Understanding pathophysiology of GNE myopathy and current progress towards drug development.

GNE myopathy is a rare genetic neuromuscular disease that is caused due to mutations in the GNE gene responsible for sialic acid biosynthesis. Foot drop is the most common initial symptom observed in GNE myopathy patients. There is slow progressive muscle weakness in the lower and upper extremities while the quadriceps muscles are usually spared. The exact pathophysiology of the disease is unknown. Besides sialic acid biosynthesis, recent studies suggest either direct or indirect involvement of GNE in other cellular functions such as protein aggregation, apoptosis, ER stress, cell migration, HSP70 chaperone activity, autophagy, muscle atrophy, and myogenesis. Both animal and in vitro cell-based model systems are generated to elucidate the mechanism of GNE myopathy and evaluate the efficacy of therapies. The many therapeutic avenues explored include supplementation with sialic acid derivatives or precursors and gene therapy. Recent studies suggest other therapeutic options such as modulators of HSP70 chaperone (BGP-15), cofilin activator (CGA), and ligands like IGF-1 that may help to rescue cellular defects due to GNE dysfunction. This review provides an overview of the pathophysiology associated with GNE function in the cell and promising therapeutic leads to be explored for future drug development.

Ex Vivo Surface Decoration of Phenylboronic Acid onto Natural Killer Cells for Sialic Acid-Mediated Versatile Cancer Cell Targeting.

Phenylboronic acid (PBA) has been highly acknowledged as a significant cancer recognition moiety in sialic acid-overexpressing cancer cells. In this investigation, lipid-mediated biomaterial integrated PBA molecules onto the surface of natural killer (NK) cells to make a receptor-mediated immune cell therapeutic module. Therefore, a 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE) lipid-conjugated di-PEG-PBA (DSPEPEG-di(PEG-PBA) biomaterial was synthesized. The DSPEPEG-di(PEG-PBA) biomaterial exhibited a high affinity for sialic acid (SA), confirmed by fluorescence spectroscopy at pH 6.5 and 7.4. DSPEPEG-di(PEG-PBA) was successfully anchored onto NK cell surfaces (PBA-NK), and this biomaterial maintains intrinsic properties such as viability, ligand availability (FasL & TRAIL), and cytokine secretion response to LPS. The anticancer efficacy of PBA-NK cells was evaluated against 2D cancer cells (MDA-MB-231, HepG2, and HCT-116) and 3D tumor spheroids of MDA-MB-231 cells. PBA-NK cells exhibited greatly enhanced anticancer effects against SA-overexpressing cancer cells. Thus, PBA-NK cells represent a new anticancer strategy for cancer immunotherapy.

Pharmacokinetics and clinical efficacy of 6'-sialyllactose in patients with GNE myopathy: Randomized pilot trial.

GNE myopathy, caused by biallelic mutations in the GNE gene, is characterized by initial ankle dorsiflexor weakness and rimmed vacuoles in the muscle histopathology, resulting in reduced sialic acid production. Sialyllactose is a source of sialic acid. We performed a pilot clinical trial to analyze the pharmacokinetic properties of 6'-sialyllactose (6SL) and evaluated the safety, and efficacy of oral 6SL in patients with GNE myopathy. Ten participants were in the pharmacokinetic study, and 20 in the subsequent clinical trial. For the pharmacokinetic study, participants were administered either 3 g (low-dose) or 6 g (high-dose) of 6SL in a single dose. Plasma concentrations of 6SL, sialic acid, and sialic acid levels on the surface of red blood cells were periodically assessed in blood samples. Patients were randomly allocated to test (low- and high-dose groups) or placebo groups for the trial. Motor function, ambulation, plasma 6SL and sialic acid concentrations, GNE myopathy-functional activity scale scores, and MRI findings were assessed. 6SL was well tolerated, except for self-limited gastrointestinal discomfort. Free sialic acid in both low- and high-dose groups significantly increased at 6 and 12 weeks, but not in the placebo group. In the high-dose group, proximal limb powers improved with daily 6SL. Considering the fat fraction on muscle MRI, results in the high-dose group were superior to those in the low-dose group. 6SL may be a good candidate for GNE myopathy therapeutics as it induces an increase or reduces the decrease in limb muscle power, attenuates muscle degeneration, and improves the biochemical properties of sialic acid.

