Novel treatment options for lysosomal acid lipase deficiency: critical appraisal of sebelipase alfa

Abstract

Lysosomal acid lipase deficiency (LAL-D) is a rare disorder of cholesterol metabolism with an autosomal recessive mode of inheritance. The absence or deficiency of the LAL enzyme gives rise to pathological accumulation of cholesterol esters in various tissues. A severe LAL-D phenotype manifesting in infancy is associated with adrenal calcification and liver and gastrointestinal involvement with characteristic early mortality. LAL-D presenting in childhood and adulthood is associated with hepatomegaly, liver fibrosis, cirrhosis, and premature atherosclerosis. There are currently no curative pharmacological treatments for this life-threatening condition. Supportive management with lipid-modifying agents does not ameliorate disease progression. Hematopoietic stem cell transplantation as a curative measure in infantile disease has mixed success and is associated with inherent risks and complications. Sebelipase alfa (Kanuma) is a recombinant human LAL protein and the first enzyme replacement therapy for the treatment of LAL-D. Clinical trials have been undertaken in infants with rapidly progressive LAL-D and in children and adults with later-onset LAL-D. Initial data have shown significant survival benefits in the infant group and improvements in biochemical parameters in the latter. Sebelipase alfa has received marketing authorization in the United States and Europe as long-term therapy for all affected individuals. The availability of enzyme replacement therapy for this rare and progressive disorder warrants greater recognition and awareness by physicians.

Prenatal sonographic findings in a case of Wolman's disease

“…Investigational therapies have included liver transplantation and hematopoietic stem cell transplantation, which have prolonged survival in some cases . Sebelipase alfa, a recombinant form of LIPA, is now offered as enzyme replacement therapy . Although this is associated with a significant prolongation of survival, as well as a reduction in symptoms and improvements in laboratory parameters, it is not considered curative …”

“…9 Sebelipase alfa, a recombinant form of LIPA, is now offered as enzyme replacement therapy. 10 Although this is associated with a significant prolongation of survival, as well as a reduction in symptoms and improvements in laboratory parameters, it is not considered curative. 11 US findings in infants diagnosed with WD have been well described, consisting of hepatomegaly, splenomegaly, and enlarged, calcified adrenal glands.…”

Persistent dyslipidemia in treatment of lysosomal acid lipase deficiency

“…Though anti-drug antibodies are more commonly reported in neonatal-onset disease associated with complete enzyme deficiency, as the ERT is then a foreign enzyme to the body, antibody production has been reported in individuals with residual enzyme activity. Experiences with antibodies reported to date in LALD patients have been relatively innocuous, suggesting that these antibodies are often transient and do not interfere with the safety or efficacy of the enzyme replacement [6,7,10,15]. There is, however, a single report of a child who experienced significant blunting of response to therapy with emergence of a high antibody titer [10].…”

Histopathological Findings in Cholesteryl Ester Storage Disease: A Report of Three Cases

“…Glutaryl (HMG) CoA reductase inhibitors to bone marrow and liver transplantation. Enzyme replacement therapy is an innovated strategy, which has shown successful outcomes in vitro (10). The epidemiology and manifestations of this disease is still unknown due to the lack of sufficient reports.…”