GAL

Researchers discovered new mutations in the GLA gene, the underlying cause of Fabry disease, but noted that all of them may be amenable to Galafold (migalastat) chaperone therapy, an approved treatment to slow or prevent organ function decline in Fabry patients, a new study reports.Clinical manifestations of these novel Fabry-causing mutations were detailed in the study. The researchers reported that each patient experienced involvement in multiple organs.“This study further enriches the Fabry disease GLA mutation database and deepens our understanding of GLA mutations and the structure and function of the [Gal A] protein,” the team wrote.Additionally, a model developed by the scientists may predict patients’ responses to Galafold treatment, per the study.The study, “Pathogenicity of novel GLA gene missense mutations in Fabry disease and the therapeutic impact of migalastat,” was published in the Journal of Advanced Research.In Fabry, mutations in the GLA gene affect alpha-galactosidase A, or alpha-Gal A, an enzyme needed to break down certain fatty molecules, including globotriaosylceramide, known as Gb3. Because people with Fabry produce very little or an abnormal version of alpha-Gal A, these fatty molecules build up to toxic levels in various tissues and organs, causing disease symptoms.There are two types of Fabry, dependent on the impact of the GLA mutation and its effect on alpha-Gal A activity. The classic form of the condition, which is more severe, is marked by less than 1% of alpha-Gal A activity, with symptoms arising in childhood. In comparison, the late-onset form is characterized by more than 1% of alpha-Gal A activity, with symptoms usually emerging in adulthood.When new GLA mutations are discovered, it’s essential to understand their impact on alpha-Gal A function and, in turn, on Fabry patients.Here, a research team in China retrospectively screened the clinical data of 163 Fabry patients, looking for new GLA mutations and examining their effect on disease development.Of the 95 different GLA mutations detected, 12 had not been previously reported. Nine of these were considered to definitely cause Fabry because they led to a shortened version of alpha-Gal A, which would be rapidly degraded. The remaining three were missense mutations, meaning they caused a change in a single amino acid — which serve as the building blocks of proteins — within an intact alpha-Gal A enzyme.The researchers then focused on the Fabry patients with missense mutations, as these specific genetic changes may still allow for the production of a partially functional enzyme. That makes these individuals suitable candidates for treatment with Galafold, an oral chaperone therapy approved for adults with Fabry carrying certain GLA mutations.Galafold works by stabilizing the abnormal alpha-Gal A enzyme, allowing it to reach lysosomes, the cell’s recycling centers, where it boosts Gb3 clearance. The therapy has been shown to help manage symptoms in people with Fabry.All of the patients with this type of mutation were men, with an average age of 14.75 years at onset and 29.5 at diagnosis.The man in the first case, found to have a p.W44G mutation, experienced hand and foot pain, a lack of sweat, and benign skin lesions during childhood. He also had symptoms of dizziness, heart palpitations, left heart enlargement, episodic ankle swelling, and diarrhea. The patient was given pain medications but not enzyme replacement therapy (ERT). Prediction analysis also suggested that this mutation was highly pathogenic, or disease-causing.The second patient, carrying a p.S65N mutation, also experienced hand and foot pain and a lack of sweat since childhood. As he aged, other symptoms emerged, including benign skin lesions, high blood pressure, and mild tinnitus, or ringing in the ears. At 31, he underwent a kidney biopsy due to unexplained proteinuria, or high levels of protein in the urine, that revealed scarring. Genetic tests confirmed Fabry, and he was treated with ERT. His mutation was deemed low pathogenic, indicating a mild impact on the enzyme.In the third case, the patient had a p.G260W mutation. Unexplained proteinuria was discovered during a routine medical examination at age 32, with a subsequent kidney biopsy revealing damage. After being diagnosed with Fabry via genetic and alpha-Gal A enzyme testing, he was started on ERT, which significantly reduced his lyso-Gb3 levels. His mutation was considered highly pathogenic.The team then created human kidney cell lines (HEK-293) harboring each mutation to investigate their impact on GLA gene expression (activity), alpha-Gal A protein expression (production), and enzyme activity. The model was designed to work at different mutation sites.The GLA gene expression levels of all of the mutations were significantly lower than those of unmutated control cells, the researchers found. The low pathogenic p.S65N mutation showed the highest expression across all of the mutations. Likewise, alpha-Gal A expression and its activity were significantly lower in all, with the p.S65N mutation showing the most residual enzyme activity at 43.75% of normal.All cell lines were exposed to Galafold, with treatment significantly increasing the expression and activity of all the mutant alpha-Gal A enzymes, particularly in the p.S65N mutant, which reached as high as 80.7% of normal, according to the scientists.“[Galafold] intervention increased the enzymatic activity in the disease models with the novel missense mutations, as well as [meeting] the amenable mutation criteria for GLA gene mutations applicable to [Galafold],” the research team concluded.

