[0001] The present invention relates to retromer complex activators and compositions for use in the treatment and/or prevention of neurological and psychiatric disorders characterized by Kidins220 dysfunction in a subject. These disorders may be further characterized by ventriculomegaly and/or excitotoxicity. It also relates to methods for screening a retromer complex activator for use in the treatment and/or prevention of said disorders in a subject.
1. A retromer complex activator, or a pharmaceutical composition comprising said activator in a therapeutically effective amount, for use in the treatment and/or prevention of neurological or psychiatric disorders characterized by a Kinase D-interacting substrate of 220 kDa (Kidins220) dysfunction in a subject. 2. The retromer complex activator or composition for use according to claim 1, wherein the disorder is further characterized by ventriculomegaly. 3. The retromer complex activator or composition for use according to claim 1 or 2, wherein the disorder is further characterized by excitotoxicity. 4. The retromer complex activator or composition for use according to any one of the preceding claims, wherein the retromer complex activator is an SNX27-retromer (SNX27-R) activator. 5. The retromer complex activator or composition for use according to any one of the preceding claims, wherein the retromer complex activator is thiophen-2-ylmethyl carbamimidothioate hydrochloride (R33) or thiophene-2,5-diylbis(methylene) dicarbamimidothioate dihydrochloride (R55); or variants thereof. 6. The retromer complex activator or composition for use according to any one of claims 1 to 4, wherein the retromer complex activator is selected from the group consisting of: Sorting nexin-27 (SNX27); Vacuolar protein sorting-associated protein 35 (VPS35); Vacuolar protein sorting-associated protein 26 (VPS26); Vacuolar protein sorting-associated protein 29 (VPS29); family with sequence similarity 21 (FAM21); Kinase D-interacting substrate of 220 kDa (KIDINS220); and Aquaporin-4 (AQP4). 7. The retromer complex activator or composition for use according to claim 6, wherein the retromer complex activator is administered to the subject as a nucleic acid. 8. The retromer complex activator or composition for use according to any one of the preceding claims, wherein the subject is a human subject. 9. The retromer complex activator or composition for use according any one of the preceding claims, wherein the neurological or psychiatric disorder is selected from the group consisting of: ischemic stroke (IS); epilepsy; hydrocephalus (HCP); idiopathic Normal Pressure Hydrocephalus (iNPH); schizophrenia; and spastic paraplegia, intellectual disability, nystagmus, and obesity (SINO) syndrome. 10. A method for screening a retromer complex activator for use according to any one of the preceding claims, comprising the following steps: (i) measuring at least one of the following parameters in a non-human animal: a. the ventricular volume of the brain ventricles; and/or b. the levels of expression of at least one gene selected from the group consisting of: SNX27; VPS35; VPS26; VPS29; FAM21; KIDINS220; and AQP4 in a biological sample from the non-human animal; (ii) administering a potentially active retromer complex activator for use according to any one of the preceding claims to the non-human animal; (iii) repeating step (i); (iv) evaluating the effect of the potentially active retromer complex activator or composition by: a. comparing the ventricular volumes obtained in (iii)a and (i)a; and/or b. comparing the expression levels obtained in (iii)b and (i)b, and (v) selecting the retromer complex activator that stabilizes the retromer complex, wherein the non-human animal is an animal model with Kidins220 dysfunction; and wherein the retromer complex activator is selected in (v) if the ventricular volumes measured in (iii)a are decreased with respect to the ventricular volumes measured in (i)a, and/or the expression levels of the at least one gene measured in (iii)b are altered with respect to the expression levels measured in (i)b. 11. The method according to claim 10, wherein the non-human animal is a rodent. 12. The method according to claim 10 or 11, wherein the rodent is a Kidins220<f/f> floxed mouse. 13. An in vitro method for the diagnosis of a neurological or psychiatric disorder characterized by ventriculomegaly in a human subject, comprising: (i) measuring the expression levels of at least one protein selected from the group consisting of: SNX27; VPS35; VPS26; VPS29; FAM21; KIDINS220; and AQP4 in a biological sample from the human subject, and (ii) comparing the expression levels measured in (i) with reference expression levels measured in a biological sample from a control human subject, wherein if the expression levels of the at least one protein listed in (i) are altered with respect to the first reference expression level, then the human subject is suffering from a neurological or psychiatric disorder characterized by Kidins220 dysfunction. 14. The in vitro method of claim 13, wherein the subject is susceptible to receive a therapy based on the retromer complex activator or composition for use according to any one of claims 1 to 9. 15. The in vitro method of any one of claims 13 to 14 wherein the neurological or psychiatric disorder is selected from the group consisting of: IS; epilepsy; HCP; iNPH; schizophrenia; and SINO syndrome.