GBA1-derived Nanobodies as a novel therapeutic strategy in neuropathic Gaucher disease

Nowadays, several diseases are waiting for a cure and neuropathic Gaucher Disease (GD) is one of them. It is a rare genetic disorder that occurs in people who produce dysfunctional mutated forms of an enzyme termed glucocerebrosidase. This enzymatic deficiency associated to GD mutations causes the accumulation of fatty materials in different organs, leading to various symptoms, including neurological ones in the most severe cases.

There are three different types of GD: type I, the most common and mild form, presenting only systemic symptoms, and type II and III, which are acute and chronic neuropathic GD (nGD) forms, respectively. Several pharmacological treatments can improve visceral and hematological symptoms, but none are effective for neurological defects.

Nanobodies are small antibodies, naturally produced by camelids, presenting peculiar characteristics that make them excellent candidates in the development of new drugs. In the past years, we have produced many nanobodies against the non-mutated glucocerebrosidase and some could improve its enzymatic function. Furthermore, some Nbs have also shown amelioration of the protein activity in the case of a mutated glucocerebrosidase, the N370S, suggesting that they may also be active on other mutations, associated to nGD. This will be the goal of our study. We will test these nanobodies in nGD patient cells with different glucocerebrosidase mutations and through different biochemical and cell biology tests we will evaluate their ability to improve the function of the protein, and expect to select a subset of Nbs with promising properties to develop as a potential new pharmacological approach.