Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease

Abstract

Background: Wolman disease is a rare, lysosomal storage disorder in which biallelic variants in the LIPA gene result in reduced or complete lack of lysosomal acid lipase. The accumulation of the substrates; cholesterol esters and triglycerides, significantly impacts cellular function. Untreated patients die within the first 12 months of life. Clinically, patients present severely malnourished, with diarrhoea and hepatosplenomegaly, many have an inflammatory phenotype, including with hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplant (HCT) had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities. More recently, enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) has significantly improved patient survival. However, ERT is life long, expensive and its utility is limited by anti-drug antibodies (ADA) and the need for central venous access.

Results: We describe five Wolman disease patients diagnosed in infancy that were treated at Royal Manchester Children's Hospital receiving ERT with DSR then HCT-multimodal therapy. In 3/5 an initial response to ERT was attenuated by ADA with associated clinical and laboratory features of deterioration. 1/5 developed anaphylaxis to ERT and the other patient died post HCT with ongoing HLH. All patients received allogeneic HCT. 4/5 patients are alive, and both disease phenotype and laboratory parameters are improved compared to when they were on ERT alone. The gastrointestinal symptoms are particularly improved after HCT, with reduced diarrhoea and vomiting. This allows gradual structured normalisation of diet with improved tolerance of dietary fat. Histologically there are reduced cholesterol clefts, fewer foamy macrophages and an improved villous structure. Disease biomarkers also show improvement with ERT, immunotherapy and HCT. Three patients have mixed chimerism after HCT, indicating a likely engraftment-defect in this condition.

Conclusion: We describe combined ERT, DSR and HCT, multimodal treatment for Wolman disease. ERT and DSR stabilises the sick infant and reduces the formerly described prohibitively high, transplant-associated mortality in this condition. HCT abrogates the problems of ERT, namely attenuating ADA, the need for continuing venous access, and continuing high cost drug treatment. HCT also brings improved efficacy, particularly evident in improved gastrointestinal function and histology. Multimodal therapy should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched transplant donor, in order to improve long term gut function, tolerance of a normal diet and quality of life.

Keywords: Dietary substrate reduction (DSR); Enzyme replacement therapy (ERT); Gene therapy; Hematopoietic stem cell transplant (HCT); Hemophagocytic lymphohistiocytosis (HLH); Lysosomal acid lipase (LAL); Lysosomal storage disorders (LSD); Wolman disease.

Fig. 1

Patient 2 duodenal biopsies post HCT showing improvement overtime. a Was taken in 2017, b was taken in 2019. b shows reduced numbers of foamy macrophages in the lamina propria (arrowheads) and repopulation by lymphoplasmacytic cells (both haematoxylin and eosin stained FFPE sections,400 original magnification). c Is duodenal tissue from Patient 2 examined using X/Y chromosome FISH. The X probe is red and the Y probe is green. The patient was female (XX) and the HCT donor was male (XY). The native duodenal glands (G) show the presence of only red X probes but donor cells in the lamina propria show both red X and green Y probes (arrows) (insert is control male tissue showing both probes)

Fig. 2

Patient 2 liver biopsies post HCT showing improvement over time. a Was taken in 2017, b was taken in 2019. b shows reduced numbers of portal tract foamy macrophages (both haematoxylin and eosin stained FFPE sections,400 original magnification)

Fig. 3

Patient 3 duodenal biopsies pre (a) and post (b) HCT showing improvement overtime. a The pre HCT biopsy shows extensive replacement of the lamina propria by foamy macrophage with broadening of villi. In comparison, the post HCT biopsy b shows an essentially normal villous structure with only a few foamy macrophages in the lamina propria (both haematoxylin and eosin stained FFPE sections,100 original magnification)

Fig. 4

Patient 3 liver biopsies pre (a) and post (b) HCT showing improvement over time. The post HCT biopsy b shows reduced numbers of portal tract foamy macrophages, including those containing cholesterol cleft (arrowheads) and reduced portal inflammation. Early hepatocellular ballooning is seen in the pre HCT biopsy (a) but not in the post HCT biopsy (b, arrows) (both haematoxylin and eosin stained FFPE sections,400 original magnification)

Fig. 5

Patient 5 liver biopsies pre and post HCT showing improvement over time. ac were pre HCT, taken in 2017, 2018 and 2019 respectively. d Was taken in 2020, 12months after HCT. ac demonstrate worsening portal tract foamy macrophage accumulation, including many containing abundant cholesterol clefts (arrowheads); there is also worsening hepatocellular ballooning (arrows) and fibrosis. d Demonstrates a dramatic improvement in histological appearances after HCT (all images haematoxylin and eosin stained FFPE sections,400 original magnification)

Fig. 6

OxysterolCholestane-3,5,6-triol (C-triol) levels overtime per patient 15. Demonstrates improvement in inflammation/C-triols after HCT. The purple arrow highlights the start of ERT, the red arrow highlights the timing of HCT, blue arrows the use of bortezomib and the green arrows rituximab

Fig. 7

Kaplan Meier survival of the multimodal group versus ERT [13] versus untreated historical Wolman disease control [2, 15]. Survival is estimated from birth to 60months. Historical control data and ERT data has been used with permission from the lead authors of the respective publications (Dr. Simon Jones and Dr. Suresh Vijay respectively)