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

Abstract

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an infantile autosomal recessive disease caused by the loss of the ubiquitously expressed IGHMBP2 gene. SMARD1 causes degeneration of alpha-motor neurons, resulting in distal muscle weakness, diaphragm paralysis, and respiratory malfunction. We have reported that delivery of a low dose of AAV9-IGHMBP2 to the CNS results in a significant rescue of the SMARD1 mouse model (nmd). To examine how a delivery route can impact efficacy, a direct comparison of intravenous (IV) and intracerebroventricular (ICV) delivery of AAV9-IGHMBP2 was performed. Using a low-dose, both IV and ICV delivery routes led to a significant extension in survival and increased body weight. Conversely, only ICV-treated animals demonstrated improvements in the hindlimb muscle, neuromuscular junction, and motor function. The hindlimb phenotype of IV-treated mice resembled the untreated nmd mice. We investigated whether the increased survival of IV-treated nmd mice was the result of a positive impact on the cardiac function. Our results revealed that cardiac function and pathology were similarly improved in IV- and ICV-treated mice. We concluded that while IV delivery of a low dose does not improve the hindlimb phenotype and motor function, partial restoration of cardiac performance is sufficient to significantly extend survival.

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

“…The benefits obtained by the in vitro use of neurotrophic factors and pharmacological agents are not encouraging, 38,39 but better results have been obtained with the injection of rAAV in nmd mice. 32,48 The pathogenetic mechanisms underlying this disease are complex and not yet completely deciphered; in fact, mutations in the same IGHMBP2 gene can determine very serious (SMARD1) or mild phenotypes (CMT). Moreover, SMARD1 itself demonstrated substantial variability in terms of age of presentation, severity of the symptoms and survival.…”

“…ICV injection was instead correlated with a better improvement in hindlimb function 48. Both treated groups showed a similar extension of lifespan (more than 200 days), weight gain and improvement in the histological features of cardiomyocytes and in cardiac fibrosis, with a significant delay in the onset of dilated cardiomyopathy compared with that of the untreated controls.…”

“…The authors concluded that the two methods of administration can be considered equally effective in the rescue of the disease phenotype of nmd mice due to the equivalent lifespan prolongation and cardiac improvement. ICV injection was instead correlated with a better improvement in hindlimb function . However, although the ICV and IV doses were the same, the quantity of lentiviral particles received by the CNS may have been higher after ICV delivery compared to IV delivery as ICV injections are delivered locally while IV injections are delivered systemically.…”

“…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. However, the ICV-treated mice gained more weight, and these mice showed significantly better rescue of hindlimb motor function, with a significant reduction in gastrocnemius contracture and a great improvement in the rotarod test performance compared to that of both the untreated controls and the IV-treated mice.…”

“…ICV injection was instead correlated with a better improvement in hindlimb function. 48 However, although the ICV and IV doses were the same, the quantity of lentiviral particles received by the CNS may have been higher after ICV delivery compared to IV delivery as ICV injections are delivered locally while IV injections are delivered systemically.…”