Defining the optimal dose and therapeutic window in SMA with respiratory distress type I model mice, FVB/NJ-Ighmpb2

Abstract

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive disorder that develops in infancy and arises from mutation of the immunoglobulin helicase μ-binding protein 2 ( IGHMBP2 ) gene. Whereas IGHMBP2 is ubiquitously expressed, loss or reduction of function leads to alpha motor neuron loss and skeletal muscle atrophy. We previously developed a gene therapy strategy for SMARD1 using a single-stranded AAV9- IGHMBP2 vector and compared two different delivery methods in a validated SMARD1 mouse model. An important question in the field relates to the temporal requirements for this or any potential treatment. To examine the therapeutic window, we utilized our recently developed SMARD1 model, FVB/NJ- Ighmpb2 nmd-2J , to deliver AAV9- IGHMBP2 at four different time points starting at post-natal day 2 (P2) through P8. At each time point, significant improvements were observed in survival, weight gain, and motor function. Similarly, treatment improved important hallmarks of disease, including motor unit pathology. Whereas improvements were more pronounced in the early-treatment groups, even the later-treatment groups displayed significant phenotypic improvements. This work suggests that an effective gene therapy strategy could provide benefits to pre-symptomatic and early-symptomatic individuals, thereby expanding the potential therapeutic window for SMARD1.

Disease Mechanisms and Therapeutic Approaches in SMARD1—Insights from Animal Models and Cell Models

“…In contrast, all atrophic disease patterns were comparable to the Nmd 2J mouse. In a subsequent study, Shababi et al then showed, very impressively, that at low and high doses, applications at an earlier time point (P2-3), as opposed to a later time point (P6-P8), had a significantly improved effect on survival, motor function, muscle pathology, gastrocnemius NMJ pathology, and spinal motoneuron numbers from L3 to L5 [65]. However, it must be acknowledged that the application of AAV9-IGHMBP2 at a later time point also leads to a significant improvement of the disease pattern, but not as significant as for P2-3 [65].…”

ABT1 modifies SMARD1 pathology via interactions with IGHMBP2 and stimulation of ATPase and helicase activity

“…We generated a FVB- Ighmbp2 +/nmd mouse that contains the same A-to-G mutation in intron 4 of Ighmbp2 . FVB- nmd lifespan is less variable (17–21 days) and while mutant mice initially gain weight, there is a rapid weight and motor function decline ( 32 , 33 ). FVB- nmd mutant mice demonstrate the same muscle weakness and hindlimb contractures as B6- nmd 2J mutant mice; however, disease pathology occurs earlier ( 32 , 33 ).…”