[Efficacy of Aceneuramic Acid for Distal Myopathy with Rimmed Vacuoles].

Distal myopathy with rimmed vacuoles (DMRV), also known as GNE myopathy, is a rare disease affecting the distal muscles, such as the tibialis anterior muscle. The GNE gene, which codes for a key enzyme in the sialic acid biosynthesis pathway, is mutated in a homozygous or compound heterozygous manner, and the lack of sialic acid in skeletal muscle is the critical underlying mechanism in DMRV pathogenesis. DMRV mouse models were established, and supplementation with sialic acid improved the phenotypes of the models. A phase 1 clinical trial using aceneuramic acid was conducted at Tohoku University Hospital, Japan, followed by trials using a slow-release product. A phase II/III study, subsequent extended trial, and confirmatory trial were also conducted. Regulatory approval is currently under review.

Sialic acid-decorated liposomes enhance the anti-cancer efficacy of docetaxel in tumor-associated macrophages.

Tumor-associated macrophages (TAMs) in the tumor microenvironment potentially enhance tumor growth and invasion through various mechanisms and are thus an essential factor in tumor immunity. The highly expressed siglec-1 receptors on the surfaces of TAMs are potential targets for cancer drug delivery systems. Sialic acid (SA) is a specific ligand for siglec-1. In this study, the sialic acid-polyethylene glycol conjugate (DSPE-PEG2000-SA) was synthesized to modify the surface of liposomes and target TAMs by interacting with the siglec-1 receptor. Three docetaxel (DTX)-loaded liposomes, conventional (DTX-CL), DSPE-PEG2000-coated (DTX-PL), and DSPE-PEG2000-SA-coated (DTX-SAPL) liposomes, were prepared, with a particle size of <100 nm, uniform polydispersity index (PDI) values, negative zeta potential, and % encapsulation efficiency (EE) exceeding 95 %. Liposomes showed high stability after 3 months of storage at 4 °C without significant changes in particle size, PDI, zeta potential, or % EE. DTX was released from liposomes according to the Weibull model, and DTX-SAPL exhibited more rapid drug release than other liposomes. In vitro studies demonstrated that DTX-SAPL liposome exhibited a higher uptake and cytotoxicity on RAW 264.7 cells (TAM model) and lower toxicity on NIH3T3 cells (normal cell model) than other formulations. The high cell uptake ability was demonstrated by the role of the SA-SA receptor. Biodistribution studies indicated a high tumor accumulation of surface-modified liposomal formulations, particularly SA-modified liposomes, showing high signal accumulation at the tumor periphery, where TAMs were highly concentrated. Ex vivo imaging showed a significantly higher accumulation of SA-modified liposomes in the tumor, kidney, and heart than conventional liposomes. In the anti-cancer efficacy study, DTX-SAPL liposomes showed effective inhibition of tumor growth and relatively low systemic toxicity, as evidenced by the tumor volume, tumor weight, body weight values, and histopathological analysis. Therefore, DSPE-PEG2000-SA-coated liposomes could be promising carriers for DTX delivery targeting TAMs in cancer therapy.

Efficacy confirmation study of aceneuramic acid administration for GNE myopathy in Japan.

BACKGROUND: A rare muscle disease, GNE myopathy is caused by mutations in the GNE gene involved in sialic acid biosynthesis. Our recent phase II/III study has indicated that oral administration of aceneuramic acid to patients slows disease progression. METHODS: We conducted a phase III, randomized, placebo-controlled, double-blind, parallel-group, multicenter study. Participants were assigned to receive an extended-release formulation of aceneuramic acid (SA-ER) or placebo. Changes in muscle strength and function over 48 weeks were compared between treatment groups using change in the upper extremity composite (UEC) score from baseline to Week 48 as the primary endpoint and the investigator-assessed efficacy rate as the key secondary endpoint. For safety, adverse events, vital signs, body weight, electrocardiogram, and clinical laboratory results were monitored. RESULTS: A total of 14 patients were enrolled and given SA-ER (n = 10) or placebo (n = 4) tablets orally. Decrease in least square mean (LSM) change in UEC score at Week 48 with SA-ER (- 0.115 kg) was numerically smaller as compared with placebo (- 2.625 kg), with LSM difference (95% confidence interval) of 2.510 (- 1.720 to 6.740) kg. In addition, efficacy was higher with SA-ER as compared with placebo. No clinically significant adverse events or other safety concerns were observed. CONCLUSIONS: The present study reproducibly showed a trend towards slowing of loss of muscle strength and function with orally administered SA-ER, indicating supplementation with sialic acid might be a promising replacement therapy for GNE myopathy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT04671472).

