A new pathway to treat cystinosis, a lysosomal storage disease

In most genetic diseases, treatment does not directly address the cause (sick genes can not yet be repaired, nor most defective proteins be replaced) but rather targets a key step in their complex consequences. Before identifying such target, it is thus necessary to correctly understand the disease mechanism. At CELL unit, Christophe Pierreux, Pierre Courtoy and their colleagues have identified a crucial step in the progression of infantile cystinosis. Cystinosis is a storage disease of lysosomes, where cystine accumulates and even forms crystals because of deficit export. Not a surprise, this perturbs the structure and function of cells and tissues, in particular in kidneys where cystinosis first manifests itself.

A detailed analysis of the early steps of the disease (Gaide Chevronnay et al., J Am Soc Nephrol, 2014) led the investigators to suggest that cystine accumulating in kidneys originates from the uptake by endocytosis and digestion in lysosomes of ultrafiltrated plasma proteins. These proteins enjoy a globular form thanks to intramolecular bridges called disulfide bonds, at the origin of cystine. Protein endocytosis and lysosomal digestion are particularly active in kidneys. This interpretation predicted that any intervention blocking endocytosis should protect kidneys against cystinosis. As a proof-of-concept, the authors recently reported that an artificial genetic manipulation (genetic excision of megalin, the receptor fueling kidney endocytosis) in a mouse model reproducing the disease, efficiently blocked cystine accumulation and protected kidney structure (Janssens et al., J Am Soc Nephrol, 2019).

These results pave the way to a novel potential therapy of cystinosis by megalin inhibition, using a simple diet supplementation with natural dibasic amino-acids (popular among body-builders). The first trial in the cystinotic mouse is promising.

Christian de Duve, who discovered lysosomes and forged the concept of endocytosis, should have appreciated that combination of his two “sons” could potentially be exploited to treat patients.

Article describing this research

Protection of cystinotic mice by kidney-specific megalin ablation supports an endocytosis-based mechanism for nephropathic cystinosis progression.

Janssens V, Gaide Chevronnay HP, Nevo N, Vincent MF, Marie S, Vaino S, Nielsen R, Christensen EI, Jouret F, Antignac C, Pierreux CE*, Courtoy PJ*. (*, equal senior authors).

J Am Soc Nephrol (2019). 30 (11) 2177-2190 doi: 10.1681/ASN.2019040371