Researchers from France developed a gene therapy approach based on hematopoietic stem cells for the erythroid-specific expression of lysosomal acid lipase (LAL) enzyme in the blood as a potential curative treatment for LAL deficiency (LAL-D).

The LAL enzyme is essential for the hydrolysis of cholesteryl ester and triglyceride in the lysosome. So its deficiency leads to the accumulation of fat inside different tissues and organs, resulting in their failure. 

The team led by Mario Amendola, PhD, used the CRISPR/Cas9 system to integrate the genetic information necessary for the synthesis of the LAL enzyme under an endogenous α-globin promoter. This way, the erythroid lineage could produce the LAL enzyme. 

Continue Reading

They showed that LAL produced by erythroid lineage using this approach retained its activity and reduced the accumulation of lipids in fibroblasts derived from patients with Wolman disease, the most severe form of LAL-D.

Read more about LAL-D

The researchers also transplanted hematopoietic stem cells modified in this way into a mouse model and showed that they could home, engraft, and differentiate into other cell types, except for erythroid cells due to the limitations of the model.

In order to obtain erythroid differentiation, the team moved to another mouse model that was humanized for the α-globin locus. “We are currently analyzing the level of LAL expression in the blood of mice transplanted with edited [murine hematopoietic stem cells],” the researchers wrote. 

The team also engineered the genetic material coding for LAL to increase the expression and secretion of the enzyme and reported that they reached an 8-fold increase in the activity of the enzyme doing so. They reported they are evaluating the therapeutic effects of their hematopoietic stem cell-based platform in another mouse model of LAL-D.

“Overall, using two different transgenic mouse models and engineering LAL cDNA, we are assessing the potential of a CRISPR based [hematopoietic stem cell] gene therapy platform for erythroid mediated protein expression for [enzyme replacement therapy],” they wrote.


Laurent M, Pavani G, Jenny C, Fabiano A, Amendola M. Ex vivo editing of hematopoietic stem cells for erythroid expression of therapeutic proteins in vivo for LAL-D therapy. Mol Ther. 2022;30,4,Sup.1; 1-592. doi:10.1016/j.ymthe.2022.04.017