Recent advances in the development of sialyltransferase inhibitors to control cancer metastasis: A comprehensive review.

Metastasis accounts for the majority of cancer-associated mortalities, representing a huge health and economic burden. One of the mechanisms that enables metastasis is hypersialylation, characterized by an overabundance of sialylated glycans on the tumor surface, which leads to repulsion and detachment of cells from the original tumor. Once the tumor cells are mobilized, sialylated glycans hijack the natural killer T-cells through self-molecular mimicry and activatea downstream cascade of molecular events that result in inhibition of cytotoxicity and inflammatory responses against cancer cells, ultimately leading to immune evasion. Sialylation is mediated by a family of enzymes known as sialyltransferases (STs), which catalyse the transfer of sialic acid residue from the donor, CMP-sialic acid, onto the terminal end of an acceptor such as N-acetylgalactosamine on the cell-surface. Upregulation of STs increases tumor hypersialylation by up to 60% which is considered a distinctive hallmark of several types of cancers such as pancreatic, breast, and ovarian cancer. Therefore, inhibiting STs has emerged as a potential strategy to prevent metastasis. In this comprehensive review, we discuss the recent advances in designing novel sialyltransferase inhibitors using ligand-based drug design and high-throughput screening of natural and synthetic entities, emphasizing the most successful approaches. We analyse the limitations and challenges of designing selective, potent, and cell-permeable ST inhibitors that hindered further development of ST inhibitors into clinical trials. We conclude by analysing emerging opportunities, including advanced delivery methods which further increase the potential of these inhibitors to enrich the clinics with novel therapeutics to combat metastasis.

Recent advances in establishing a cure for GNE myopathy.

PURPOSE OF REVIEW: GNE myopathy is a rare autosomal recessive disease caused by biallelic variants in the GNE gene, which encodes an enzyme involved in sialic acid biosynthesis. No drugs are approved for the treatment of GNE myopathy. Following proof-of-concept of sialic acid supplementation efficacy in mouse models, multiple clinical trials have been conducted. Here, we review clinical trials of sialic acid supplementation therapies and provide new insights into the additional clinical features of GNE myopathy. RECENT FINDINGS: Clinical trials of sialic acid supplementation have been conducted in Europe, the USA, Japan, and South Korea. Some clinical trials of NeuAc-extended release tablets demonstrated amelioration of decline in upper extremity muscle strength; however, no significant improvement was observed in phase 3 trials in Europe and USA. A phase 2 trial of ManNAc showed slowed decline of both upper and lower extremity strength. GNE myopathy patient registries have been established in Europe and Japan, and have provided information on extramuscular manifestations such as thrombocytopenia, respiratory dysfunction, and sleep apnea syndrome. Sensitive and reliable biomarkers, and a disease-specific functional activity scale, have also been investigated. SUMMARY: We discuss recent advances in establishing a GNE myopathy cure, and discuss other prospective therapeutic options, including gene therapy.

Aggregation-Induced Emission (AIE) Photosensitizer Combined Polydopamine Nanomaterials for Organelle-Targeting Photodynamic and Photothermal Therapy by the Recognition of Sialic Acid.

The construction of organelle-targeting nanomaterials is an effective way to improve tumor imaging and treatment. Here, a new type of composite nanomaterial named as PTTPB is developed. PTTPB is composed of organelle-targeting aggregation-induced emission photosensitizer TTPB and polydopamine nanomaterials. With the functional modification of TTPB, PTTPB can recognize sialic acid on the cell membrane and present mitochondrial targeted capabilities. The intake of PTTPB in cancerous cells can be increased by the recognition process of cell membrane. PTTPB can generate singlet oxygen for photodynamic therapy (PDT), and present good photothermal conversion ability with irradiation. The PTTPB with organelle-targeting imaging-guided can realize the tumor ablation with the synergistic effect of PDT and photothermal therapy.

