Cyclocreatine treatment ameliorates the cognitive, autistic and epileptic phenotype in a mouse model of Creatine Transporter Deficiency

Francesco Cacciante,John C Mckew,Leonardo Lupori,Tommaso Pizzorusso,Raffaele Mazziotti,Mark Butt,Giovanni Cioni,Roberta Battini,Maria Grazia Alessandrì,Laura Baroncelli,Elena Putignano,Mariangela Gennaro,Elisa Cerri,Minh-Ha T Do,Giulia Sagona

doi:10.1038/s41598-020-75436-4

Abstract

Creatine Transporter Deficiency (CTD) is an inborn error of metabolism presenting with intellectual disability, behavioral disturbances and epilepsy. There is currently no cure for this disorder. Here, we employed novel biomarkers for monitoring brain function, together with well-established behavioral readouts for CTD mice, to longitudinally study the therapeutic efficacy of cyclocreatine (cCr) at the preclinical level. Our results show that cCr treatment is able to partially correct hemodynamic responses and EEG abnormalities, improve cognitive deficits, revert autistic-like behaviors and protect against seizures. This study provides encouraging data to support the potential therapeutic benefit of cyclocreatine or other chemically modified lipophilic analogs of Cr.

Highlights

Creatine Transporter Deficiency (CTD) is an inborn error of metabolism with X-linked inheritance pattern (OMIM #300352)
We longitudinally evaluated the therapeutic efficacy of cCr treatment in the same animals, using intrinsic optical signal (IOS) imaging, a panel of behavioral test (Y maze, Morris water maze, rotarod, self-grooming) and video-EEG recordings (Fig. 1a)
Since we recently reported that hemodynamic responses are altered in the visual cortex C rT−/y mice with no impairment of visually-evoked potentials and that hemodynamic measurements are a reliable biomarker of brain function in CTD15, we first explored the therapeutic efficacy of cyclocreatine using IOS imaging (Fig. 1a)

Summary

Introduction

Creatine Transporter Deficiency (CTD) is an inborn error of metabolism with X-linked inheritance pattern (OMIM #300352). Knock-out murine models for the creatine transporter (CrT) gene showing high face validity and the discovery of novel quantitative biomarkers have led to a significant leap for the development of potential therapeutic a gents[9,10,11,12,13,14,15]. We performed a randomized, blinded, placebo-controlled, preclinical study to explore the therapeutic efficacy of a chronic (24 week) oral daily treatment with cyclocreatine (cCr) at three different dose levels in CrT knock-out (CrT−/y) mice. It has been reported that lipophilic analogs and other derivatives of Cr can enter cells independently of CrT and could represent a promising approach for CTD t reatment[10,16,17,18,19]. The evaluation of cCr and other treatment options in CTD has been limited to biochemical measurements, behavioral outcomes and in vitro assays of neuronal function. We combined functional biomarker assessment with well-established behavioral readouts for C TD11,15 to monitor brain function of CrT−/y mice in response to pharmacological intervention with cCr

Methods

Results

Conclusion