Biomedical Scientist, doctorate in Bioengineering. Determined to contribute to a world in which Healthcare and Innovation are accessible to everyone.
Lysosomal Acid Lipase Deficiency (LAL-D) is a life-threatening disorder caused by an abnormal LAL activity, which results in widespread accumulation of cholesteryl esters and triglycerides.1 It presents a broad spectrum of clinical manifestations, including general dyslipidemia, hepatosplenomegaly and adrenal calcifications, which lead to multi-organ damage and systemic disease (particularly affecting the liver, gastrointestinal and vascular systems).1
Infantile-onset severe and lethal forms of LAL-D are known as Wolman disease (WD) while child-to-adulthood-onset attenuated and progressive forms are denominated as cholesteryl ester storage disease (CESD).2 Due to overlapping of symptoms with other cardiovascular, liver and metabolic disorders, LAL-D is often under diagnosed or misdiagnosed, which leads to inadequate management.1–3 Therefore, an early differential diagnosis is essential to establish an appropriate therapy approach and control disease progression, avoiding secondary comorbidity-associated complications.3
For a considerable time, there were only supportive therapies available for LAL-D.1,4 These were primarily symptomatic and consisted either monotherapies or combinatorial strategies of low-fat diets, statins and other lipid-lowering agents, stem cell transplant and liver transplant.4 In December 2015, the human recombinant LAL enzyme sebelipase alfa (Kanuma©, Alexion Pharmaceuticals, Inc., Cheshire, CT, USA) was approved by US Food and Drug Administration (FDA) as the first therapy that addresses the underlying cause of LAL-D.5 The goal of sebelipase alfa is to replace the defective LAL enzyme, which is referred to as enzyme replacement therapy (ERT).4 Since its development, ERT has been the preferential treatment option for LAL-D.
Low Fat Diet
Dietary manipulation has been used to control the lipid profile of LAL-D patients but with limited success when used alone.4,6 Parenteral nutrition and diets free of hydrophobic esters have been applied in WD infants, but without improvements in their long-term survival.6,7
Statins, Ezetimibe and Cholestyramine
Statins are competitive inhibitors of hydroxymethylglutaryl coenzyme A reductase (HMG-CoA-reductase).1,4 Increased HMG-CoA reductase activity promotes the upregulation of apolipoprotein (apo) B, low- and very-low-density cholesterol (LDL and VLDL), while downregulating the synthesis of high-density cholesterol (HDL), apo A1 and apo A2.8–10 Therefore, statins (such as lovastatin) were found to reduce cholesterol biosynthesis in several patients with LAL-D.4,11–15 However, cholesterol elevations and progression of hepatic damage were still reported in some patients.14,16
Ezetimibe (a cholesterol absorption inhibitor) and cholestyramine (a bile acid sequestrant) have also been used for treatment of LAL-D in combination with lovastatin, further improving the resultant lipid profile.4,17–19
Lipid-lowering drugs were the first-line therapy before ERT became available. However, their efficacy was heterogeneous, they had a poor impact on liver disease and were rarely capable of retuning the lipid profile to normal levels.3,4 This is thought to be due to the existence of other morbidity-associated mechanisms of disease beyond those attributable to disruption of lipid metabolism.4 Thus, the impact of lipid-lowering agents after ERT has been initiated to provide increased benefits to LAL-D therapy.
Stem Cell and Liver Transplantation
Hematopoietic stem cell transplantation (HSCT) and liver transplantation have both been performed in LAL-D patients, mainly in WD infants, but with limited success in halting disease progression and several reports of procedure-related morbidities, particularly for the most severe cases have been reported.4,20–26
There are no reported cases of patients with LAL deficiency subjected to both HSCT and liver transplantation.4 Alone, these approaches have revealed their inadequacy, as they fail to address the multi-system nature of LAL-D; yet the outcome of each procedure following pretreatment or in combination with ERT remains to be investigated.4
Sebelipase Alfa (Kanuma©)
The first human investigational study using sebelipase alfa (LAL-CL01) was described in 2013 by Balwani and colleagues.27 9 CESD patients received 4 once-weekly intravenous infusions (0.35, 1, or 3 mg·kg−1) of sebelipase alfa and, of those, 7 patients enrolled in the extension study (LAL-CL04) in which they received another 4 once-weekly intravenous infusions (0.35, 1, or 3 mg·kg−1). Long-term dosing was then performed weekly (1 or 3 mg·kg−1). Data revealed that sebelipase alfa treatment was well tolerated and did not generate anti-drug antibodies. Moreover, administration of sebelipase alfa rapidly decreased serum transaminases in both studies and improved the serum lipid profile (decreased triglycerides, total and LDL cholesterols, as well as increased HDL cholesterol) sustained by longterm dosing.