Sialic Acid Conjugated Chitosan Nanoparticles: Modulation to Target Tumour Cells and Therapeutic Opportunities.

Targeted delivery of therapeutics forestalls the dreadful delocalized effects, drug toxicities and needless immunosuppression. Cancer cells are bounteous with sialic acid and the differential expression of glycosyl transferase, glycosidase and monosaccharide transporter compared to healthy tissues. The current study entails the development and characterisation of sialic acid (SA)-labelled chitosan nanoparticles encapsulating gemcitabine (GEM). Chitosan (CS) was conjugated with SA using coupling reaction and characterised spectroscopically. Furthermore, different concentrations of chitosan and tripolyphosphate (TPP) were optimised to fabricate surface modified chitosan nanoparticles. SA conjugated chitosan nanoparticles encapsulating GEM (SA-CS_GEM NPs) of 232 ± 9.69 nm with narrow distribution (PDI < 0.5) and zeta potential of - 19 ± 0.97 mV was fabricated. GEM was successfully loaded in the SA-CS NPs, depicting prolonged and biphasic drug release pattern more elated at low pH. Pronounced cellular uptake (FITC tagged) and cytotoxicity (IC50 487.4 nM) was observed in SA-CS_GEM NPs against A549 cells. IC50 for SA-CS_GEM NPs plunged with an increase in the time points from 24 to 72 h. Concentration-dependent haemolytic study confirmed significant haemocompatibility of SA-CS_GEM NPs. Pharmacokinetic study was performed on Sprague-Dawley rats and the kinetic parameters were calculated using PKSolver 2.0. Results demonstrated a consequential refinement of 2.98 times in modified SA-CS_GEM NPs with a significant increase in retention time, bioavailability and elimination half-life, and decrease in elimination rate constant and volume of distribution in comparison to CS_GEM NPs. Therefore, SA-CS shell core nanoparticles could be a beneficial approach to target and treat NSCLC (non-small cell lung cancer) and direct for research possibilities to target the other tumour cells.

Prognostic Value of Elevated Levels of Plasma N-Acetylneuraminic Acid in Patients With Heart Failure.

BACKGROUND: Cardiac sialylation is involved in a variety of physiological processes in the heart. Altered sialylation has been implicated in heart failure (HF) mice. However, its role in patients with HF is unclear, and the potential effect of modulation of cardiac sialylation is worth exploring. METHODS: We first assessed the association between plasma N-acetylneuraminic acid levels and the incidence of adverse cardiovascular events in patients with HF over a median follow-up period of 2 years. Next, immunoblot analysis and lectin histochemistry were performed in cardiac tissue to determine the expression levels of neuraminidases and the extent of cardiac desialylation. Finally, the therapeutic impact of a neuraminidase inhibitor was evaluated in animal models of HF. RESULTS: Among 1699 patients with HF, 464 (27%) died of cardiovascular-related deaths or underwent heart transplantation. We found that the elevated plasma N-acetylneuraminic acid level was independently associated with a higher risk of incident cardiovascular death and heart transplantation (third tertile adjusted hazard ratio, 2.11 [95% CI, 1.67-2.66], P<0.001). In addition, in cardiac tissues from patients with HF, neuraminidase expression was upregulated, accompanied by desialylation. Treatment with oseltamivir, a neuraminidase inhibitor, in HF mice infused with isoproterenol and angiotensin II significantly inhibited desialylation and ameliorated cardiac dysfunction. CONCLUSIONS: This study uncovered a significant association between elevated plasma N-acetylneuraminic acid level and an increased risk of a poor clinical outcome in patients with HF. Our data support the notion that desialylation represents an important contributor to the progression of HF, and neuraminidase inhibition may be a potential therapeutic strategy for HF.

More Is Always Better Than One: The N-Terminal Domain of the Spike Protein as Another Emerging Target for Hampering the SARS-CoV-2 Attachment to Host Cells.

