Reversibility of motor dysfunction in the rat model of NGLY1 deficiency

Abstract

N-glycanase 1 (NGLY1) deficiency is a rare inherited disorder characterized by developmental delay, hypolacrima or alacrima, seizure, intellectual disability, motor deficits, and other neurological symptoms. The underlying mechanisms of the NGLY1 phenotype are poorly understood, and no effective therapy is currently available. Similar to human patients, the rat model of NGLY1 deficiency, Ngly1−/−, shows developmental delay, movement disorder, somatosensory impairment, scoliosis, and learning disability. Here we show that single intracerebroventricular administration of AAV9 expressing human NGLY1 cDNA (AAV9-hNGLY1) to Ngly1−/− rats during the weaning period restored NGLY1 expression in the brain and spinal cord, concomitant with increased enzymatic activity of NGLY1 in the brain. hNGLY1 protein expressed by AAV9 was found predominantly in mature neurons, but not in glial cells, of Ngly1−/− rats. Strikingly, intracerebroventricular administration of AAV9-hNGLY1 normalized the motor phenotypes of Ngly1−/− rats assessed by the rota-rod test and gait analysis. The reversibility of motor deficits in Ngly1−/− rats by central nervous system (CNS)-restricted gene delivery suggests that the CNS is the primary therapeutic target organs for NGLY1 deficiency, and that the Ngly1−/− rat model may be useful for evaluating therapeutic treatments in pre-clinical studies.

NGLY1 Deficiency, a Congenital Disorder of Deglycosylation: From Disease Gene Function to Pathophysiology

“…Survival of Ngly1 −/− rats beyond the embryonic period and identification of progressive neurological features in them associated with histopathology in the nervous system suggest these animals to be a valuable model for preclinical studies on NGLY1 deficiency. Indeed, Asahina and colleagues have recently reported the utilization of Ngly1 −/− rats to develop a therapeutic measure for the reversal of their neurological phenotypes [ 47 ]. The authors generated a recombinant adeno-associated virus serotype 9 (AAV9) vector expressing the human NGLY1 cDNA under the constitutive CMV promoter (AAV9-hNGLY1).…”

“…CNS-restricted delivery of AAV9-hNGLY1 in Ngly1 −/− rats improved the motor function and reduced neuroinflammation in these animals. The data provide clear evidence that the neurological phenotypes associated with loss of NGLY1 are at least in part reversible and offer an exciting framework for therapeutic intervention in NGLY1-deficient patients [ 47 ]. Therapeutic introduction of a protein in patients with loss-of-function mutations through enzyme replacement therapy, gene therapy, or gene correction runs the risk of eliciting an immune response to the introduced protein, as it can be perceived as “foreign” by the patient’s immune system [ 48 ].…”

Peptide: N-Glycanase 1 and Its Relationship with Congenital Disorder of Deglycosylation

“…AAV9s carrying a copy of human NGLY1 gene (AAV9-hNGLY1) were injected to Ngly1-KO SD rats during the weaning period via intracerebroventricular (i.c.v.) administration in order to reverse the deterioration of neuronal symptoms [100]. The reexpression of NGLY1 were identified in pons, thalamus, hippocampus, cerebral cortex and cerebellar Purkinje cells, but not detected in liver.…”

Correction to: Reversibility of motor dysfunction in the rat model of NGLY1 deficiency

“…Following publication of the original article [ 1 ], the authors would like to correct 2 errors in the "Methods" section.…”

“…These errors do not affect any of the conclusions presented in the article. The original article [ 1 ] has been corrected.…”