the unique fetal immune system enables exposure to new proteins with the potential to prevent an immune response and may induce sustained tolerance. However, there are challenges and limitations for any fetal procedure that involves two patients. This article reviews the current state of IUERT for LSDs, including its advantages, limitations, and potential future directions for definitive therapies.

Pneumonia vaccine response in individuals with Down syndrome at three specialty clinics.

Individuals with Down syndrome (DS) have been particularly impacted by respiratory conditions, such as pneumonia. However, the description of co-occurring recurrent infections, the response to pneumococcal immunization, and the association of these was previously unknown. We screened individuals with DS using an 11-item screener and prospectively collected pneumococcal titers and laboratory results. We found that the screener did not successfully predict which individuals with DS who would have inadequate pneumococcal titers. Thirty four of the 55 individuals with DS (62%) had abnormal pneumococcal titers demonstrating an inadequate response to routine immunization. In the absence of a valid screener, clinicians should consider screening all individuals with DS through the use of pneumococcal titers to 23 serotypes to assess vaccine response.

Muscle ultrasound in patients with late-onset Pompe disease identified by newborn screening.

Importance: Implementation of newborn screening (NBS) in the United States now detects infants with late-onset Pompe disease (LOPD), a lysosomal storage disease characterized by slowly progressive muscle weakness, and detailed clinical evaluation has identified early muscle weakness. Biomarkers may be uninformative; thus, non-invasive imaging is needed to assess early LOPD muscle changes. Muscle ultrasound (US) measuring echointensity (EI) is a non-invasive measure of muscle health. Objective: In this study, we aimed to evaluate if EI can identify characteristic patterns of muscle involvement in LOPD patients identified by NBS. Design/setting: Prospective, cross-sectional, single time point study. Setting: One-center study. Participants: We examined 20 infants with NBS-identified LOPD (ages 5-20 months). All had standardized physical therapy assessments. Exposures: Creatine Kinase (CK) and Urine Hexose Tetrasaccharide (Glc4) were obtained. Muscle US of deltoid, biceps brachii, forearm flexors, thoracic paraspinals, gluteus maximus, quadriceps, tibialis anterior and medial gastrocnemius was performed. Main outcomes and measures: Mean EI was calculated for all involved muscle groups. Quantitative EI Sum Scores were calculated as total EI divided by number of muscle groups assessed. We performed a comprehensive literature review to compare our results to previous LOPD muscle ultrasound studies. Results: Six of 20 participants had elevated CK and 15 had ≥50% of the most common concerning kinematic physical findings; with normal urine Glc4 in all except one. Based upon muscle EI, the most affected muscles were quadriceps and medial gastrocnemius, with notable elevated EI in thoracic paraspinals. Biceps brachii was the most frequently affected upper extremity muscle. EI sum scores correlated moderately with increasing CK. Statistically significant positive correlation was found between posterior pelvic tilt in sitting and EI of gluteus maximus. Sonographic pattern of muscle involvement was similar to previous studies assessing older patients with LOPD. Conclusions and relevance: In this study, muscle EI was elevated most often in the quadriceps, tibialis anterior, medial gastrocnemius, thoracic paraspinals, and biceps brachii. Involved muscles generally fit the profile of physical and muscle ultrasound/MRI exam findings in LOPD patients. Muscle ultrasound is recommended for rapid, focused muscle assessment in LOPD, especially those identified via NBS. Future studies should focus on this pattern of ultrasonographic abnormality and changes over time.

Glycogen storage diseases.

Glycogen storage diseases (GSDs) are a group of rare, monogenic disorders that share a defect in the synthesis or breakdown of glycogen. This Primer describes the multi-organ clinical features of hepatic GSDs and muscle GSDs, in addition to their epidemiology, biochemistry and mechanisms of disease, diagnosis, management, quality of life and future research directions. Some GSDs have available guidelines for diagnosis and management. Diagnostic considerations include phenotypic characterization, biomarkers, imaging, genetic testing, enzyme activity analysis and histology. Management includes surveillance for development of characteristic disease sequelae, avoidance of fasting in several hepatic GSDs, medically prescribed diets, appropriate exercise regimens and emergency letters. Specific therapeutic interventions are available for some diseases, such as enzyme replacement therapy to correct enzyme deficiency in Pompe disease and SGLT2 inhibitors for neutropenia and neutrophil dysfunction in GSD Ib. Progress in diagnosis, management and definitive therapies affects the natural course and hence morbidity and mortality. The natural history of GSDs is still being described. The quality of life of patients with these conditions varies, and standard sets of patient-centred outcomes have not yet been developed. The landscape of novel therapeutics and GSD clinical trials is vast, and emerging research is discussed herein.