Although the approved vaccines are proving to be of utmost importance in containing the Coronavirus disease 2019 (COVID-19) threat, they will hardly be resolutive as new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, a single-stranded RNA virus) variants might be insensitive to the immune response they induce. In this scenario, developing an effective therapy is still a dire need. Different targets for therapeutic antibodies and diagnostics have been identified, among which the SARS-CoV-2 spike (S) glycoprotein, particularly its receptor-binding domain, has been defined as crucial. In this context, we aim to focus attention also on the role played by the S N-terminal domain (S1-NTD) in the virus attachment, already recognized as a valuable target for neutralizing antibodies, in particular, building on a cavity mapping indicating the presence of two druggable pockets and on the recent literature hypothesizing the presence of a ganglioside-binding domain. In this perspective, we aim at proposing S1-NTD as a putative target for designing small molecules hopefully able to hamper the SARS-CoV-2 attachment to host cells.

The therapeutic potential of sialylated Fc domains of human IgG.

Pathogens frequently use multivalent binding to sialic acid to infect cells or to modulate immunity through interactions with human sialic acid-binding immunoglobulin-type lectins (Siglecs). Molecules that interfere with these interactions could be of interest as diagnostics, anti-infectives or as immune modulators. This review describes the development of molecular scaffolds based on the crystallizable fragment (Fc) region of immunoglobulin (Ig) G that deliver high-avidity binding to innate immune receptors, including sialic acid-dependent receptors. The ways in which the sialylated Fc may be engineered as immune modulators that mimic the anti-inflammatory properties of intravenous polyclonal Ig or as blockers of sialic-acid-dependent infectivity by viruses are also discussed.

Sialic Acid Conjugate-Modified Liposomal Dexamethasone Palmitate Targeting Neutrophils for Rheumatoid Arthritis Therapy: Influence of Particle Size.

Many anti-inflammatory therapies targeting neutrophils have been developed so far. A sialic acid (SA)-modified liposomal (SAL) formulation, based on the high expression of L-selectin in peripheral blood neutrophils (PBNs) and SA as its targeting ligand, has proved to be an effective neutrophil-mediated drug delivery system targeting rheumatoid arthritis (RA). The objective of this study was to investigate the influence of particle size of drug-carrying SALs transported and delivered by neutrophils on their anti-RA effect. Dexamethasone palmitate-loaded SALs (DP-SALs) of different particle sizes (300.2 ± 5.5 nm, 150.3 ± 4.3 nm, and 75.0 ± 3.9 nm) were prepared with DP as a model drug. Our study indicated that DP-SALs could efficiently target PBNs, with larger liposomes leading to higher drug accumulation in cells. However, a high intake of large DP-SALs by PBNs inhibited their migration ability and capacity to release the payload at the target site. In contrast, small DP-SALs (75.0 ± 3.9 nm) could maintain the drug delivery potential of PBNs, leading to their efficient accumulation at the inflammatory site, where PBNs would be excessively activated to form neutrophil extracellular traps along with efficient payload release (small DP-SALs) and finally to induce excellent anti-RA effect.

Therapeutic Effect of Neuraminidase-1-Selective Inhibition in Mouse Models of Bleomycin-Induced Pulmonary Inflammation and Fibrosis.

