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Many people with long COVID symptoms suffer from debilitating neurologic post-acute sequelae of SARS-CoV-2 infection (Neuro-PASC). Although symptoms of Neuro-PASC are widely documented, it is still unclear whether PASC symptoms impact virus-specific immune responses. Therefore, we examined T cell and antibody responses to SARS-CoV-2 Nucleocapsid protein to identify activation signatures distinguishing Neuro-PASC patients from healthy COVID convalescents. We report that Neuro-PASC patients exhibit distinct immunological signatures composed of elevated CD4 T cell responses and diminished CD8 memory T cell activation toward the C-terminal region of SARS-CoV-2 Nucleocapsid protein when examined both functionally and using TCR sequencing. CD8 T cell production of IL-6 correlated with increased plasma IL-6 levels as well as heightened severity of neurologic symptoms, including pain. Elevated plasma immunoregulatory and reduced pro-inflammatory and antiviral response signatures were evident in Neuro-PASC patients compared with COVID convalescent controls without lasting symptoms, correlating with worse neurocognitive dysfunction. We conclude that these data provide new insight into the impact of virus-specific cellular immunity on the pathogenesis of long COVID and pave the way for the rational design of predictive biomarkers and therapeutic interventions.

ATL1102 is a 2'MOE gapmer antisense oligonucleotide to the CD49d alpha subunit of VLA-4, inhibiting expression of CD49d on lymphocytes, reducing survival, activation and migration to sites of inflammation. Children with DMD have dystrophin deficient muscles susceptible to contraction induced injury, which triggers the immune system, exacerbating muscle damage. CD49d is a biomarker of disease severity in DMD, with increased numbers of high CD49d expressing T cells correlating with more severe and progressive weakess, despite corticosteroid treatment. This Phase 2 open label study assessed the safety, efficacy and pharmacokinetic profile of ATL1102 administered as 25 mg weekly by subcutaneous injection for 24 weeks in 9 non-ambulatory boys with DMD aged 10-18 years. The main objective was to assess safety and tolerability of ATL1102. Secondary objectives included the effect of ATL1102 on lymphocyte numbers in the blood, functional changes in upper limb function as assessed by Performance of Upper Limb test (PUL 2.0) and upper limb strength using MyoGrip and MyoPinch compared to baseline. Eight out of nine participants were on a stable dose of corticosteroids. ATL1102 was generally safe and well tolerated. No serious adverse events were reported. There were no participant withdrawals from the study. The most commonly reported adverse events were injection site erythema and skin discoloration. There was no statistically significant change in lymphocyte count from baseline to week 8, 12 or 24 of dosing however, the CD3+CD49d+ T lymphocytes were statistically significantly higher at week 28 compared to week 24, four weeks past the last dose (mean change 0.40x109/L 95%CI 0.05, 0.74; p = 0.030). Functional muscle strength, as measured by the PUL2.0, EK2 and Myoset grip and pinch measures, and MRI fat fraction of the forearm muscles were stable throughout the trial period. ATL1102, a novel antisense drug being developed for the treatment of inflammation that exacerbates muscle fibre damage in DMD, appears to be safe and well tolerated in non-ambulant boys with DMD. The apparent stabilisation observed on multiple muscle disease progression parameters assessed over the study duration support the continued development of ATL1102 for the treatment of DMD. Clinical Trial Registration. Australian New Zealand Clinical Trials Registry Number: ACTRN12618000970246.

[This corrects the article DOI: 10.3389/fimmu.2023.1155770.].[This corrects the article DOI: 10.3389/fimmu.2023.1155770.].

We recently demonstrated the effectiveness of blocking CD49d with anti-functional antibodies or small molecule inhibitors as a rational targeted approach to the treatment of acute leukemia in combination with chemotherapy. Antisense oligonucleotide promises to be no less specific than antibodies and inhibitors, but more interesting for pharmacokinetics and pharmacodynamics. We addressed this using the published CD49d antisense drug ATL1102. In vitro, we incubated/nucleofected the ALL cell line Kasumi-2 with ATL1102. In vivo, immunodeficient hosts were engrafted with primary ALL cells and treated with ATL1102. Changes in expression of CD49d mRNA and CD49d protein, and of cooperating gene products, including ß1 integrin and CXCR4, as well as survival in the mouse experiments were quantified. We observed dose-dependent down-regulation of CD49d mRNA and protein levels and its partner integrin ß1 cell surface protein level and, up-regulation of CXCR4 surface expression. The suppression was more pronounced after nucleofection than after incubation, where down-regulation was significant only at the higher doses. In vivo effects of ATL1102 were not sufficient to translate into \"clinical\" benefit in the leukemia model. In summary, antisense oligonucleotides are successful tools for specifically modulating gene expression but sufficient delivery to down-regulate CD49d in vivo may be difficult to achieve.

