Imagine all the metabolic pathways that support human life–everything from respiration to protein synthesis–as one vast roadmap.
If you look very closely, you'll see roads converging on busy intersections: hubs where multiple biological processes come together. When the traffic signal fails, or when just one road is blocked, the effects can be felt through the whole system.
Our R&D teams are investigating the faulty roadwork at one metabolic hub called the GSL pathway, where critical cellular building blocks called glycosphingolipids (GSLs)1 are made and metabolized. They have found that the GSL pathway is a crossroads for several lysosomal storage disorders—rare genetic conditions caused by enzyme deficiencies—and are laying the foundations for new therapies.
What is the GSL pathway?
GSLs are fatty molecules that are essential for maintaining cell membranes. The GSL pathway is the supply chain for these building blocks: ample fresh GSLs are available on demand, while old or damaged GSLs are removed and recycled.
The GSL pathway is a series of biochemical reactions, in which GSLs are metabolized and turned into fresh cell-membrane components as needed. A lipid called glucosylceramide (GL-1)2 sits at a critical junction in this pathway, where one enzyme initiates production of GL-1 and another enzyme breaks it down. When the road is clear, GSLs remain in balance. But in people with certain gene mutations, a metabolic traffic jam can cause GSLs to build up abnormally in cells.3
Overview of the glycosphingolipid (GSL) pathway, showing how GL-1 leads to the production of GSLs, which are part of the cell membrane. GSL-degrading enzymes are shown flowing up, while GSL synthesizing enzymes are flowing down. In several rare diseases, a genetic mutation impairs the cell's ability to break down GSLs – but in ADPKD, the cell produces too much GL-1. In all cases, there is abnormal accumulation of GSLs in cells, leading to serious health challenges. This is not an exhaustive list of disorders associated with GSL dysregulation.
Overview of the glycosphingolipid (GSL) pathway, showing how GL-1 leads to the production of cell membrane components called GSLs. Enzymes that break down GSL are shown flowing up, while enzymes that produce GSL are shown flowing down. In several rare diseases, a genetic mutation impairs the cell's ability to break down GSLs. GSLs accumulate in cells, leading to serious health challenges. This is not an exhaustive list of disorders associated with GSL dysregulation.
How GSLs can accumulate
In people with certain lysosomal storage disorders, enzymes that metabolize GSLs either do not work properly or there may not be enough of them. As a result, GSLs cannot be broken down, and they gradually build up in cells.4 This can lead to progressive cellular injury that can damage vital tissues and organs, and other symptoms that can significantly impact quality of life.
Our teams are investigating how to rebalance the GSL pathway to reduce GSL buildup and restore equilibrium. This work builds on the strong legacy of Sanofi Genzyme, which pioneered the first treatments for rare diseases in the 1990s by engineering therapies that replace the faulty enzymes. Enzyme replacement therapies essentially remove roadblocks to get GSLs moving again.
A path to innovation
A deeper understanding the GSL pathway is opening up new possibilities for lysosomal storage disorders. Our research and development teams are actively investigating potential therapeutics that center on the GSL pathway for many rare conditions.
- In people with Gaucher disease, mutations in the GBA gene affect the production of an enzyme that metabolizes GL-1, called β-glucosidase. The impaired enzyme causes GSLs to accumulate primarily in the liver, spleen, and bone marrow, and sometimes in the brain. People with Gaucher disease type 3 (GD3), also called neuronopathic Gaucher disease,5 may experience slowly progressive neurologic symptoms, severe fatigue, enlargement of the liver and spleen, bone pain, and fractures. Our scientists are studying the potential therapeutic benefits of modulating the GSL pathway in the brains of GD3 patients.
- People with Fabry disease, a progressive, potentially life-threatening inherited rare genetic disorder, may experience complications in the kidneys, heart, brain, gastrointestinal tract, and skin. Fabry disease is caused by mutations in GLA, the gene that provides the blueprint for making α-galactosidase A, an enzyme that metabolizes GSL.6
- GM2 gangliosidosis encompasses three related, inherited conditions: Tay-Sachs disease, Sandhoff disease, and AB variant, which all involve a deficiency in the enzyme β-hexosaminidase.7 People with these conditions can go through progressive destruction of nerve cells in the brain, spinal cord, or both.8,9
- People with complex hereditary spastic paraplegia (GM2/GD2) experience mild to moderate cognitive impairment and developmental delay. GM2/GD2 is caused by a mutation in the B4GALNT1 gene.10
"We are leading the way to discovery in this area, working in a very connected ecosystem of academic, foundation, and industry research that is dedicated to moving this field ahead. Our solid scientific foundation and culture of innovation in Sanofi R&D has been essential in bringing us quickly toward potential new options for these patients, who are in dire need." - Pablo Sardi, Global Head of Rare and Neurological Diseases Research
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- Merscher S, Fornoni A (2014) Frontiers in Endocrinology 5:127; doi: 10.3389/fendo.2014.00127
- Murugesan V, et al. (2016) Glucosylsphingosine is a key biomarker of Gaucher disease. American Journal of Hematology 91:1082–1089; doi: 10.1002/ajh.24491
- Breiden B, Sandhoff K (2019) Lysosomal Glycosphingolipid Storage Diseases. Annual Review of Biochemistry 88:461–485; doi: 10.1146/annurev-biochem-013118-111518
- Kingma SD, Bodamer OA, Wijburg FA (2015) Clinical Endocrinology & Metabolism 29:145–157; doi: 10.1016/j.beem.2014.08.004
- El-Beshlawy A, et al. (2017) Molecular Genetics and Metabolism 120:47–56; doi: 10.1016/j.ymgme.2016.12.001
- National Institutes of Health, U.S. National Library (2019) Genetics Home Reference: Fabry Disease. Accessed December 2021
- Toro C, Shirvan L, Tifft C (1999) In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews. Seattle (WA): University of Washington; 1993-2020. Accessed December 2021 at https://www.ncbi.nlm.nih.gov/books/NBK1218/
- National Institutes of Health, U.S. National Library (2019) Genetics Home Reference: GM2 Gangliosidosis. Accessed December 2021
- National Institute of Neurological Disorders and Stroke (2019) Generalized-Gangliosidoses-Information-Page. Accessed December 2021
- Li TA, Schnaar RL (2018) Congenital Disorders of Ganglioside Biosynthesis. In: Schnaar RL, Lopez PHH, Eds. Progress in Molecular Biology and Translational Science156: 63-82; doi: 10.1016/bs.pmbts.2018.01.001