The challenges of the lysosomal storage disorder
Gaucher disease is the most prevalent lysosomal storage disorder, with an estimated incidence of 1 in 40,000–50,000 in the general population and 1:800 among the Ashkenazi Jewish population. Gaucher disease can lead to liver and spleen enlargement, anemia, painful bone lesions and, in some cases, neurological damage. Gaucher disease results from an accumulation of glucosylceramide in macrophage lysosomes due to deficiencies in the enzymatic activity of lysosomal GCase.
Gaucher disease is further categorized into three clinical subtypes: Type I – Chronic Non-neuronopathic, Type II – Acute Neuronopathic and Type III – Subacute Neuronopathic.
The most frequently occurring subtype, Type I, accounts for 98% of affected Ashkenazi Jews and 56% of affected non-Jews. Symptoms of Type I usually appear in adulthood. These include enlarged spleen and liver, anemia, low platelet counts and fractures and bone pain. Patients do not experience the neurological features associated with Types II and III. The clinical severity of Type I is extremely variable, some patients experiencing the full range of symptoms, while others remain asymptomatic throughout most of their lives.
Type II symptoms typically appear by three months of age with rapid neurodegeneration, extensive visceral involvement and death before two years of age (typically due to respiratory complications). The clinical presentation in Type II is typically more uniform than that of Type I.
Type III symptoms can appear either in infancy or early childhood, with neurological, visceral and bone complications. Although disease severity can vary widely, progression is typically slower than Type II.
A promising treatment for Gaucher disease – under development at ExSAR
EXR-202 is a drug that has already been approved in most countries, although not in the US, for the treatment of disorders other than Gaucher. Recent studies showed that this agent is a pH-dependent, mixed-type inhibitor of GCase24. Its inhibitory activity was maximal at neutral pH (found in the endoplasmic reticulum), and undetectable at the acidic pH (found within the lysosomes). This profile of EXR-202 would allow EXR-202 to bind and stabilize GCase in the endoplasmic reticulum (thus preventing its degradation within endoplasmic reticulum), but without affecting GCase in the lysosomes (thus allowing it to degrade glucosylceramide). Indeed, studies showed that EXR-202 treatment significantly increased N370S and F213I mutant GCase activity and protein levels in fibroblasts originally obtained from Gaucher patients.* The increases in GCase activities were found to be primarily confined to the lysosome-enriched fraction of treated cells, as confirmed by confocal immunofluorescence microscopy. EXR-202 treatment also enhanced GCase activity and reduced glucosylceramide levels in lymphoblasts (N370S/N370S) originally obtained from Gaucher patients.
Additional studies on the effectiveness of EXR-202 were performed on L444P mutation-derived GCase. (L444P mutation is the second most prevalent Gaucher-causing mutation, and it is a severe mutation that, in homozygosity, causes neuropathic Type 3 Gaucher.) These additional studies showed that GCase levels in skin fibroblasts originated from Gaucher patients homozygous for L444P mutation is 12%–21% of normal and at least 50% of it is in the endoplasmic reticulum. The L444P mutant protein undergoes extensive endoplasmic reticulum-associated degradation, including polyubiquitination and proteasome-dependent degradation. EXR-202 enhances the removal of the mutant enzyme from the endoplasmic reticulum (ER) and, in some cases, resulting in a concomitant increase in GCase activity. The results from these additional studies showed that EXR-202 is a potential therapy for Gaucher.
In late 2011, ExSAR filed an IND with the FDA for EXR-202, and is planning Phase I clinical trials
The current therapeutic standard of care involves enzyme replacement therapy with recombinant GCase (Cerezyme, Genzyme Corporation). Enzyme replacement therapy involves regular infusions to compensate for the deficient lysosomal enzyme. A therapeutic alternative involving the use of small molecules is substrate reduction therapy.
We believe that the use of EXR-202 for Gaucher disease patients who respond to the drug may have advantages relative to the use of Cerezyme. From pharmacokinetics studies in rats, EXR-202 is widely distributed in lung, liver, kidney and brain tissues. Specifically after 7.5 mg/kg IV infusion, approximately 70µg/g of EXR-202 were found in lung tissue and 15µg/g in brain tissue. This is a critical observation. Because Cerezyme is a large protein molecule, it is believed to have difficulty penetrating some tissue and cell types. In particular, it is widely believed that Cerezyme is unable to cross the blood- brain barrier and thus unlikely to address the neurological symptoms of Type II and Type III Gaucher disease. Presenting both an inconvenience and risk of infection to Gaucher disease patients, treatment with Cerezyme requires intravenous infusions every other week. Oral treatment with EXR-202 is more convenient for patients and not associated with the safety risks of intravenous infusions.
* Maegawa GHB, Tropak MB, Buttner JD, Rigat BA, Fuller M, et al. Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease. J Biol Chem. 2009;284:23502-23516.