We recently demonstrated the effectiveness of blocking CD49d with anti-functional antibodies or small molecule inhibitors as a rational targeted approach to the treatment of acute leukemia in combination with chemotherapy. Antisense oligonucleotide promises to be no less specific than antibodies and inhibitors, but more interesting for pharmacokinetics and pharmacodynamics. We addressed this using the published CD49d antisense drug ATL1102. In vitro, we incubated/nucleofected the ALL cell line Kasumi-2 with ATL1102. In vivo, immunodeficient hosts were engrafted with primary ALL cells and treated with ATL1102. Changes in expression of CD49d mRNA and CD49d protein, and of cooperating gene products, including ß1 integrin and CXCR4, as well as survival in the mouse experiments were quantified. We observed dose-dependent down-regulation of CD49d mRNA and protein levels and its partner integrin ß1 cell surface protein level and, up-regulation of CXCR4 surface expression. The suppression was more pronounced after nucleofection than after incubation, where down-regulation was significant only at the higher doses. In vivo effects of ATL1102 were not sufficient to translate into \"clinical\" benefit in the leukemia model. In summary, antisense oligonucleotides are successful tools for specifically modulating gene expression but sufficient delivery to down-regulate CD49d in vivo may be difficult to achieve.

Background: VLA-4 is a disease progression biomarker in patients with Duchenne Muscular Dystrophy (DMD) including those treated with corticosteroids. ATL1102 an antisense oligonucleotide (ASO) inhibitor of human CD49d chain of adhesion molecule VLA-4 shows promising phase-2 results in non-ambulant DMD stabilizing upper limb function (PUL2.0), grip strength, and MRI muscle fat fraction, compared to worsening with corticosteroids. Methods: ASO to mouse CD49d (ISIS348574) was used in combination with a known mdx dystrophin morpholino exon-23 skipping restoration drug (PMO), dose-time chosen for low dystrophin restoration. Mdx mice were treated once weekly for 8 weeks with ASO, control mismatch oligonucleotide, saline, or PMO alone for 4 weeks, and PMO in combination with ASO or mismatch. Results: ASO+PMO demonstrated increased specific maximum force and eccentric muscle force retention in the exterior digitorum longus (EDL) muscle after 1-7 muscle eccentric contractions relative to saline. Area-under-curve force remaining after 8-10 contractions was higher for ASO+PMO versus PMO monotherapy and ASO monotherapy, PMO monotherapy versus saline, and the ASO monotherapy versus saline and mismatch. RNA-sequencing of quadriceps muscle evaluated gene expression changes, with false discovery rate (FDR) adjusted p-values up to <0.1. ASO monotherapy at FDR<0.05 showed 2 unique genes, Gm2a in immune neutrophil function and Trdn with Ryr2 muscle calcium channel function, versus mdx saline and none with MM. The lowest FDR PMO gene was another calcium channel Cacna1s, with PMO+MM FDR<0.05. ASO+PMO treatment at FDR<0.05 modulated 55 genes, 53 unique to the combination and 2* also in ASO FDR<0.06. Affected genes were involved in immune response (Btla*, Ppml1, Tnfsm13), lipolysis (Fabp4*, G0s2), fibrosis (Igfbp-7, Calu), muscle cell (Asb15) and muscle stem cell function (Adam10, Mt-Tp, Myom1). Conclusion: ASO+PMO EDL muscle function protection in mdx mice, and gene expression pathways affected, support the development of ATL1102 in combination therapy with conditionally approved morpholino dystrophin restoration drugs in DMD patients.Competing Interest StatementI have read the journal's policy and the following authors of this manuscript have the following competing interests: Employed by Percheron Therapeutics: Padhye A S and Tachas G. Patent Application (inventors): Tachas G and Houweling P J.