Pulmonary fibrosis remains a serious biomedical problem with no cure and an urgent need for better therapies. Neuraminidases (NEUs), including NEU1, have been recently implicated in the mechanism of pulmonary fibrosis by us and others. We now have tested the ability of a broad-spectrum neuraminidase inhibitor, 2,3-dehydro-2-deoxy-N-acetylneuraminic acid (DANA), to modulate the in vivo response to acute intratracheal bleomycin challenge as an experimental model of pulmonary fibrosis. A marked alleviation of bleomycin-induced body weight loss and notable declines in accumulation of pulmonary lymphocytes and collagen deposition were observed. Real-time polymerase chain reaction analyses of human and mouse lung tissues and primary human lung fibroblast cultures were also performed. A predominant expression and pronounced elevation in the levels of NEU1 mRNA were observed in patients with idiopathic pulmonary fibrosis and bleomycin-challenged mice compared with their corresponding controls, whereas NEU2, NEU3, and NEU4 were expressed at far lower levels. The levels of mRNA for the NEU1 chaperone, protective protein/cathepsin A (PPCA), were also elevated by bleomycin. Western blotting analyses demonstrated bleomycin-induced elevations in protein expression of both NEU1 and PPCA in mouse lungs. Two known selective NEU1 inhibitors, C9-pentyl-amide-DANA (C9-BA-DANA) and C5-hexanamido-C9-acetamido-DANA, dramatically reduced bleomycin-induced loss of body weight, accumulation of pulmonary lymphocytes, and deposition of collagen. Importantly, C9-BA-DANA was therapeutic in the chronic bleomycin exposure model with no toxic effects observed within the experimental timeframe. Moreover, in the acute bleomycin model, C9-BA-DANA attenuated NEU1-mediated desialylation and shedding of the mucin-1 ectodomain. These data indicate that NEU1-selective inhibition offers a potential therapeutic intervention for pulmonary fibrotic diseases. SIGNIFICANCE STATEMENT: Neuraminidase-1-selective therapeutic targeting in the acute and chronic bleomycin models of pulmonary fibrosis reverses pulmonary collagen deposition, accumulation of lymphocytes in the lungs, and the disease-associated loss of body weight-all without observable toxic effects. Such therapy is as efficacious as nonspecific inhibition of all neuraminidases in these models, thus indicating the central role of neuraminidase-1 as well as offering a potential innovative, specifically targeted, and safe approach to treating human patients with a severe malady: pulmonary fibrosis.

A CD209 ligand and a sialidase inhibitor differentially modulate adipose tissue and liver macrophage populations and steatosis in mice on the Methionine and Choline-Deficient (MCD) diet.

Non-alcoholic fatty liver disease (NAFLD) is associated with obesity and type 2 diabetes and is characterized by the accumulation of fat in the liver (steatosis). NAFLD can transition into non-alcoholic steatohepatitis (NASH), with liver cell injury, inflammation, and an increased risk of fibrosis. We previously found that injections of either 1866, a synthetic ligand for the lectin receptor CD209, or DANA, a sialidase inhibitor, can inhibit inflammation and fibrosis in multiple animal models. The methionine and choline-deficient (MCD) diet is a model of NASH which results in the rapid induction of liver steatosis and inflammation. In this report, we show that for C57BL/6 mice on a MCD diet, injections of both 1866 and DANA reversed MCD diet-induced decreases in white fat, decreases in adipocyte size, and white fat inflammation. However, these effects were not observed in type 2 diabetic db/db mice on a MCD diet. In db/db mice on a MCD diet, 1866 decreased liver steatosis, but these effects were not observed in C57BL/6 mice. There was no correlation between the ability of 1866 or DANA to affect steatosis and the effects of these compounds on the density of liver macrophage cells expressing CLEC4F, CD64, F4/80, or Mac2. Together these results indicate that 1866 and DANA modulate adipocyte size and adipose tissue macrophage populations, that 1866 could be useful for modulating steatosis, and that changes in the local density of 4 different liver macrophages cell types do not correlate with effects on liver steatosis.

The Effects of Ganglioside-Monosialic Acid in Taxane-Induced Peripheral Neurotoxicity in Patients with Breast Cancer: A Randomized Trial.

BACKGROUND: Taxane-induced peripheral neuropathy (TIPN) is a dose-limiting adverse effect. Ganglioside-monosialic acid (GM1) functions as a neuroprotective factor. We assessed the effects of GM1 on the prevention of TIPN in breast cancer patients. METHODS: We conducted a randomized, double-blind, placebo-controlled trial including 206 patients with early-stage breast cancer planning to receive taxane-based adjuvant chemotherapy with a follow-up of more than 1 year. Subjects were randomly assigned to receive GM1 (80 mg, day -1 to day 2) or placebo. The primary endpoint was the Functional Assessment of Cancer Treatment Neurotoxicity subscale score after four cycles of chemotherapy. Secondary endpoints included neurotoxicity evaluated by National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 and the Eastern Cooperative Oncology Group neuropathy scale. All statistical tests were two-sided. RESULTS: In 183 evaluable patients, the GM1 group reported better mean Functional Assessment of Cancer Treatment Neurotoxicity subscale scores than patients in the placebo group after four cycles of chemotherapy (43.27, 95% confidence interval [CI] = 43.05 to 43.49 vs 34.34, 95% CI = 33.78 to 34.89; mean difference = 8.96, 95% CI = 8.38 to 9.54, P < .001). Grade 1 or higher peripheral neurotoxicity in Common Terminology Criteria for Adverse Events v4.0 scale was statistically significantly lower in the GM1 group (14.3% vs 100.0%, P < .001). Additionally, the GM1 group had a statistically significantly lower incidence of grade 1 or higher neurotoxicity assessed by Eastern Cooperative Oncology Group neuropathy scale sensory neuropathy (26.4% vs 97.8%, P < .001) and motor neuropathy subscales (20.9% vs 81.5%, P < .001). CONCLUSIONS: The treatment with GM1 resulted in a reduction in the severity and incidence of TIPN after four cycles of taxane-containing chemotherapy in patients with breast cancer.

