Lessons learned from the long-term use of enzyme replacement therapy in the treatment of lysosomal acid lipase deficiency

Lysosomal acid lipase deficiency (LALD, OMIM #278000) is an inborn error of lipid metabolism caused by biallelic pathogenic variants in LIPA, which encodes the enzyme lysosomal acid lipase (LAL). LAL deficiency impairs the intra-lysosomal hydrolysis of cholesteryl esters and triglycerides, resulting in their intracellular accumulation. LAL deficiency also impairs liberation of free fatty acids and free cholesterol leading to perceived cholesterol paucity and inappropriate activation of de novo cholesterol biosynthesis and inhibition of cholesterol efflux (Figure 1) (1).

Figure 1:

Low-density lipoprotein cholesterol (LDL) is taken up by the low-density lipoprotein receptor (LDLR) (1) and brought to the lysosome where its cholesteryl esters and triglycerides are hydrolyzed by lysosomal acid lipase (LAL) to generate free cholesterol (FC) and free fatty acids (FFA) (2). FC is effluxed from the lysosome by the Niemann-Pick C1 (NPC1/2) cholesterol transporter (3). FC inhibits sterol regulatory-element binding protein (SREBP) to inhibit cholesterol biosynthesis (4). FC also induces liver X receptor (LXR) expression to induce production of ATP Binding Cassette Subfamily A Member 1 (ABCA1) (5). FC can also be effluxed through ABCA1 to generate high-density lipoprotein cholesterol (HDL) (6). Sebelipase alfa (SA) is taken up by the mannose-6-phosphate receptor (M6PR) and is brought to the lysosome to facilitate cholesteryl ester and triglyceride hydrolysis (7).

Abbreviations: Apolipoprotein A1 (A1); ATP Binding Cassette Subfamily A Member 1 (ABCA1); Apolipoprotein B (B); Free cholesterol (FC); Free fatty acids (FFA); High-density lipoprotein cholesterol (HDL); Lysosomal acid lipase (LAL); Low-density lipoprotein cholesterol (LDL); Low-density lipoprotein receptor (LDLR); Liver X receptor (LXR); Mannose-6-phosphate receptor (M6PR); Niemann–Pick C1 cholesterol transporter (NPC1/2); Sebelipase alfa (SA); Sterol regulatory-element binding protein (SREBP)

Disease severity is dictated by residual enzyme activity and ranges from infantile Wolman Disease (WD) to cholesteryl ester storage disease (CESD). WD is characterized by failure to thrive, malabsorption, hepatosplenomegaly, cholestasis, elevated aminotransferases, hepatic fibrosis, and adrenal insufficiency and was historically fatal without bone marrow transplantation. CESD is characterized by childhood to adult-onset hepatomegaly, elevated aminotransferases, liver dysfunction, cirrhosis, dyslipidemia, premature atherosclerotic cardiovascular disease, and hepatocellular carcinoma (2,3).

In 2015 the Food and Drug Administration approved the enzyme replacement therapy (ERT) sebelipase alfa for the treatment of LALD. Early studies showed improved survival for infants with WD and improved dyslipidemia, aminotransferases, and liver volumes in individuals with CESD receiving recombinant enzyme (4–6). Long-term efficacy studies and the effect of ERT in individuals who failed liver or bone marrow transplant have not been done.

Burton et al. report a single-arm, open-label study of ERT safety and efficacy in 31 LALD patients (22 children and 9 adults) across 19 international sites (7). Starting ERT dose was 1 mg/kg every other week, with the option to decrease to 0.35 mg/kg every other week for poor tolerability or increase up to 3 mg/kg weekly for poor response. Fifty-two percent of patients were concurrently taking lipid-lowering medications. In contrast to past studies, this study included individuals who had residual disease after bone marrow or liver transplant. Participants were followed for up to 144 weeks, and growth (children), dyslipidemia, aminotransferase levels, liver and spleen volumes, and liver pathology were assessed throughout the study. One patient had an anaphylactic reaction to ERT and 2 patients developed non-neutralizing antibodies. ERT was overall associated with improvement in all parameters, albeit with significant inter-patient variability.

