Targeting the 5′ untranslated region of SMN2 as a therapeutic strategy for spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations in the survival motor neuron 1 ( SMN1 ) gene. All patients have at least one copy of a paralog, SMN2 , but a C-to-T transition in this gene results in exon 7 skipping in a majority of transcripts. Approved treatment for SMA involves promoting exon 7 inclusion in the SMN2 transcript or increasing the amount of full-length SMN by gene replacement with a viral vector. Increasing the pool of SMN2 transcripts and increasing their translational efficiency can be used to enhance splice correction. We sought to determine whether the 5′ untranslated region (5′ UTR) of SMN2 contains a repressive feature that can be targeted to increase SMN levels. We found that antisense oligonucleotides (ASOs) complementary to the 5′ end of SMN2 increase SMN mRNA and protein levels and that this effect is due to inhibition of SMN2 mRNA decay. Moreover, use of the 5′ UTR ASO in combination with a splice-switching oligonucleotide (SSO) increases SMN levels above those attained with the SSO alone. Our results add to the current understanding of SMN regulation and point toward a new therapeutic target for SMA.

Treatability of the KMT2-Associated Neurodevelopmental Disorders Using Antisense Oligonucleotide-Based Treatments

“…Another ASO-based strategy that could also be employed but was not explicitly explored in this work is to restore gene function by modulating pseudogenes as done for spinal muscular atrophy [68,70]. This approach requires in-depth knowledge regarding the overlap in function of the two genes to understand which ASO strategy would be most beneficial.…”

“…However, not all uORFs are necessarily inhibitory and can encode polypeptides with separate functions. The exact effect of these uORFs should be ascertained to ensure that interference via ASO has the desired effect [70]. Although no ASO based on this strategy has yet been approved as a drug, this approach has already been tested for several genes in vitro and in vivo [76,106].…”

Upstream open reading frames: new players in the landscape of cancer gene regulation

“…For example, uORF-specific antisense oligonucleotides may block translation of the uORF to promote main CDS translation, which may ameliorate disease phenotypes. This approach has already been exploited in neurological diseases such as spinal muscular atrophy ( 147 ).…”

Intervenção fisioterapêutica na amiotrofia muscular espinhal tipo 1: revisão de literatura

“…A AME geralmente ocorre em pessoas que herdam duas cópias defeituosas do gene SMN1uma herdada do pai e outra da mãe. (Winkelsas et al, 2020;Chrun et al, 2017;Zanoteli et al, 2020) Pacientes não afetados pela AME tem essas 4 cópias dos genes em perfeita harmonia (2 cópias do SMN2 e 2 cópias do SMN1). E de acordo com a classificação e gravidade da AME o gene SMN2 possui sua quantidade definida: AME tipo Ipossui 2 cópias do gene SMN2 e nenhuma cópia do gene SMN1; AME tipo II-possui 3 cópias do gene SMN2 e nenhuma cópia do gene SMN1; AME tipo III e IV-possui as 4 cópias do gene SMN2.…”