A novel sialidase-activatable fluorescence probe with improved stability for the sensitive detection of sialidase.

Sialidases catalyse the hydrolysis of terminal sialic acid residues of various glycoconjugates and visualising sialidase activity is important for understanding its function in the biological and pathological context. Upon developing a novel fluorescence probe for sialidase with improved fluorescence characteristics based on our previously reported fluorophore, HMRef, an inherent instability of sialic acid conjugates was found to both reduce selectivity and sensitivity. We aimed at increasing the stability of the probes by incorporating a self-immolative spacer with a higher pKa between the sialic acid residue and HMRef to develop HMRef-S-Neu5Ac, which shows superior stability allowing for the specific detection of sialidase.

A phase 3 randomized study evaluating sialic acid extended-release for GNE myopathy.

OBJECTIVE: To investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), a treatment intended to replace deficient sialic acid, in patients with GNE myopathy. METHODS: UX001-CL301 was a phase 3, double-blind, placebo-controlled, randomized, international study evaluating the efficacy and safety of Ace-ER in patients with GNE myopathy. Participants who could walk ≥200 meters in a 6-minute walk test at screening were randomized 1:1, and stratified by sex, to receive Ace-ER 6 g/d or placebo for 48 weeks and assessed every 8 weeks. The primary endpoint was change in muscle strength over 48 weeks measured by upper extremity composite (UEC) score. Key secondary endpoints included change in lower extremity composite (LEC) score, knee extensor strength, and GNE myopathy-Functional Activity Scale (GNEM-FAS) mobility domain score. Safety assessments included adverse events (AEs), vital signs, and clinical laboratory results. RESULTS: Eighty-nine patients were randomized (Ace-ER n = 45; placebo n = 44). Change from baseline to week 48 for UEC score between treatments did not differ (least square mean [LSM] Ace-ER -2.25 kg vs placebo -2.99 kg; LSM difference confidence interval [CI] 0.74 [-1.61 to 3.09]; p = 0.5387). At week 48, there was no significant difference between treatments for the change in key secondary endpoints: LEC LSM difference (CI) -1.49 (-5.83 to 2.86); knee extension strength -0.40 (-2.38 to 1.58); and GNEM-FAS mobility domain score -0.72 (-2.01 to 0.57). Gastrointestinal events were the most common AEs. CONCLUSIONS: Ace-ER was not superior to placebo in improving muscle strength and function in patients with GNE myopathy. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with GNE myopathy, Ace-ER does not improve muscle strength compared to placebo.

GNE myopathy: from clinics and genetics to pathology and research strategies.

GNE myopathy is an ultra-rare autosomal recessive disease, which starts as a distal muscle weakness and ultimately leads to a wheelchair bound state. Molecular research and animal modelling significantly moved forward understanding of GNE myopathy mechanisms and suggested therapeutic interventions to alleviate the symptoms. Multiple therapeutic attempts are being made to supplement sialic acid depleted in GNE myopathy muscle cells. Translational research field provided valuable knowledge through natural history studies, patient registries and clinical trial, which significantly contributed to bringing forward an era of GNE myopathy treatment. In this review, we are summarising current GNE myopathy, scientific trends and open questions, which would be of significant interest for a wide neuromuscular diseases community.