SL-101 / Menarini - LARVOL DELTA

Engineered Cardioskeletal-Directed AAV Capsids That Detarget the Liver (ASGCT 2024) - "Among them, AAV-SLB101 has a 2-4x increase in muscle transduction and ~0.5x decrease in liver tropism in comparison to AAV9 in mice, both DMDmdx and wild type, and non-human primates. This capsid is being used in Solid Biosciences' SGT-003 program for the treatment of DMD that recently had an IND cleared by the US FDA...Through the combination of liver detargeting and muscle targeting modifications in wild type capsids the resulting capsids maintained or improved cardiac and musculoskeletal transduction while detargeting the liver. These precisely engineered capsids could lead to gene therapy vectors with high efficiency, efficacy, and safety profiles for treating cardiac and musculoskeletal indications, which require a systemic delivery approach."

Gene Therapies • Hepatology • Liver Failure • Musculoskeletal Diseases

Novel Mechanism to Increase rAAV Yield through Blocking rAAV Transduction of the Manufacturing Hek293 Cells During rAAV Production (ASGCT 2024) - "Increased yield through transduction inhibition by Compound A has been extensively studied with rAAV-SLB101 (a novel capsid with AAV9 backbone) production; moreover, a similar effect has also been observed during rAAV rh74 manufacture...Addition of endocytosis inhibitors limits this transduction and consequently improves rAAV yield and quality via this previously unreported mechanism. Studies are underway to better understand how broadly applicable this novel finding may be across various rAAV manufacturing processes and platforms."

Gene Therapies

Systemic Delivery of SGT-003 Microdystrophin Gene Therapy Using the Novel Capsid AAV-SLB101 Ameliorates Muscle Pathology and Rescues Muscle Function in the mdx Mouse Model of Duchenne Muscular Dystrophy (ASGCT 2024) - "Improvements in muscle pathology were also observed in response to microdystrophin expression. Overall, these data provided proof of concept for the use of SGT-003 in the treatment of DMD and supported initiation of a Phase I/II clinical study in boys with DMD."

Gene therapy • Preclinical • Cardiovascular • CNS Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Novel AAV Capsid Identification and Characterization for Neuromuscular and Cardiac Indications (ASGCT 2023) - "Previously, we have described AAV-SLB101, a novel AAV capsid that Solid is using in its SGT-003 pipeline program for DMD after observing a 2-4x increase in muscle transduction and ~0.5x decrease in liver tropism in comparison to AAV9 in mice (DMDmdx and wild type) and non-human primates. This is one example of advances in AAV capsid engineering and the possibility to change the course of AAV-based gene therapy for numerous neuromuscular and cardiac diseases, maintaining high transduction of target tissues at potentially lower doses while decreasing likelihood of safety events."

Ataxia • Duchenne Muscular Dystrophy • Friedreich ataxia • Gene Therapies • Genetic Disorders • Heart Failure • Movement Disorders • Muscular Dystrophy

Ribosomal S6 kinase regulates the timing and entrainment of the mammalian circadian clock located in the suprachiasmatic nucleus. (PubMed, Neuroscience) - "To test for RSK functionality following light treatment, animals received an intraventricular infusion of the selective RSK inhibitor, SL0101, 30 min prior to light (100 lux) exposure during the early circadian night (circadian time 15)...Suppression of RSK signaling led to a significant lengthening of the circadian period (∼ 40 min), relative to vehicle-treated slices. Together, these data reveal that RSK functions as a signaling intermediate that regulates light-evoked clock entrainment and the inherent time keeping properties of the SCN."

Journal • PER1

Identifying requirements for RSK2 specific inhibitors. (PubMed, J Enzyme Inhib Med Chem) - "An analogue with an n-propyl-carbamate at the 4" position on the rhamnose moiety was identified that forms a highly stable inhibitor complex with RSK2 but not with RSK1. These results identify a SL0101 modification that will aid the identification of RSK2 specific inhibitors."

