One Pathway, Many Rare Diseases

The GSL pathway is a metabolic “hub” at the crossroads of many rare diseases

Multiple biological pathways converge on a single metabolic hub where the body produces and breaks down glycosphingolipids (GSLs) – fatty substances that form part of the cell membrane.1 Sanofi scientists are uncovering the unique role of this hub in three different categories of rare disease: lysosomal storage disorders, autosomal dominant polycystic kidney disease (ADPKD), and a genetic form of Parkinson's disease.

Here, Sanofi scientists walk us through the GSL pathway and share what makes it so intriguing for rare-disease researchers.

What is the GSL pathway?

GSLs are routinely metabolized in healthy cells.2 They go through a known series of chemical reactions to create fresh cell-membrane components and to recycle other components as needed. In people with certain gene mutations, things can go wrong on this pathway, causing GSLs to build up abnormally in cells.

Glucosylceramide (GL-1) is at a critical juncture in this metabolic pathway,3 where an enzyme called glucosylceramide synthase (GCS) initiates production of GL-1, while another, glucocerebrosidase, breaks it down.

GLS Pathway Infographic

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.

Caption: 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.

In patients with ADPKD, too much GL-1 is produced, overloading kidney cell membranes with GSLs. In patients with lysosomal storage disorders, such as Fabry or Gaucher disease, metabolizing enzymes do not work properly or are deficient. GSLs cannot be broken down, so they gradually build up in cells.

Abnormal GSL accumulation is seen in several rare, inherited diseases for which few, if any, treatments are available. Sanofi researchers are investigating how to rebalance the GSL pathway to reduce GSL buildup and restore equilibrium. 

The GSL pathway and ADPKD

Rare disease researchers at Sanofi were investigating the GSL pathway in lysosomal storage disorders, which affect only one in 20,000 to one in a million people.4,5 They shared their findings with their colleagues in nephrology, leading to the discovery of a connection with ADPKD – a genetic kidney condition that affects a much larger population of between 1 in 400 and 1 in 1,000 people.6,7

ADPKD is caused by a mutation in the PKD1 or PKD2 gene, but it is not a lysosomal storage disorder. In ADPKD, GSL builds up in the kidneys not because of a defect in a metabolizing enzyme but because increased GCS activity over-produces GL-1 (and other downstream GSLs). The resulting accumulation of GSL is thought to be an important driver of cyst growth.8,9

People with ADPKD develop cysts on their kidneys that can grow to be as large as an American football. Usually, patients see the first signs of the disease before the age of 30, and around half of them develop kidney failure, requiring dialysis or kidney transplant before the age of 60.3,4 

Sanofi researchers are exploring ways to slow the production of GL-1,10 which they hope will head off abnormal GSL accumulation in cells.

Gaucher disease and GBA-associated Parkinson's disease

In people with Gaucher disease, mutations in the GBA gene affect the production of β-glucocerebrosidase – the GL-1 metabolizing enzyme. This causes GSLs to accumulate primarily in the liver, spleen, and bone marrow, and sometimes in the brain. Patients with Gaucher disease type 3 (GD3), also called neuronopathic Gaucher disease, may experience slowly progressive neurologic symptoms, severe fatigue, enlargement of the liver and spleen, bone pain, and fractures. As of September 2020, no treatments are approved to treat patients experiencing the neurological manifestations of GD3.11

GBA-associated Parkinson's Disease (GBA-PD), which affects around 7-10% of Parkinson’s patients, is also associated with mutations in the GBA gene and GSL pathway.12 GBA-PD often results in earlier onset of the degenerative condition and a higher prevalence of cognitive impairment.13

Sanofi scientists are studying the potential therapeutic benefits of modulating the GSL pathway in the brain of GD3 and GBA-PD patients.

The GSL Pathway and lysosomal storage disorders

The GSL pathway plays an important role in Gaucher disease and many other lysosomal storage disorders, in which a gene mutation impairs a GSL-metabolizing enzyme. For some of these diseases, existing therapies address the problem by adding the missing enzyme. Understanding the GSL pathway opens new avenues of research and pathways to potential treatment for lysosomal storage disorders.

