Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis

Ly, Cindy V.; Miller, Timothy M.

doi:10.1097/wco.0000000000000594

Cited by 51 publications

(43 citation statements)

References 53 publications

(46 reference statements)

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“…However, efforts to optimize their potential clinical benefit are constrained by limited data describing normal, SMA disease baseline or present dosage regimen-achieved drug-induced SMN transcript and protein levels in the CNS, which cannot be assessed in living patients. The data reported here have important implications for optimization of therapeutics for SMA patients, but also highlight the importance of implementing such expedited autopsy programs to collect high-quality human CNS tissues in patients with other neurological diseases being targeted with novel gene targeting therapeutics (34,35).…”

Section: Discussionmentioning

confidence: 86%

Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment

Ramos¹,

d’Ydewalle²,

Gabbeta³

et al. 2019

Journal of Clinical Investigation

123

114

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BACKGROUND. Spinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein. New SMN-enhancing therapeutics are associated with variable clinical benefits. Limited knowledge of baseline and druginduced SMN levels in disease-relevant tissues hinders efforts to optimize these treatments. METHODS. SMN mRNA and protein levels were quantified in human tissues isolated during expedited autopsies. RESULTS. SMN protein expression varied broadly among prenatal control spinal cord samples, but was restricted at relatively low levels in controls and SMA patients after 3 months of life. A 2.3-fold perinatal decrease in median SMN protein levels was not paralleled by comparable changes in SMN mRNA. In tissues isolated from nusinersen-treated SMA patients, antisense oligonucleotide (ASO) concentration and full-length (exon 7 including) SMN2 (SMN2-FL) mRNA level increases were highest in lumbar and thoracic spinal cord. An increased number of cells showed SMN immunolabeling in spinal cord of treated patients, but was not associated with an increase in whole-tissue SMN protein levels. CONCLUSIONS. A normally occurring perinatal decrease in whole-tissue SMN protein levels supports efforts to initiate SMN-inducing therapies as soon after birth as possible. Limited ASO distribution to rostral spinal and brain regions in some patients likely limits clinical response of motor units in these regions for those patients. These results have important implications for optimizing treatment of SMA patients and warrant further investigations to enhance bioavailability of intrathecally administered ASOs.

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Section: Discussionmentioning

confidence: 86%

Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment

Ramos¹,

d’Ydewalle²,

Gabbeta³

et al. 2019

Journal of Clinical Investigation

123

114

View full text Add to dashboard Cite

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“…Expansion of this repeat to hundreds or thousands of repeated segments is a recognized cause of fALS, frontotemporal dementia, and occasionally also sALS (Mis et al, 2017). The DNA encoding this repeat is transcribed bi-directionally, resulting in nuclear RNA inclusions, and is thought to promote gain of function toxicity (Ly and Miller, 2018;Staats et al, 2019). Other potential mechanisms include C9orf72 loss of function (Shi et al, 2018;Staats et al, 2019), or proteotoxicity (Gitler and Tsuiji, 2016).…”

Section: Structural Variants In Alsmentioning

confidence: 99%

“…One of the current strategies employed in the development of therapeutics for C9orf72 is to target the SV region with antisense oligonucleotides to induce transcript degradation by RNase H enzymatic cleavage, preventing the build-up of toxic C9orf72 transcript and protein. Other strategies focus on modulating the expression of transcription factors specifically involved in transcribing expanded repeats (Ly and Miller, 2018). Recently, it was shown that small ribosomal subunit protein (RPS25) plays a direct role in RAN translation, and decreasing its levels through RNA interface mediated reduction prolonged the lifespan of Drosophila with the expanded repeat (Yamada et al, 2019).…”

Section: Structural Variants In Alsmentioning

confidence: 99%

Structural Variants May Be a Source of Missing Heritability in sALS

et al. 2020

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“…Hence, repeated tests of the same mouse is feasible, which enables longitudinal studies of drug efficacy with a powerful statistical design in which individual subjects are compared to themselves over time. Therapies that target patients with mutations of the SOD1 gene have successfully completed early clinical study phases, and have prolonged survival in SOD1 related animal models 27,28 . Microendoscopy measurements in animal models given these drugs should be performed to understand the effects of the drug on motor unit distribution over time in individuals, and further validate the measurement method.…”

Section: Scientific Reports |mentioning

confidence: 99%

Microendoscopy detects altered muscular contractile dynamics in a mouse model of amyotrophic lateral sclerosis

Chen

Sanchez

Schnitzer

et al. 2020

Sci Rep

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Amyotrophic lateral sclerosis (ALS) is a fatal disease involving motor neuron degeneration. Effective diagnosis of ALS and quantitative monitoring of its progression are crucial to the success of clinical trials. Second harmonic generation (SHG) microendoscopy is an emerging technology for imaging single motor unit contractions. to assess the potential value of microendoscopy for diagnosing and tracking ALS, we monitored motor unit dynamics in a B6.SOD1G93A mouse model of ALS for several weeks. prior to overt symptoms, muscle twitch rise and relaxation time constants both increased, consistent with a loss of fast-fatigable motor units. These effects became more pronounced with disease progression, consistent with the death of fast fatigue-resistant motor units and superior survival of slow motor units. From these measurements we constructed a physiological metric that reflects the changing distributions of measured motor unit time constants and effectively diagnoses mice before symptomatic onset and tracks disease state. these results indicate that SHG microendoscopy provides a means for developing a quantitative, physiologic characterization of ALS progression.ALS is a paralytic, fatal neurodegenerative disease characterized by a progressive loss of motor neurons 1 . The first approved drug to treat ALS, riluzole, which only prolongs survival by a few months 2 , was approved over 20 years ago. Since then, over 50 clinical trials 3 have resulted in only 1 new recently approved drug 4 , edaravone, whose effect on survival has yet to be studied. Development of effective treatments has suffered from a lack of methods for early diagnosis and sensitive monitoring of the disease 5 . Patients enter clinical trials at late disease stages that may be too advanced to gain therapeutic benefit, and subtle improvements might be undetectable. Sensitive diagnostics are needed to reduce diagnostic delay so that earlier-stage patients can be identified and participate in clinical trials.To assess if a therapy is effective, it is also important to have biomarkers of disease progression. Currently, the Revised ALS Functional Rating Score (ALSFRS-R) -a numerical score from 0-48 based on assessments of bulbar, limb, and respiratory function 6 -is the predominant clinical method for measuring disease progression. This score is subjective and a sum of multiple metrics, some of which are highly correlated, making changes in the ALSFRS-R score hard to relate to changes in disease state 7 . As new candidate treatments enter clinical trials, the field needs quantitative diagnostics that reflect the neurophysiologic changes in ALS, provide accurate assessments of disease progression, and inform treatment development and usage.To meet this challenge, we examined whether second harmonic generation (SHG) microendoscopy might detect the physiological changes that occur in ALS. SHG microendoscopy is a minimally invasive approach to imaging the twitch contractions of individual motor units in live patients 8 . Myosin filaments within muscle sar-

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Emerging antisense oligonucleotide and viral therapies for amyotrophic lateral sclerosis

Abstract: Advances in preclinical and clinical studies of ASO and viral directed approaches to neuromuscular disease, particularly ALS, indicate that these approaches have high specificity and are relatively well tolerated.

Cited by 51 publications

References 53 publications

Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment

Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment

Structural Variants May Be a Source of Missing Heritability in sALS

Microendoscopy detects altered muscular contractile dynamics in a mouse model of amyotrophic lateral sclerosis

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