The protein galectin-1 (Gal-1) has been identified as a new PET imaging biomarker for immune checkpoint blockade (ICB) therapy, allowing physicians to predict the tumor responses before beginning treatment. Information garnered from Gal-1 PET imaging could also be used to facilitate patient stratification and optimize immunotherapy, enabling targeted interventions and improving patient outcomes. The protein galectin-1 (Gal-1) has been identified as a new PET imaging biomarker for immune checkpoint blockade (ICB) therapy, allowing physicians to predict the tumor responses before beginning treatment. Information garnered from Gal-1 PET imaging could also be used to facilitate patient stratification and optimize immunotherapy, enabling targeted interventions and improving patient outcomes. This research was published in the May issue of The Journal of Nuclear Medicine. Immunotherapies, such as ICB, have produced promising clinical outcomes in melanoma, non-small cell lung cancer, and several other types of tumors. However, only a subgroup of patients experiences positive outcomes with objective response rates spanning between five and 60 percent. "Developing reliable approaches for assessing responses and selecting eligible patients for immunotherapy remains challenging," said Zhaofei Liu, PhD, Boya Distinguished Professor at Peking University in Beijing, China. "Current clinical criteria for monitoring solid tumor responses to immunotherapy are based on CT and MRI scans, but these methods result in a considerable delay between treatment commencement and response evaluation. Molecular imaging techniques, especially PET, have emerged as robust tools for predicting immunotherapy effectiveness through the real-time, quantitative, and noninvasive assessment of biomarkers in vivo." In the study, a mouse model was utilized to identify new imaging biomarkers for tumor responses to ICB therapy. Through a proteomic analysis (separation, identification, and quantification of proteins in a tumor), researchers found that tumors exhibiting low Gal-1 expression responded positively to ICB therapy. Next, Gal-1 was labeled with 124I and the radiotracer (124I-α-Gal-1) and small animal PET imaging and biodistribution studies were conducted to assess the specificity of the radiotracer. PET imaging with 124I-αGal-1 showed the immunosuppressive status of the tumor microenvironment, thus enabling the prediction of ICB resistance in advance of treatment. For tumors that were not predicted to respond well to ICB therapy, researchers developed a rescue strategy that utilized a Gal-1 inhibitor that significantly improved the chance for success. "Gal-1 PET opens avenues for the early prediction of ICB efficacy before treatment initiation and facilitates the precision design of combinational regimes," noted Liu. "This sensitive approach has the potential to achieve individualized precision treatment for patients in the future." This research was published online in March 2024.

A team of researchers has identified the molecular and cellular mechanisms that regulate selective autophagy in the fruit fly Drosophila melanogaster. While the function of these processes is increasingly understood in mammals this is one of the first studies in insects. The study of autophagy -- the recycling and repair process within cells -- has huge potential to aid in fighting the ageing process, bacterial and viral infections and diseases including cancer, Alzheimer's and Parkinson's. The study of autophagy -- the recycling and repair process within cells -- has huge potential to aid in fighting the ageing process, bacterial and viral infections and diseases including cancer, Alzheimer's and Parkinson's. A team of researchers led by Professor Ioannis Nezis from the School of Life Sciences at the University of Warwick, has identified the molecular and cellular mechanisms that regulate selective autophagy in the fruit fly Drosophila melanogaster. While the function of these processes is increasingly understood in mammals this is one of the first studies in insects. The study opens new avenues in our understanding of the regulation of Golgi complex turnover by selective autophagy.The Golgi complex is a stack of flat sacs formed by membranes inside the cell. It prepares proteins and fat molecules for transportation and use in other places inside and outside the cell. Professor Nezis and his team used gene editing, confocal and electron microscopy to identify a novel type of selective autophagy, termed Golgiphagy, meaning how cells degrade a cell organelle called Golgi complex by autophagy. In the paper, 'GMAP is an Atg8a-inteacting protein that regulates Golgi turnover in Drosophila' published today in the journal Cell Reports, PhD students Ashrafur Rahman, Raksha Gohel and colleagues describe how gene editing was used to create fruit flies unable to process specific proteins by autophagy. Comparison of the gene edited flies with their wild type counterparts showed:- Lead author of the research Professor Ioannis Nezis from the School of Life Sciences at the University of Warwick, said: "Understanding the molecular mechanisms of selective autophagy of Golgi complex in cells will help open new avenues of research that will assist elucidating the underlying cellular mechanisms of diseases."