Substrate reduction therapy (SRT) may help manage Gaucher disease symptoms that do not respond to first-line enzyme replacement therapies (ERT), according to a case report featured in the journal Molecular Genetics and Metabolism Report.
The current main treatment options for Gaucher disease are ERT and SRT. ERT is based on intravenous administration of engineered glucocerebrosidase – the enzyme that is lacking in Gaucher disease – whereas SRT reduces the disease-causing accumulation of the substrate glucocerebroside due to the missing glucocerebrosidase enzyme.
Because miglustat, an approved oral SRT, has been associated with severe side effects, it is only indicated in cases in which patients show signs of ERT intolerance. Cerdelga (eliglustat), another oral SRT approved years later, has fewer side effects and is now considered an alternative first-line treatment to ERT in adults with Gaucher disease.
Previous studies have demonstrated that the use of these therapeutic strategies can reduce and control several symptoms of Gaucher disease, including pancytopenia (reduced levels of white and red blood cells, along with platelets), hepatosplenomegaly (swollen liver and spleen), and bone and bone marrow abnormalities.
However, little is known about the effectiveness of these therapies in treating specific symptoms, or even the potential therapeutic effects of combining ERT and SRT.
In an article titled “Treatment of profound thrombocytopenia in a patient with Gaucher disease type 1: Is there a role for substrate reduction therapy,” researchers at the Duke University Medical Center reported a case of an adult with Gaucher disease type 1 whom they treated with ERT and SRT to improve persistent and severe low levels of blood platelets (thrombocytopenia) and a swollen spleen (splenomegaly).
Thrombocytopenia is one of the many symptoms of Gaucher disease, which is commonly associated with a swollen spleen and reduced response to ERT. In these cases, the main therapeutic goal is to elevate the levels of platelets (cells essential to stop bleedings) and reduce the size of the spleen.
In this patient, the clinical team initiated therapy with first-line ERT treatment: twice-weekly Cerezyme (imiglucerase). The patient’s spleen improved, but the strategy failed to increase the levels of platelets, even after six years of persistent ERT therapy.
The healthcare team decided to add twice-daily orally administered SRT using Cerdelga to the therapy plan. Within one month of the combined therapy, platelet levels increased with no changes in spleen size reported.
Because the previous ERT monotherapy was inefficient at controlling the thrombocytopenia, and due to the increased financial burden of the combination therapy, after two months the patient continued therapy only with oral Cerdelga. Changing to SRT improved the patient’s Gaucher disease symptoms with no significant side effects and good overall health.
Moreover, “In our patient there was an improvement in platelet counts along with improved quality of life due to the added benefit of an oral treatment, which better met the needs of this patient given her demanding career and busy lifestyle,” the researchers wrote.
“While this report may not allow for conclusions regarding optimal treatment of thrombocytopenia in GD, it highlights the possibility of differing responses to ERT or SRT treatment in individual patients,” they concluded.