Recently, we observed “Rare Disease day” to raise awareness of the rare diseases that afflict millions of people in the United States. While the definition of rare diseases varies in every country, in the United States a rare disease is one that affects less than 200,000 people at a given time. Scientists worldwide have made tremendous progress to identify and understand the clinical manifestations and pathogenesis of these diseases leading to several treatment options and saving many lives. In a recent article by Pandey et al in the journal Nature, scientists unraveled a critical role played by the body’s immune system in Gaucher disease, thereby prompting a potential treatment option.
Gaucher disease is an inherited disorder characterized by a mutation in the gene Gba1 that leads to a deficiency in the enzyme glucocerebrosidase.(GCase). This enzyme is present in the lysosome, the digestive system of the cell, that contains numerous enzymes necessary for the break down of complex molecules. GCAse, in particular, is required for the breakdown of a fatty acid compound, glucosylceramide (GC) into simpler components that can be recycled and utilized for other cellular processes. Consequently, a deficiency of this enzyme leads to the accumulation of GC within the lysosomes in the immune cells of the spleen, bone marrow and liver leading to chronic inflammation. The reason for this tissue inflammation remains elusive.
Enzyme replacement therapy (ERT) is effective in compensating for the enzyme deficiency associated with Gaucher disease. Genzyme’s Cerezyme (imiglucerase) was the first approved ERT treatment. Alternatively, substrate reduction therapy (SRT) prevents the formation of GC itself thereby reducing its accumulation. Two oral drugs, Actelion pharmaceutical’s Zavesca (miglustat ) and Genzyme’s Cerdelga (eliglustat) are commonly used for SRT. However, neither of them address the inflammation associated with the disease. The study by Pandey et al identifies a novel target that can help overcome some of the limitations of the current treatment and potentially benefit patients.
In a mouse model of Gaucher disease, Gba19V/-, Pandey et al found elevated levels of C5a in the immune cells of the spleen, liver and lung in these mice compared to normal mice. This was accompanied by an increased expression of C5aR1 in these cells. C5a is part of the complement immune system that plays an important role in inflammation and homeostasis. It is a cleavage product of C5 and is produced upon activation of macrophages and circulating monocytes, cells of the innate immune system that play a critical role in protecting the body by generating effective immune responses. C5a binds to the receptor C5aR1 on the surface of some innate immune cells that perpetuates the inflammatory response by activating another type of immune cells, namely T cells. Strikingly, double-deficient mice lacking GCase and the C5aR1 receptor (Gba19V/- C5aR1-/-) showed little to no GC accumulation and a significantly reduced inflammatory response with an improved survival. Another interesting feature of these double-deficient mice was the decreased expression of the enzyme glucosyl ceramide synthase (GCS), an enzyme that is required for the synthesis of GC. The treatment of Gba19V/- mice , with an antagonist compound that blocks C5aR (C5aRA) also resulted in decreased GC accumulation and reduced inflammation.
This study suggests that targeting C5aR1 or C5 itself can potentially ameliorate inflammation and GC accumulation. There are two options available pharmaceutically to test this proposition in preclinical models. Alexion pharmaceuticals’ Soliris (eculizumab) is an anti-C5 monoclonal antibody that binds C5 and prevents its cleavage into C5a. It is currently approved for the treatment of a rare disorder, paroxysomal nocturnal hemoglobinuria. Another option is to target the C5a receptor (C5aR1) using antagonists such as Avacopan (CCX168) developed by Chemocentryx which is currently in clinical trials for the treatment of inflammatory disorders that affect the kidney.
Another interesting implication of these studies arises from the observation that Gaucher disease is closely associated with the neurodegenerative disorder, Parkinson’s disease (PD). Studies indicate that GCase and alpha- synuclein, the protein whose dysfunction is a major phenomenon in PD, have a reciprocal relationship and several ongoing investigations are focused on parsing apart this connection. This study published by Pandey et al opens up an area of investigation to determine the interplay between the complement system and inflammation in the brain that can perhaps explain the correlation between these diseases.
There are over 50 lysosomal storage disorders (LSDs) that are rare, inherited and commonly driven by enzyme deficiencies leading to unwanted accumulation of materials in the body. This study provides a promising therapeutic strategy not only for Gaucher disease but also for other LSDs associated with chronic inflammation.
Journal article :
Manoj K. Pandey et al, Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease, Nature (2017). DOI: 10.1038/nature21368
Additional newsfeed :
https://gaucherdiseasenews.com/2017/03/02/
could-lead-to-new-gaucher-therapies/
http://www.alzforum.org/papers/complement-drives-
glucosylceramide-accumulation-and-tissue-inflammation-
https://www.sciencedaily.com/releases/
http://healthmedicinet.com/nature-study-suggests-new-therapy-
Photo source : Stocktrek images
Edited by Isha Verma
About the author
Radhika completed her PhD from Cornell University and is currently a Postdoctoral fellow at the Brigham and Women’s Hospital. Her research interests have centered around oncology and neuroimmunology. Among other things, she is striving to effectively communicate scientific discoveries to the community.
