Traffic light-trails at night

Metabolic Hub May Offer New Hope for Rare Diseases

Sanofi scientists Pablo Sardi and Ali Hariri share how the GSL pathway could point to potential new options for three classes of rare disease

Imagine all the metabolic pathways that support human life – everything from respiration to protein synthesis – as one vast roadmap. If you scrutinized it carefully you would 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.

Rare disease researchers at Sanofi are investigating the faulty roadwork at a metabolic hub called the GSL pathway, where critical cellular building blocks called glycosphingolipids (GSLs) are made and metabolized. They have found that the GSL pathway is a crossroads for three different classes of diseases. Now, they are laying the foundations for new therapies aimed at lysosomal storage disorders, a rare genetic kidney disease, and a genetic form of Parkinson’s disease.

“It is truly fascinating – and sometimes surprising – how many different diseases are associated with the GSL pathway,” said Ali Hariri, Global Project Head of Rare Disease. “What allowed us to discover its various biological connections, especially to kidney disease, was really collaboration.”

Two-way GSL traffic

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. 

Dysfunction in the GSL pathway is notorious for its central role in causing lysosomal storage disorders, the most common of which are Gaucher disease and Fabry disease. In patients with these conditions, different enzymes within the GSL pathway do not function properly, causing GSLs to accumulate within cells. The result is inflammation that can damage vital tissues and organs. This leads to symptoms that can significantly impact the quality of life for people suffering from these diseases.

Sanofi Genzyme researchers pioneered the first treatments for rare diseases in the 1990s by engineering therapies that replace the faulty enzymes. If GSLs were cars entering an old city and faulty enzymes a broken traffic light, enzyme replacement therapies would prevent gridlock by removing the roadblock, allowing the GSLs to get moving again. 

"Enzyme replacement therapies have made a huge difference for people with certain diseases, and inspired a generation of rare disease research," said Pablo Sardi, Global Head of Rare and Neurologic Diseases Research Therapeutic Area, whose team is taking a fresh approach. "The pathway to innovation is not an easy one – so it was a real revelation to discover the potential of this metabolic hub, the GSL pathway, for many diseases. It has allowed us to radically expand our thinking about rare disease." 

Keeping the pathway clear

Sanofi scientists have been deeply scrutinizing the biology of the GSL pathway to tackle the “gridlock” from another direction: slowing down production. 

“There are other points of intervention in this pathway that may be more helpful for patients,” said Hariri. “If you think about it, there are really two options: clear the blocked road or stop the cars from driving into town in the first place. What we are working on now is a way to reduce the number of cars – effectively preventing GSL gridlock in the cell. This pathway is giving us a whole new perspective on a very large cohort of rare diseases for which there are currently few or no treatments, and that is really exciting."

Sanofi R&D teams are investigating a potential therapy for certain rare diseases that are designed to modulate the GSL pathway.

3D illustration of cell

How the GSL pathway works

The scientists next door

But how did Sanofi scientists studying lysosomal storage disorders discover that the GSL pathway touches ADPKD – a completely different category of disease?

“That discovery was the genuine byproduct of teams of Sanofi scientists working next to each other and one day hatching a bold idea,” explained Sardi. "It is a perfect example of how collaboration moves science forward and brings us more quickly toward potential new options that are so desperately needed."

For several years the Sanofi group studying lysosomal storage disorders, which are quite rare, worked next door to another team studying kidney diseases that affect a much larger population of patients. After exchanging updates on their latest research, the researchers realized that their respective projects had some intriguingly common threads. So, they teamed up to explore the role of the GSL pathway in ADPKD. 

Their collaboration sparked an effort to probe the GSL pathway in kidney cells, laying the foundation for potential new treatments for ADPKD – a disease that affects roughly 12.5 million people worldwide. About half of people who experience ADPKD develop kidney failure and require dialysis or a kidney transplant before the age of 60. 

"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," explained Sardi. "Precompetitive research collaborations have been an important driver, allowing us to progress our understanding of this mission-critical pathway. 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."

Related articles

Illustration of a cell

One Pathway, Many Rare Diseases

Ashley and her mother

How My Mom’s ADPKD Diagnosis Sparked My Own Health Discovery

Woman looking ahead

From Acceptance to Advocacy: Megan’s Fabry Disease Journey

References

  • Chatterjee S, Shi WY, Wilson P, Mazumdar A. Journal of Lipid Research. 1996 Jun;37(6):1334-1344
  • Chebib FT, Torres VE. American Journal of Kidney Diseases. 2016 May;67(5):792-810. DOI: 10.1053/j.ajkd.2015.07.037
  • Deshmukh GD, Radin NS, Gattone VH 2nd, Shayman JA. Journal of Lipid Research. 1994 Sep;35(9):1611-1618
  • 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
  • Fuller M, Meikle PJ, Hopwood JJ. In: Mehta A, Beck M, Sunder-Plassmann G, editors. Fabry Disease: Perspectives from 5 Years of FOS. Oxford: Oxford PharmaGenesis; 2006. Chapter 2. Available from: https://www.ncbi.nlm.nih.gov/books/NBK11603/. Accessed October 2020
  • Kingma SD, Bodamer OA, Wijburg FA. Clinical Endocrinology & Metabolism. 2015 Mar;29(2):145-157. DOI: 10.1016/j.beem.2014.08.004
  • Merscher S, Fornoni A. Frontiers in Endocrinology. 2014 ;5:127. DOI: 10.3389/fendo.2014.00127
  • Murugesan V, Chuang WL, Liu J, et al. American Journal of Hematology. 2016 Nov;91(11):1082-1089. DOI: 10.1002/ajh.24491
  • 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
  • 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
  • Ng BG, Freeze HH. Journal of Inherited Metabolic Disease. 2015 Jan;38(1):171-178. DOI: 10.1007/s10545-014-9752-1
  • Public summary of opinion on orphan designation. 12 August 2015. EMA/COMP/432098/2015, Committee for Orphan Medicinal Products
  • Schapira AH. Mol Cell Neurosci. 2015;66(Pt A):37-42. doi:10.1016/j.mcn.2015.03.013
  • Torres, V. E. (2010). Advances in Chronic Kidney Disease. 17(2), 190–204. doi: 10.1053/j.ackd.2010.01.006

This website uses cookies to track its audience and improve its content. By continuing to browse this website, you agree to the use of such cookies.

Click here for more information on cookies
OK