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 genetic metabolic disorder affecting multiple organ systems.1,2 It is characterized by a persistent intralysosomal accumulation of cholesteryl esters and triglycerides resulting from a residual enzymatic activity of LAL, which is caused by abnormal mutations in the LIPA gene.2,3 The amount of residual LAL function typically determines the severity of the disease and inherent symptoms. Common clinical manifestations include organomegaly, liver disease and/or failure, diarrhea, abdominal and epigastric pain, vomiting, anemia, malabsorption, cholestasis, steatorrhea, poor growth, gallbladder dysfunction, cardiovascular disease, adrenal calcifications, and esophageal varices.2
In its aggressive infantile-onset form known as Wolman disease (WD), LAL-D inevitably leads to premature death in the first months of life due to profound failure to thrive.2,3 In turn, progressive later-onset forms, collectively known as cholesteryl ester storage disease (CESD), have a very heterogeneous spectrum of clinical manifestations that may arise throughout different ages.2,3 Death of CESD patients mainly results from atherosclerosis- and liver disease-associated complications.
There is currently no cure for LAL-D and therapeutic options focus on managing symptoms and increasing patients’ quality of life.4 In the case of CESD patients, early treatment may prove fundamental to halt disease progression and delay cardiovascular problems. Similar to other lysosomal storage disorders, evidence suggests that an early diagnosis is critical for establishing a proper patient management and treatment approach, as the burden of disease when therapy is initiated can limit the clinical response.4,5
There are a few experimental therapies undergoing clinical trials for LAL-D patients. The most promising one is Sebelipase alfa (Kanuma©, Alexion Pharmaceuticals, Inc., Cheshire, CT, USA).6 Others consist of stem cell transplantation or diet manipulation.
Enzyme Replacement Therapy – Sebelipase Alfa (Kanuma©)
Enzyme Replacement Therapy (ERT) has come to replace previous supporting therapies for LAL-D. The aim of ERT is to re-establish the enzymatic activity of LAL and this strategy has generated significant improvements in disease prognosis.4 Sebelipase alfa is a recombinant human LAL enzyme that was first reported by Balwani and colleagues.7 Patients enrolled in this first experimental study (LAL-CL01 and follow-up LAL-CL04) exhibited good toleration to sebelipase alfa, as well as decreased serum transaminases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and improved serum lipid profile sustained by long-term dosing. In the pediatric experimental study LAL-CL03, sebelipase alfa increased the lifespan to over 24 months of age in 5 out of 9 WD infants.8 Patients had reduced markers of liver disease, less gastrointestinal and anemia symptoms, as well as improved growth.
In 2015, Kanuma was approved by US FDA to treat LAL-D patients of all ages.6 Kanuma needs to be given indefinitely and administration doses may vary between 1 mg·kg−1 and 3 mg·kg−1, with the latter dosage in case of infantile severe patients who do not achieve an optimal clinical response with the former dose.6
Kanuma has been shown to be relatively safe and efficacious across both WD and CESD patients.4 However, ongoing long-term studies will clarify the scope of clinical benefit. In this regard, it is important to determine whether the changes in the natural course of the disease upon treatment with sebelipase alfa are full or can in some cases lead to other previously unrecognized emergent phenotypes. It also remains to be investigated if ERT can benefit the impact of other therapies, namely lipid-lowering drugs, such as statins.
There is currently one ongoing phase I clinical trial (NCT04532047) testing in utero ERT for prenatally diagnosed lysosomal storage disorders, in which WD is included.9 This may be particularly relevant when there is evidence of an expected poor outcome based on genetic testing or a prior family history of aggressive disease.
Stem Cell Transplantation
Hematopoietic stem cell transplantation (HSCT) has been performed in LAL-D patients, mainly in WD infants, but with limited success.4,10–12 HSCT has failed to halt disease progression and has been associated with several procedure-related morbidities. In sum, HSCT fails to address the multi-system nature of LAL-D. However, the outcome of HSCT following pretreatment with ERT remains to be elucidated.
Currently, there is an ongoing phase I clinical trial (NCT01586455) investigating the safety of the transplantation of human placental-derived stem cells (HPDSC) given in conjunction with umbilical cord blood stem cells in patients with several disorders, including WD.13
Diet manipulation has also been tested in order to control the lipid profile of LAL-D patients.1,4 When used alone, its success has been very limited. In WD infants, dietary manipulation has not been able to improve their long-term survival.14,15 For CESD patients, dietary precautions are still advised for disease management.1,16
An experimental trial (NCT03564002) is ongoing to investigate the metabolic effects of a very low carbohydrate ketogenic diet in subjects with severe obesity, including those with LAL-D.17 This study is estimated to be completed by the end of December 2022.
Though data from long-term studies is still lacking, ERT seems to be a promising strategy and will likely become the standard of care in jurisdictions where available. It will be important to carefully evaluate each case for the possible development of neutralizing antibodies, immunologic reactions, including infusion and hypersensitivity reactions against the enzyme, in which scenario desensitization measures can be introduced as a mitigating method.18
The impact of sebelipase alfa pretreatment on the effects of other therapies (in a combinatorial or multi-modality approach) should be evaluated in order to search for better or more optimal outcomes.4
1. 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.
2. 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:10.1016/j.atherosclerosis.2014.04.003
3. 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
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. 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
6. Kanuma (Sebelipase alfa). accessdata.fda.gov. Accessed on June 15, 2021.
7. 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
8. 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
9. NCT04532047. clinicaltrials.gov. Accessed on July 9, 2021.
10. 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
11. 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
12. 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
13. NCT01586455. clinicaltrials.gov. Accessed on July 9, 2021.
14. Meyers WF, Hoeg JM, Demosky SJ, Herbst JJ, Brewer HB. The use of parenteral hyperalimentation and elemental formula feeding in the treatment of wolman disease. Nutr Res. 1985;5(4):423-429. doi:https://doi.org/10.1016/S0271-5317(85)80226-8
15. Wolman M. Proposed treatment for infants with wolman disease. Pediatrics. 1989;83(6):1074-1075.
16. 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
17. NCT03564002. clinicaltrials.gov. Accessed on July 9, 2021.
18. Huffaker MF, Liu AY, Enns GM, Vijay S, Amor AJ, Adkinson Jr NF. Case series of sebelipase alfa hypersensitivity reactions and successful sebelipase alfa rapid desensitization. JIMD Rep. 2019;49(1):30-36. doi:10.1002/jmd2.12066
Reviewed by Debjyoti Talukdar, MD, 7/1/2021.