Nusinersen (Spinraza), was effective in a phase III trial in infants with SMA [88] and
has received FDA approval. However, this strategy is contingent on the number of
SMN2 copies retained. The most severe cases of SMA are associated with the fewest
copies of SMN2. Therefore, while SMN2 pre-mRNA splicing correction may be an
effective strategy for recovering SMN protein levels in cases with high SMN2 copy
numbers and abundant levels of SMN2 pre-mRNA, it will not suffice in more severe
cases with few SMN2 copies and low amounts of targetable SMN2 pre-mRNA [85].
However, a potential solution involving lncRNA targeting has recently emerged.
SMN2 transcription has recently been shown in two independent studies to be
negatively regulated by its NAT, SMN-AS1, through PRC2 recruitment and epigenetic repression [89, 90]. In one of the studies, targeting SMN-AS1 for RNase
H-mediated degradation with ASOs was found to be effective at restoring SMN2
transcription and functional SMN protein production in SMA patient-derived cells,
while combined systemic administration of ASOs targeting SMN-AS1 with SMN2targeting SSOs alleviated SMA symptoms in mice [89]. The other study demonstrated the effectiveness of using SMN1-AS-targeting ASOs to sterically inhibit the
SMN1-AS:EZH2 interaction to epigenetically derepress and upregulate full-length
SMN2 expression in human SMA fibroblasts and SMA neuronal cells [90].
The mechanistic roles of lncRNAs in cardiac physiology and disease that have
been discovered to date have been comprehensively reviewed elsewhere [91–93].
However, an intriguing recent example that immediately offers a potential therapeutic target is the novel lncRNA CHAST. It is upregulated in the hearts of aortic
stenosis patients, and CHAST silencing with GapmeR treatment effectively
prevented cardiac hypertrophy in a mouse model of CHAST-inducible cardiac
hypertrophy [94]. CHAST inhibition was also effective in attenuating established
cardiac hypertrophy in mice with pre-established cardiac disease. These findings
demonstrate that ASO-mediated CHAST inhibition may be an effective strategy to
ameliorate or even prevent cardiac hypertrophy in patients with aortic stenosis [94].
There remain many outstanding issues regarding lncRNA and epigenetics.
Firstly, owing to their highly tissue-specific expression profiles, it remains necessary
to more comprehensively characterise endogenous lncRNA transcriptomes in different human tissues. Second, the methodological hurdles that limit our current
knowledge of lncRNAs must be overcome. Recent advances in the biochemical
study of RNA-protein interactions have already deepened and refined our mechanistic understanding of some lncRNAs. Sustained progress in this regard, combined
with sharper prediction of RNA secondary structure, will enable an increasingly
detailed and comprehensive appreciation of how lncRNAs dynamically modulate
epigenetic processes in physiological settings and of how these processes go awry in
disease. Moreover, the pharmacological development of RNA-targeting agents
such as ASOs has been rejuvenated by the emergence of lncRNAs as major players
in epigenetics. This is precisely because they offer a novel opportunity to solve
the problem of how to upregulate targets that are aberrantly downregulated in
disease. As outlined in the various examples described in this review, the use of
ASOs to target specific lncRNAs overexpressed in disease contexts of lncRNA
overexpression can lead to direct and highly specific transcriptional and posttranscriptional upregulation of the targets whose expression they repress [95].
Altered Long Non-coding RNA Expression in Cancer: Potential Biomarkers. . .
419
has received FDA approval. However, this strategy is contingent on the number of
SMN2 copies retained. The most severe cases of SMA are associated with the fewest
copies of SMN2. Therefore, while SMN2 pre-mRNA splicing correction may be an
effective strategy for recovering SMN protein levels in cases with high SMN2 copy
numbers and abundant levels of SMN2 pre-mRNA, it will not suffice in more severe
cases with few SMN2 copies and low amounts of targetable SMN2 pre-mRNA [85].
However, a potential solution involving lncRNA targeting has recently emerged.
SMN2 transcription has recently been shown in two independent studies to be
negatively regulated by its NAT, SMN-AS1, through PRC2 recruitment and epigenetic repression [89, 90]. In one of the studies, targeting SMN-AS1 for RNase
H-mediated degradation with ASOs was found to be effective at restoring SMN2
transcription and functional SMN protein production in SMA patient-derived cells,
while combined systemic administration of ASOs targeting SMN-AS1 with SMN2targeting SSOs alleviated SMA symptoms in mice [89]. The other study demonstrated the effectiveness of using SMN1-AS-targeting ASOs to sterically inhibit the
SMN1-AS:EZH2 interaction to epigenetically derepress and upregulate full-length
SMN2 expression in human SMA fibroblasts and SMA neuronal cells [90].
The mechanistic roles of lncRNAs in cardiac physiology and disease that have
been discovered to date have been comprehensively reviewed elsewhere [91–93].
However, an intriguing recent example that immediately offers a potential therapeutic target is the novel lncRNA CHAST. It is upregulated in the hearts of aortic
stenosis patients, and CHAST silencing with GapmeR treatment effectively
prevented cardiac hypertrophy in a mouse model of CHAST-inducible cardiac
hypertrophy [94]. CHAST inhibition was also effective in attenuating established
cardiac hypertrophy in mice with pre-established cardiac disease. These findings
demonstrate that ASO-mediated CHAST inhibition may be an effective strategy to
ameliorate or even prevent cardiac hypertrophy in patients with aortic stenosis [94].
There remain many outstanding issues regarding lncRNA and epigenetics.
Firstly, owing to their highly tissue-specific expression profiles, it remains necessary
to more comprehensively characterise endogenous lncRNA transcriptomes in different human tissues. Second, the methodological hurdles that limit our current
knowledge of lncRNAs must be overcome. Recent advances in the biochemical
study of RNA-protein interactions have already deepened and refined our mechanistic understanding of some lncRNAs. Sustained progress in this regard, combined
with sharper prediction of RNA secondary structure, will enable an increasingly
detailed and comprehensive appreciation of how lncRNAs dynamically modulate
epigenetic processes in physiological settings and of how these processes go awry in
disease. Moreover, the pharmacological development of RNA-targeting agents
such as ASOs has been rejuvenated by the emergence of lncRNAs as major players
in epigenetics. This is precisely because they offer a novel opportunity to solve
the problem of how to upregulate targets that are aberrantly downregulated in
disease. As outlined in the various examples described in this review, the use of
ASOs to target specific lncRNAs overexpressed in disease contexts of lncRNA
overexpression can lead to direct and highly specific transcriptional and posttranscriptional upregulation of the targets whose expression they repress [95].
Altered Long Non-coding RNA Expression in Cancer: Potential Biomarkers. . .
419