Targeting a Single Pathway to Impact a Range of Rare Diseases

Photo: Molecules closed together, indicative of a biological interaction in renal disease
Courtesy of Sharda Jha


For scientists in R&D, the chance to improve the lives of people living with a rare disease can provide a unique motivation to discover new medicines. Long hours in the lab stretch into long months as scientists grapple with the complexities of human biology around a disease that may afflict few people but may have devastating consequences for those it affects.

With the right insights, though, scientists can sometimes make a discovery that has the potential to do more than treat a single condition. Sometimes, by focusing on one errant biological process, it is possible to discover new therapies that hold the promise of targeting a range of diseases.

One of the areas our scientists have been focused on is the pathway in the body’s synthesis of glucosylceramide (GL-1). GL-1 is the core building block of more complex glycosphingolipids (GSLs) and gangliosides that can cause disease when too many of them build up in cells. Genetic defects that result in the excessive buildup of GSLs or gangliosides are implicated in several rare inherited diseases, which have few, if any, effective treatments today. 

Finding a promising solution for an entire pathway

By focusing relentlessly on this key early step in GSL production, Sanofi researchers are working to find a solution for diseases linked to excess buildup of GSL. 

While each disease is rare, with its own unique symptoms and life challenges for individuals who live with it, all of them are affected by genetic errors that result in buildup of GSLs and/or gangliosides.

“By targeting a metabolic “hub” that leads to multiple downstream pathways, you have the potential to treat many genetic conditions. Think of it like a tree: The same treatment can affect many different branches.”

Dietmar Berger, Global Head of Development, Sanofi

Crossing the blood-brain barrier

In Gaucher disease, a genetic mutation causes an individual to produce too little of a key enzyme. As a result, the body accumulates excessive levels of lipids, mostly in the spleen, liver and bone marrow. Patients with Gaucher disease type 3 not only experience symptoms like severe fatigue, enlargement of the liver and spleen, bone pain and fractures – but also have nervous system damage that can cause seizures, eye movement problems, cognitive issues and poor muscular coordination. While current treatment options available to patients address non-neuropathic Gaucher disease manifestations, there are no effective treatments available for the neurological manifestations of patients with type 3 Gaucher's disease (GD3).1

“We want to go further for these patients and see if we can develop therapies that would enter the central nervous system, be active in the brain, and aim to address the neurological aspect of the disease,” Berger said.

“We have an outstanding chemistry group that designs small molecules, knows their three-dimensional characteristics, and with the help of computational biologists, finds ways to modify them to go across the blood-brain barrier,” he said.

Unmet needs for rare and serious conditions

In addition to Gaucher disease, Sanofi’s researchers also understand that several other diseases are associated with mutations in the GSL metabolic pathway, such as*: 

  • GBA-Associated Parkinson's disease (GBA-PD), which affects around 5% of all Parkinson’s patients and often results in earlier onset of the degenerative condition and a higher prevalence of cognitive impairment.2
  • Autosomal dominant polycystic kidney disease (ADPKD), in which the kidneys develop numerous cysts that can cause the kidneys to grow to be as large as an American football; Berger notes that about half of ADPKD patients develop end-stage renal failure, requiring dialysis or kidney transplant between the ages of 50 to 60.3,4
  • Fabry disease, a progressive, potentially life-threatening inherited rare genetic disorder that causes complications in the kidneys, heart, brain, gastrointestinal tract and skin.5
  • GM2 gangliosidosis, a set of three related conditions—Tay-Sachs disease, Sandhoff disease, and AB variant—all of which lead to progressive destruction of nerve cells in the brain, spinal cord, or both. There are currently no treatment options for these diseases that can have a significant impact on quality of life, and in their most severe forms, lead to premature death.6
  • Complex hereditary spastic paraplegia (GM2/GD2), which involves mutations in B4GALNT1 and causes mild to moderate cognitive impairment and developmental delay. This may lead to being wheelchair-bound later in life.7
  • Amish infantile epilepsy, a GM3-associated disease, linked to the ST3GAL5 mutation, is associated with developmental stagnation and blindness.7
  • Salt and pepper syndrome, another GM3-associated disease, is characterized by altered dermal pigmentation alongside severe intellectual disability, epilepsy, scoliosis, choreoathetosis and dysmorphic facial features.7

“When you feel like you have no hope and no options, it can lead to isolation and fear on the part of patients and their families. The work we do inspires us to change that,” Berger said. “Being able to target diseases can really make a big difference, and it makes it very easy to be motivated.”

*There are many more conditions associated to the GSL pathway, the list provided in this article is not exhaustive.


1 Amal El-B, Anna TS, Ashok V, et al. Long-term hematological, visceral, and growth outcomes in children with Gaucher disease type 3 treated with imiglucerase in the International Collaborative Gaucher Group Gaucher Registry. Molecular Genetics and Metabolism 120 (2017) 47–56. #48 [30-36]
2 Schapira AH. Glucocerebrosidase and Parkinson disease: Recent advances. Mol Cell Neurosci. May 2015;66(Pt A):37-42.
3 Chatterjee S, Shi WY, Wilson P, Mazumdar A. Role of lactosylceramide and MAP kinase in the proliferation of proximal tubular cells in human polycystic kidney disease. J Lipid Res. Jun 1996;37(6):1334-1344.
4 Natoli TA, Smith LA, Rogers KA, et al. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat Med. Jul 2010;16(7):788-792.
5 National Institutes of Health, U.S. National Library. (2019, Sep 10). Genetics Home Reference; Your Guide to Understanding Genetic Conditions, Fabry Disease. Retrieved from, Accessed: 16 October, 2019
6 National Institutes of Health, U.S. National Library (2019, Sep 10). Genetics Home Reference; Your Guide to Understanding Genetic Conditions, GM2-gangliosidosis, AB variant. Retrieved from, Accessed: 16 October, 2019
Human genetic disorders involving glycosylphosphatidylinositol (GPI) anchors and glycosphingolipids (GSL), Bobby G. Ng and Hudson H. Freeze. J Inherit Metab Dis. 2015 Jan; 38(1): 171–178.