A pediatric study (LAL-CL03) was conducted in 9 WD patients treated with sebelipase alfa.28 56% infants survived to 24 months of age with sebelipase alfa therapy, well beyond the historical life expectancy for WD. Patients exhibited significant improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, as well as improvements in anemia and gastrointestinal symptoms. One patient presented serious adverse effects related to treatment, including tachycardia, pallor, chills, and pyrexia.
Get detailed prescribing information on the Kanuma monograh page on MPR.
Kanuma was approved by US FDA to treat LAL-D patients of all ages.5 Indications for dosage and administration are 1 mg·kg−1 once a week for infants presenting with rapidly progressive LAL-D within the first six months of life, and once every other week for children and adults.5 Kanuma needs to be given indefinitely and, in case of LAL-D infantile severe patients who do not achieve an optimal clinical response, dosage should be increased to 3 mg·kg−1.
Common side effects of Kanuma in infants (≥30%) include diarrhea, vomiting, fever, rhinitis, cough, anemia and urticaria.5 In children and adults (≥8%), these include headache, fever, asthenia, oropharyngeal pain, constipation and nausea.
The outcome of ERT clinical trials in LAL-D patients indicate that sebelipase alfa has a favorable impact on disease course and therapy is beneficial for a significant proportion of patients. Given the limited success and procedure-related morbidity risks of other therapies, sebelipase alfa treatment will likely become the standard of care for LAL-D, at least in jurisdictions where available.
1. Reiner Ž, Guardamagna O, Nair D, et al. Lysosomal acid lipase deficiency – an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis. 2014;235(1):21-30. doi:https://doi.org/10.1016/j.atherosclerosis.2014.04.003
2. Pericleous M, Kelly C, Wang T, Livingstone C, Ala A. Wolman’s disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency. Lancet Gastroenterol Hepatol. 2017;2(9):670-679. doi:10.1016/S2468-1253(17)30052-3
3. Strebinger G, Müller E, Feldman A, Aigner E. Lysosomal acid lipase deficiency – early diagnosis is the key. Hepat Med. 2019;11:79-88. doi:10.2147/HMER.S201630
4. Pastores GM, Hughes DA. Lysosomal acid lipase deficiency: therapeutic options. Drug Des Devel Ther. 2020;14:591-601. doi:10.2147/DDDT.S149264
5. Kanuma (Sebelipase alfa). accessdata.fda.gov. Accessed on June 15, 2021.
6. Hoffman EP, Barr ML, Giovanni MA, Murray MF. Lysosomal Acid Lipase Deficiency. 2015 Jul 30 [updated 2016 Sep 1]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2021.
7. Kohli R, Ratziu V, Fiel MI, Waldmann E, Wilson DP, Balwani M. Initial assessment and ongoing monitoring of lysosomal acid lipase deficiency in children and adults: consensus recommendations from an international collaborative working group. Mol Genet Metab. 2020;129(2):59-66. doi:10.1016/j.ymgme.2019.11.004
8. Brown MS, Dana SE, Goldstein JL. Receptor-dependent hydrolysis of cholesteryl esters contained in plasma low density lipoprotein. Proc Natl Acad Sci U S A. 1975;72(8):2925-2929. doi:10.1073/pnas.72.8.2925
9. Goldstein JL, Dana SE, Faust JR, Beaudet AL, Brown MS. Role of lysosomal acid lipase in the metabolism of plasma low density lipoprotein. Observations in cultured fibroblasts from a patient with cholesteryl ester storage disease. J Biol Chem. 1975;250(21):8487-8495.
10. Kostner GM, Hadorn B, Roscher A, Zechner R. Plasma lipids and lipoproteins of a patient with cholesteryl ester storage disease. J Inherit Metab Dis. 1985;8(1):9-12. doi:10.1007/BF01805475
11. Ginsberg HN, Le NA, Short MP, Ramakrishnan R, Desnick RJ. Suppression of apolipoprotein B production during treatment of cholesteryl ester storage disease with lovastatin. Implications for regulation of apolipoprotein B synthesis. J Clin Invest. 1987;80(6):1692-1697. doi:10.1172/JCI113259
12. Rassoul F, Richter V, Lohse P, Naumann A, Purschwitz K, Keller E. Long-term administration of the HMG-CoA reductase inhibitor lovastatin in two patients with cholesteryl ester storage disease. Int J Clin Pharmacol Ther. 2001;39(5):199-204. doi:10.5414/cpp39199
13. Gasche C, Aslanidis C, Kain R, et al. A novel variant of lysosomal acid lipase in cholesteryl ester storage disease associated with mild phenotype and improvement on lovastatin. J Hepatol. 1997;27(4):744-750. doi:10.1016/s0168-8278(97)80092-x
14. Levy R, Ostlund REJ, Schonfeld G, Wong P, Semenkovich CF. Cholesteryl ester storage disease: complex molecular effects of chronic lovastatin therapy. J Lipid Res. 1992;33(7):1005-1015.
