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Friend or Foe(tal): challenges in development of a large animal model for pre-clinical fetal gene therapy

Gene Therapy volume 29, pages 316–318 (2022)Cite this article

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Classic 5q-linked spinal muscular atrophy (SMA) has been at the leading edge of translational and clinical research. Following discovery of the SMA-causative gene, Survival Motor Neuron 1 (SMN1) in 1995, and its gene product, survival motor neuron (SMN) protein, it was readily identified that this disease is eminently targetable [1]. Several animal models were developed in the following years including Drosophila, C. elegans, zebrafish, mouse, and swine models, each providing an opportunity to understand the basic biology of how SMN deficiency is responsible for the complex SMA phenotype, including important features such as neurodegeneration, neuromuscular junction pathology, and developmental arrest [2]. Rich et al. in this issue report their experience in developing a swine model of SMA for fetal therapy [3].

Humans retain an additional closely related SMN gene, SMN2, which is a nearly identical homolog and generates a small amount of full-length SMN protein, but not enough to prevent disease development in the absence of SMN1. Animal models and patients demonstrate that, in general, the more SMN2 copies an individual has, disease severity is decreased because of the incremental increase in SMN protein [1, 2]. Therefore, while ~2 copies of SMN2 are sufficient to permit live birth, it is highly prognostic for the most severe form of the disease (SMA type 1), with symptoms presenting within the first weeks of life, leading to limited survival beyond infancy and virtually no attainment of motor skills [1]. In parallel to the generation and study of animal models was a two-pronged approach to therapeutics which has resulted in three effective therapeutics gaining regulatory approval. Two of these compounds modulate SMN2 splicing and lead to an increase in SMN protein production: an antisense oligonucleotide (ASO) (nusinersen) and a small molecule drug (risdiplam). A gene therapy approach (onasemnogene abeparvovec) replaces the missing or faulty SMN1 gene by using an AAV-9 vector packaged with the SMN1 cDNA. Each of these successful therapeutics leveraged the fundamental biology of the field and the disease-relevant animal models, allowing for a successful translation into the clinic [1].

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Authors and Affiliations

  1. Center for Experimental Neurotherapeutics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Richard S. Finkel

  2. Bond Life Sciences Center, University of Missouri, Columbia, MO, USA

    Christian L. Lorson

  3. Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Missouri, Columbia, MO, USA

    Christian L. Lorson

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  1. Richard S. Finkel
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  2. Christian L. Lorson
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Contributions

RSF and CLL contributed equally to the design and writing of this commentary.

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Correspondence to Richard S. Finkel.

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Competing interests

RSF has served as an advisor to Biogen, AveXis/Novartis, Roche, ScholarRock, and Shift; has participated as an investigator in clinical trials of nusinersen, onasemnogene abeparvovec and risdiplam in patients with SMA. CLL is the co-founder and Chief Scientific Officer of Shift Pharmaceuticals.

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Finkel, R.S., Lorson, C.L. Friend or Foe(tal): challenges in development of a large animal model for pre-clinical fetal gene therapy. Gene Ther 29, 316–318 (2022). https://doi.org/10.1038/s41434-022-00327-4

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