Physicians who are used to treating rare diseases often find themselves at a crossroads between the routine administration of established medications based on existing limitations, and the exciting prospect of new and effective medications backed by the latest research.
The great difficulty with rare diseases, as we all know, is the lack of funding needed to really help scientists reach breakthrough points. Therefore, it is always a good idea to take stock of the therapeutic options currently available at a physician’s disposal, ranging from the tried and tested, to those more promising and innovative that may yield better patient outcomes or could be just a flash in the pan.
The hard slog of reading, treating patients, and documenting results is the backbone of research, and although we as physicians would like a solid cure for every disease we treat, the reality is that we are often left with a few treatment options, none of which produce results that are entirely satisfactory. This is certainly the case in lysosomal acid lipase deficiency (LAL-D).
A team of researchers sought to explore the currently available therapeutic options for LAL-D in a paper published in Drug Design, Development, and Therapy. The researchers evaluated the efficacy of more established therapies as well as those that are more novel in nature.
Read more about LAL-D etiology
LAL-D is a metabolic disorder inherited via autosomal recessive genes. It is caused by defects in the LIPA gene, which results in the intralysosomal degradation of cholesterol esters and triglycerides, together with the accumulation of relevant substrates. This disease primarily affects the liver, as well as the vascular and the reticuloendothelial systems.
Here are the cardinal symptoms of this disease:
- Hepatomegaly with liver dysfunction and an abnormal lipid profile (elevated low-density lipoproteins (LDL) with decreased high-density lipoproteins (HDL).
- Dyslipidemia caused by an inability to release free cholesterol from lysosomes.
- Micro- or macro-vesicular steatosis involving Kupffer cells and hepatocytes demonstrated by liver biopsy and seen together with fibrosis and cirrhosis as the pathology progresses.
Read more about LAL-D prognosis
Until recently, treatment for LAL-D was primarily about reducing symptoms, which commonly involves dietary manipulation and the use of lipid-lowering drugs. In advanced disease, surgical measures are typically introduced, such as splenectomy, ligation of esophageal varices, and liver transplantation. Hematopoietic stem cells have also been known to slow disease progression.
Let’s take a look at a few of the therapeutic options we have on hand and discuss their merits:
Hematopoietic Stem Cell/Bone Marrow Transplantation
This was often the treatment physicians had to resort to, especially before enzyme replacement therapy (ERT) was discovered. A number of small studies show that this last-resort treatment method generally results in poor outcomes, with some patients developing sepsis and liver failure within days postoperatively.
As with hematopoietic stem cell transplant (HSCT), liver transplantation is a course of action commonly taken prior to the availability of disease-specific enzyme therapy. However, currently available research does not show it to be as effective as once thought. For example, a report by Bernstein et al shows that in 18 patients needing liver transplantation, post-surgical disease progression was seen in 11 of them (61%) and 6 died (33%). These observations “demonstrate both the inadequacy of liver transplantation alone as a therapeutic approach” due to its high “procedure-related morbidity,” the study says.
Enzyme Replacement Therapy
ERT is touted as a promising new therapeutic option due to its success in targeting disruption of the LAL locus in mice experiments. The treated experimental mice had reduced macrophage lipid accumulation, as well as significant triglyceride and cholesterol level reduction.
Based on these promising results, researchers then conducted clinical trials on humans involving recombinant human LAL (sebelipase alfa). The majority of the patients enrolled in this sebelipase alfa trial were children.
The patients were given an escalating dose of sebelipase alfa over a period of 12 weeks. At week 12, their aminotransaminase (ALT) and aspartate aminotransferase (AST) levels dropped significantly. For ALT, it was −46 ± 21 U/L (−52%); for AST, it was −21 ± 14 U/L (−36%), respectively (P <.05).
At week 52, mean ALT and AST levels for the group were within normal limits, representing a mean change from baseline of −58% and −40%, respectively. The mean changes for LDL cholesterol, total cholesterol, triglycerides, and HDL cholesterol were −60%, −39%, −36%, and +29%, respectively, which translated to a decrease in disease burden.
These results demonstrate that ERT with sebelipase alfa can be useful in bringing abnormal liver values back to normal, which translates to better patient outcomes. The results of this study are good news indeed to those of us who have been looking for nontraditional approaches to treating LAL-D.
Adjuvant Therapies/Lipid-Lowering Drugs
There are several classes of lipid-lowering medication, and the first line for patients with hypercholesterolemia is statins. There are huge benefits to lipid-lowering drugs, among them the “regression of atherosclerosis, plaque stabilization, reversal of endothelial dysfunction, inhibition of inflammatory pathways, and decreased thrombogenicity,” the authors of the present study wrote.
Recently, the drug ezetimibe (another cholesterol-lowering drug) has been used in patients with LAL deficiency. The aim of prescribing this drug is to “promote an increase in the circulatory clearance of cholesterol and a reduction of hepatic cholesterol deposits,” the study states.
Three patients with cholesteryl ester storage disease (CESD), which is a type of LAL-D, who were treated with ezetimibe for 9 to 10 years (with 2 of the 3 patients supplemented with low-dose atorvastatin during the last 6 years of observation) showed significant improvements in their lipid profile, including a reduction in ALT, cholesterol, and triglycerides. In addition, there was no demonstrable progression of liver fibrosis. This suggests that ezetimibe is ripe to be used more widely to treat LAD once more research becomes available.
Looking to the Future
Based on the different therapies highlighted in this article, “the outcome of enzyme replacement therapy with sebelipase alfa points to a more beneficial prognosis among treated cases,” researchers wrote. Ultimately, long-term studies will help us understand better their impact on disease progression and prognosis.
As we have gone through each of the therapeutic options currently available for LAL-D in this article, we are reminded yet again that it is still well-crafted and well-funded research that holds the key in helping us make meaningful advancements in combating rare diseases. As long as we keep an open mind, innovative therapies like ERT might soon gather enough data to become a routine method of caring for LAL-D patients, with better patient outcomes.
Pastores GM, Hughes DA. Lysosomal acid lipase deficiency: therapeutic options. Drug Des Devel Ther. 2020;14:591-601. doi:10.2147/DDDT.S149264
Valayannopoulos V, Malinova V, Honzík T, et al. Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency. J Hepatol. 2014;61(5):1135-1142. doi:10.1016/j.jhep.2014.06.022