Liver biopsies were performed at baseline, and weeks 48 and 96. Ishak stage was unchanged or increased relative to baseline in 18/27 patients (67%) and 13/16 patients (81%) at weeks 48 at 96, respectively. Macrovesicular steatosis was unchanged or increased relative to baseline in 24/27 patients (89%) and 16/16 patients (100%) at 48 and 96 weeks, respectively. Microvesicular steatosis was unchanged or increased relative to baseline in 12/27 patients (44%) and 9/16 patients (56%) at 48 and 96 weeks, respectively. Lobular and portal inflammation were similarly affected by ERT, with stable or increased inflammation relative to baseline.

Though early studies unequivocally demonstrate improved survival with ERT for infantile WD (6) and overall improved aminotransferase levels, dyslipidemia, and liver and spleen volumes with ERT in CESD (4,5) few long-term studies have been performed, progression of liver pathology has not been systemically evaluated, and inter-patient variability is common and unexplained (8). Response may be influenced by age and severity of disease at diagnosis. Differences in mannose-6-phosphate receptor kinetics, which are required for cellular uptake of recombinant enzyme, may also contribute to ERT response. The degree of intra-lysosomal cholesterol load likely also plays a role – a high fat, high cholesterol diet would lead to increased lysosomal cholesterol accumulation. Genetic polymorphisms that affect LDL receptor kinetics, Niemann Pick C transporter efflux activity, SREBP and LXR pathway activity, and ABCA1 efflux kinetics could also modulate ERT response (Figure 1). Variability in hepatic inflammatory pathway activation likely also modulates disease. Indeed, there is a strong genetic component to the progression of nonalcoholic steatosis to hepatitis and cirrhosis (9,10). These pathways are undoubtedly relevant in LALD. A combination of these factors likely contributed to the failure of liver and bone marrow transplantation to cure disease in some patients. Specific to progression of liver pathology, a systematic evaluation of serial liver biopsies with and without enzyme replacement has not been performed. It is therefore difficult to determine whether all patients had improvement in liver pathology relative to the natural history. Indeed, intermittent and rapidly liberation of free cholesterol and free fatty acids within the liver parenchyma with enzyme replacement would be predicted to induce an inflammatory response and severe dysregulation of cholesterol homeostasis.

Burton et al demonstrate that in contrast to infantile disease, ERT is not universally beneficial in individuals with attenuated disease: though many individuals show improvement, many have persistent hepatitis, dyslipidemia, and histological evidence of disease progression despite ERT. Importantly, it is impossible to predict response to ERT and there is little data on the long-term effect of ERT on overall morbidity and mortality, meaning that it is still critically important to promptly diagnosed LALD. Additionally, low-fat diet and lipid-lowering medications such as HMG-CoA reductase inhibitors, fibrates, bile acid sequestrants, and ezetimibe have demonstrated efficacy in reducing dyslipidemia and aminotransferase levels in adult patients and can be used alone or in conjunction with ERT (11). We propose that enzymology for LALD be performed in any infant presenting with hepatomegaly, failure to thrive, diarrhea or adrenal insufficiency. Critically, dyslipidemia is not universally present early in infantile disease, so a lipid panel is not an appropriate screening tool. In the adult population, LALD should be on the differential of hepatomegaly, steatosis, and dyslipidemia. Follow up genetic testing should be performed for confirmation. More widespread diagnosis will improve morbidity and mortality and clarify the full spectrum of disease and response to therapy.

Importantly, many questions regarding the efficacy of ERT in LALD remain, including the long-term clinical course for infants saved by ERT, the long-term benefit in individuals with mild disease, the ability of ERT to reduce the risk of hepatocellular carcinoma, the etiology of poor ERT response, and the benefit of ERT to survival relative to the effect on quality of life. As LALD is more frequently diagnosed and ERT more widely used these questions will undoubtedly be answered. The work by Burton et al contributes to our understanding of the long-term use of ERT in a diverse LALD population. Indeed, knowing when a treatment is not beneficial is of critical importance for appropriate anticipatory guidance for patients and appropriate risk analysis.