GM2 gangliosidosis encompasses three related, inherited conditions: Tay-Sachs14 disease, Sandhoff disease, and AB variant15, which involve a deficiency in the enzyme β-hexosaminidase. All these diseases could lead to progressive destruction of nerve cells in the brain, spinal cord, or both.16

Complex hereditary spastic paraplegia (GM2/GD2) causes mild to moderate cognitive impairment and developmental delay.17 GM2/GD2 is caused by a mutation in the B4GALNT1 gene.

Fabry disease, a progressive, potentially life-threatening inherited rare genetic disorder, may cause complications in the kidneys, heart, brain, gastrointestinal tract and skin.18 It is caused by mutations in GLA, the gene that provides instructions for making the GSL-metabolizing enzyme a-galactosidase A.

Sanofi scientists are actively investigating potential therapeutics that center on the GSL pathway for many of these diseases.

Many people with rare diseases, and their families, feel as though there is no hope, and no options. We are deeply committed to these communities and motivated to follow the science, knowing that it has the potential to make a difference for patients.

Dietmar Berger, CMO and Head of Clinical Development at Sanofi

References

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  2. Merscher S, Fornoni A. Podocyte pathology and nephropathy - sphingolipids in glomerular diseases. Frontiers in Endocrinology. 2014 ;5:127. DOI: 10.3389/fendo.2014.00127
  3. Murugesan V, Chuang WL, Liu J, et al. Glucosylsphingosine is a key biomarker of Gaucher disease. American Journal of Hematology. 2016 Nov;91(11):1082-1089. DOI: 10.1002/ajh.24491
  4. Kingma SD, Bodamer OA, Wijburg FA. Clinical Endocrinology & Metabolism. 2015 Mar;29(2):145-157. DOI: 10.1016/j.beem.2014.08.004
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  6. Public summary of opinion on orphan designation. 12 August 2015. EMA/COMP/432098/2015, Committee for Orphan Medicinal Products. Accessed October 2020
  7. Torres, V. E. (2010). Advances in Chronic Kidney Disease. 17(2), 190–204. doi: 10.1053/j.ackd.2010.01.006
  8. Chatterjee S, Shi WY, Wilson P, Mazumdar A. Journal of Lipid Research. 1996 Jun;37(6):1334-1344
  9. Deshmukh GD, Radin NS, Gattone VH 2nd, Shayman JA. Journal of Lipid Research. 1994 Sep;35(9):1611-1618
  10. El-Beshlawy A, Tylki-Szymanska A, Vellodi A, et al. Molecular Genetics and Metabolism. 2017 Jan - Feb;120(1-2):47-56. DOI: 10.1016/j.ymgme.2016.12.001
  11. El-Beshlawy A, Tylki-Szymanska A, Vellodi A, et al. Molecular Genetics and Metabolism. 2017 Jan - Feb;120(1-2):47-56. DOI: 10.1016/j.ymgme.2016.12.001
  12. Schapira AH. Mol Cell Neurosci. 2015;66(Pt A):37-42. doi:10.1016/j.mcn.2015.03.013
  13. Schapira AH. Mol Cell Neurosci. 2015;66(Pt A):37-42. doi:10.1016/j.mcn.2015.03.013
  14. Toro C, Shirvan L, Tifft C. 1999 Mar 11 [Updated 2020 Oct 1]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1218/. Accessed October 2020
  15. National Institute of Neurological Disorders and Stroke (2019) Retrieved from https://www.ninds.nih.gov/Disorders/All-Disorders/Generalized-Gangliosidoses-Information-Page, last modified 27 March 2019. Accessed October 2020
  16. National Institutes of Health, U.S. National Library (2019, Sep 10). Genetics Home Reference. Retrieved from https://ghr.nlm.nih.gov/condition/gm2-gangliosidosis-ab-variant#definition, accessed October 2020
  17. Ng BG, Freeze HH. Journal of Inherited Metabolic Disease. 2015 Jan;38(1):171-178. DOI: 10.1007/s10545-014-9752-1
  18. National Institutes of Health, U.S. National Library. (2019, Sep 10). Genetics Home Reference. Retrieved from https://ghr.nlm.nih.gov/condition/fabry-disease#definition. Accessed October 2020

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