Deficiency in Aralar/AGC1 is a rare disease with impaired neurodevelopment, epilepsy and hypomyelination. We have explored treatments for Aralar deficiency and found that β-hydroxybutyrate (βOHB), the main metabolic product of ketogenic diets, is able to overcome the defect in basal and workload-stimulated respiration in Aralar-deficient neurons and partially reverts their failure to produce aspartate and NAA. In vivo administration of βOHB to Aralar-KO mice increases myelin protein levels and dopaminergic markers in these mice, suggesting βHB administration as a potential treatment in Aralar deficiency.

However, whether the defect in myelination of the Aralar-KO mouse is due to the lack of aralar in neurons or oligodendrocytes is unclear. Our present aim is to generate neuron or oligodendrocyte-specific Aralar KO to address these issues.

Citrin deficiency is a urea cycle disorder with different manifestations. Citrin/AGC2 is mainly expressed in liver. In the frame of the Citrin Foundation, we are exploring the exogenous expression of Aralar, which has low expression in normal liver, as possible therapy for Citrin deficiency. We have generated Citrin-KO mice carrying liver-specific Aralar transgene and are studying the effect of the transgene in recovering liver MAS activity and other traits of Citrin deficiency reproduced in Citrin-KO mice.

An ongoing COVID-19 project (CvK), is aimed at developing a therapy against COVID-19 symptoms with the use of senolytics, which would selectively eliminate organisms’ senescent cells.