Journal • RPS6KA3

[VIRTUAL] Continued In Vitro and In Vivo Characterization of Novel AAV Vectors Engineered for Muscle Gene Delivery (ASGCT 2021) - "Additional in vitro assays were also performed to understand transduction increases observed with AAV-SLB101 over AAV9. More information on the capacity and specificity of engineered rAAVs in DMD muscle and other related cells will enhance our understanding of muscle tropism of these novel capsids, and ultimately may lead to the design of more efficacious muscle-tropic vectors."

Preclinical • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Muscular Dystrophy

Regioselective Synthesis of a C-4'' Carbamate,C-6'' n-Pr Substituted Cyclitol Analogue of SL0101. (PubMed, Org Lett) - "The route relies upon the use of the Taylor catalyst to regioselectively install C-3″ acetyl or carbamate functionality. This study led to the identification of a third-generation analogue of SL0101 with a C-4″ n-Pr-carbamate and a C-3″ acetate with improved RSK inhibitory activity."

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Divergent off-target effects of RSK N-terminal and C-terminal kinase inhibitors in cardiac myocytes. (PubMed, Cell Signal) - "Inhibition of β-adrenoceptors by atenolol or cAMP-dependent protein kinase (PKA) by H89 prevented the D1870-mediated increase in PLN phosphorylation, suggesting that PKA is the kinase responsible for the observed phosphorylation. The data reveal enhanced cardiac protein phosphorylation by D1870 and SL0101 that was not detectable in response to FMK. This disparate effect might be attributed to off-target inhibition of PDEs with impact on muscle function as demonstrated for D1870."

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Cellular Signaling Analysis shows antiviral, ribavirin-mediated ribosomal signaling modulation. (PubMed, Antiviral Res) - "We go on to show that the S6 kinase inhibitor SL0101 blocks HSV-1 replication in vitro and in an in vivo animal model of HSV-1 infection. Overall, we have used an unbiased analysis of cellular signaling pathways during treatment by antiviral drug combinations to discover a novel antiviral drug target against HSV-1 infection. The outcomes of the approach we present highlight the importance of analyzing how antiviral drugs modulate cellular and pathogen-induced signaling as a method to discover new drug therapy targets."

Journal • Herpes Simplex

"$SLDB Novel Capsid AAV-SLB101 #ASGCT20" (@MauriceOnTW)

The affinity of RSK for cylitol analogues of SL0101 is critically dependent on the B-ring C-4'-hydroxy. (PubMed, Chem Commun (Camb)) - "The series of analogues were evaluated for their ability to inhibit p90 ribosomal S6 kinase (RSK) activity. The study demonstrated the importance of the B-ring C-4' hydroxy group for RSK1/2 inhibition."

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Whole-Genome Sequencing-Based Characterization of 100 Listeria monocytogenes Isolates Collected from Food Processing Environments over a Four-Year Period. (PubMed, mSphere) - "The predominant L. monocytogenes sublineages (SLs) identified were SL101 (21%), SL9 (17%), SL121 (12%), and SL5 (12%)...It has also facilitated the identification of those isolates with genes conferring tolerance to commercially used biocides. Findings from this study highlight the potential for the application of WGS as a proactive tool to support food safety controls as applied to L. monocytogenes."

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Involvement of RSK1 activation in malformin-enhanced cellular fibrinolytic activity. (PubMed, Sci Rep) - "SL0101, an inhibitor of RSK, inhibited MA-induced fibrinolytic activity, and CRISPR/Cas9-mediated knockout of RSK1 but not RSK2 suppressed MA-enhanced fibrinolysis in U937 cells...PD98059, an inhibitor of MEK1/2, inhibited MA-induced phosphorylation of RSK1 and ERK1/2, indicating that MA induces the activation of the MEK-ERK-RSK pathway...These inductions were abrogated in RSK1 knockout cells. These results indicate that RSK1 is a key regulator of MA-induced extracellular fibrinolytic activity."

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