15. Tarantino MD, McNamara DJ, Granstrom P, Ellefson RD, Unger EC, Udall JNJ. Lovastatin therapy for cholesterol ester storage disease in two sisters. J Pediatr. 1991;118(1):131-135. doi:10.1016/s0022-3476(05)81866-9
16. Bernstein DL, Hülkova H, Bialer MG, Desnick RJ. Cholesteryl ester storage disease: Review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013;58(6):1230-1243. doi:https://doi.org/10.1016/j.jhep.2013.02.014
17. Abello F, Guardamagna O, Baracco V, Bonardi R. P55 the treatment of cholesteryl storage disease (cesd) by ezetimibe monotherapy. Atheroscler Suppl. 2010;11(2):28. doi:https://doi.org/10.1016/S1567-5688(10)70122-7
18. McCoy E, Yokoyama S. Treatment of cholesteryl ester storage disease with combined cholestyramine and lovastatin. Ann N Y Acad Sci. 1991;623:453-454. doi:10.1111/j.1749-6632.1991.tb43768.x
19. Tadiboyina VT, Liu DM, Miskie BA, Wang J, Hegele RA. Treatment of dyslipidemia with lovastatin and ezetimibe in an adolescent with cholesterol ester storage disease. Lipids Health Dis. 2005;4(1):26. doi:10.1186/1476-511X-4-26
20. Stein J, Garty BZ, Dror Y, Fenig E, Zeigler M, Yaniv I. Successful treatment of wolman disease by unrelated umbilical cord blood transplantation. Eur J Pediatr. 2007;166(7):663-666. doi:10.1007/s00431-006-0298-6
21. Tolar J, Petryk A, Khan K, et al. Long-term metabolic, endocrine, and neuropsychological outcome of hematopoietic cell transplantation for Wolman disease. Bone Marrow Transplant. 2009;43(1):21-27. doi:10.1038/bmt.2008.273
22. Gramatges MM, Dvorak CC, Regula DP, Enns GM, Weinberg K, Agarwal R. Pathological evidence of Wolman’s disease following hematopoietic stem cell transplantation despite correction of lysosomal acid lipase activity. Bone Marrow Transplant. 2009;44(7):449-450. doi:10.1038/bmt.2009.57
23. Yanir A, Allatif MA, Weintraub M, Stepensky P. Unfavorable outcome of hematopoietic stem cell transplantation in two siblings with Wolman disease due to graft failure and hepatic complications. Mol Genet Metab. 2013;109(2):224-226. doi:https://doi.org/10.1016/j.ymgme.2013.03.007
24. Krivit W, Peters C, Dusenbery K, et al. Wolman disease successfully treated by bone marrow transplantation. Bone Marrow Transplant. 2000;26(5):567-570. doi:10.1038/sj.bmt.1702557
25. Bernstein DL, Lobritto S, Iuga A, et al. Lysosomal acid lipase deficiency allograft recurrence and liver failure – clinical outcomes of 18 liver transplantation patients. Mol Genet Metab. 2018;124(1):11-19. doi:https://doi.org/10.1016/j.ymgme.2018.03.010
26. Ferry GD, Whisennand HH, Finegold MJ, Alpert E, Glombicki A. Liver transplantation for cholesteryl ester storage disease. J Pediatr Gastroenterol Nutr. 1991;12(3):376-378. doi:10.1097/00005176-199104000-00016
27. Balwani M, Breen C, Enns GM, et al. Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients with cholesteryl ester storage disease. Hepatology. 2013;58(3):950-957. doi:10.1002/hep.26289
28. Jones SA, Rojas-Caro S, Quinn AG, et al. Survival in infants treated with sebelipase alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study. Orphanet J Rare Dis. 2017;12(1):25. doi:10.1186/s13023-017-0587-3
Reviewed by Harshi Dhingra, MD, on 7/1/2021.