Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent

Abstract

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive disease occurring during childhood. The gene responsible for disease development is a ubiquitously expressed protein, IGHMBP2. Mutations in IGHMBP2 result in the loss of α-motor neurons leading to muscle atrophy in the distal limbs accompanied by respiratory complications. Although genetically and clinically distinct, proximal SMA is also caused by the loss of a ubiquitously expressed gene (SMN). Significant preclinical success has been achieved in proximal SMA using viral-based gene replacement strategies. We leveraged the technologies employed in SMA to demonstrate gene replacement efficacy in an SMARD1 animal model. Intracerebroventricular (ICV) injection of single-stranded AAV9 expressing the full-length cDNA of IGHMBP2 in a low dose led to a significant level of rescue in treated SMARD1 animals. Consistent with drastically increased survival, weight gain, and strength, the rescued animals demonstrated a significant improvement in muscle, NMJ, motor neurons, and axonal pathology. In addition, increased levels of IGHMBP2 in lumbar motor neurons verified the efficacy of the virus to transduce the target tissues. Our results indicate that AAV9-based gene replacement is a viable strategy for SMARD1, although dosing effects and potential negative impacts of high dose and ICV injection should be thoroughly investigated.

Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes, molecular pathogenesis and therapeutic insights

“…Gene therapy is the third possible approach to SMARD1 treatment, and its great advantage is that this therapy may have the potential to replace the deficient gene and restore a In two recent studies, Shababi and colleagues tested the ICV route (Shababi et al, 47 ) and compared this route with the IV route. 48 In the first paper, these authors treated mice by ICV injection with In conclusion, gene therapy seems to show encouraging results in laboratory and in vivo tests and thus requires great effort to reach the knowledge necessary to treat SMARD1.…”

“…In two recent studies, Shababi and colleagues tested the ICV route (Shababi et al, 47 ) and compared this route with the IV route. 48 In the first paper, these authors treated mice by ICV injection with 2 doses of virus (1.25 × 10 11 or 2.5 × 10 11 viral genomes, with the higher dose in a double volume of injection with a significant delay in the onset of dilated cardiomyopathy compared with that of the untreated controls.…”

Perspektywy terapii w polineuropatiach genetycznie uwarunkowanych

“…Chociaż dokładny mechanizm prowadzący do degeneracji aksonów zarówno w SMARD1, jak i CMT nie jest poznany, wydaje się, że duże znaczenie odgrywa poziom białka IGHMBP2 w komórkach. W przypadku choroby CMT poziom białka oznaczanego metodą Western blot jest większy niż w SMARD1 [57,63].…”

“…Prowadzone badania u chorych ze SMARD1, stanowią również szansę na skuteczną terapię w przypadku chorych z CMT2S. Jednak skuteczność tej terapii jest silnie zależna od dawki i przy wysokiej podaży wektora AAV9--IGHMBP2, może mieć skutki negatywne [63]. Zatem niezwykle ważne przy tej formie leczenia jest bardzo ścisłe dobranie dawki podawanego wektora, tak aby leczenie mogło być skutecznie lecz nietoksyczne.…”

A Direct Comparison of IV and ICV Delivery Methods for Gene Replacement Therapy in a Mouse Model of SMARD1

“… 14 , 16 The lifespan of nmd mice is variable, ranging from 10 weeks to 7 months. 14 , 17 , 18 A hallmark of the nmd phenotype includes hindlimb muscle weakness and retrenchment that appears within the second week of age and progresses to the forelimb and trunk muscles. 16 , 18 While cardiomyopathy is rarely reported in SMARD1 patients, it is a consistent phenotype observed in nmd mice.…”