A meta-analysis of preclinical gene therapy trials in spinal muscular atrophy (SMA) mouse models revealed that treated mice had a 3.23-fold increase in survival duration compared to controls.

The results of the study, published in Gene Therapy, showed that this increased survival was observed for both nusinersen (Spinraza®) and onasemnogene abeparvovec-xioi (Zolgensma®) in preclinical trials (median survival ratio [MSR], 3.18 and 3.33, respectively).

Stratification of the meta-analysis revealed that the type of therapy, mouse model used, time of administration, and method of administration had impacts on the perceived treatment effect.

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“This systematic review and meta-analysis of pre-clinical research has confirmed that genetic therapies can significantly prolong survival, but also that experimental design has a fundamental influence on perceived study outcome,” the authors said.

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While therapies that focus on the augmentation of survival motor neuron (SMN) protein such as nusinersen and onasemnogene abeparvovec-xioi showed robust increases in survival (MSR, 3.65), treatments that target other proteins—including Uba1, Plastin3, phosphatase and tensin homolog (PTEN), insulin-like growth factor 1 (IGF1), cardiotrophin 1 (CT1), stathmin, stasimon, myostatin, and synaptotagmin13—showed much more modest results (MSR, 1.30).

The article also found large differences in survival depending on the mouse model used. The most commonly used model, SMNΔ7, resulted in untreated survival times of around 15 to 22 days compared to the more severe Taiwanese model that only survived 15 days on average. These models affected the survival ratios, yielding MSRs of 2.92 (95% CI, 2.45–3.49) for SMNΔ7 compared to 5.49 (95% CI, 3.83–7.87) in the Taiwanese model. Mouse models that were used less frequently only showed a modest increase in survival (MSR, 1.65; 95% CI, 1.28–2.12).

The earlier intervention was also found to be more effective than later administration, with animals treated between birth and 5 days of age having a roughly 3-fold increase in survival compared to those treated at 6 days of age or later (MSR, 1.37). Repeated administrations also resulted in increased survival time (MSR, 4.08).

The route of treatment administration also appeared to affect survival rates, with the intracranial or intrathecal (MSR, 2.70), intravascular (MSR, 2.79), and intraperitoneal (MSR, 2.71) routes all yielding similar results. Subcutaneous delivery yielded the highest impact on survival (MSR, 5.75), while local intramuscular administration yielded the least (MSR, 2.05). Additionally, combinations of multiple routes, usually intracranial with another route, yielded robust increases in survival (MSR, 5.32).

The study authors hoped to correlate preclinical results with clinical trial results, but meta-analysis could not be applied due to a lack of consistent outcomes reported between trials. In addition, only a third of the clinical trials included control groups for comparison.

Fifty-one preclinical publications were included in the meta-analysis, yielding 155 individual comparisons, which corresponded to 2573 animals. For clinical trial publications, 5 were analyzed that assessed the use of nusinersen and 1 assessed the use of onasemnogene abeparvovec-xioi.


Chilcott EM, Muiruri EW, Hirst TC, Yáñez-Muñoz RJ. Systematic review and meta-analysis determining the benefits of in vivo genetic therapy in spinal muscular atrophy rodent models. Gene Ther. Published online October 6, 2021. doi:10.1038/s41434-021-00292-4