Mirna Therapeutics (United States)

Abstract Background: BCL-XL is a pro-survival protein that restrains pro-apoptotic proteins and protects cells from apoptotic cell death. BCL-XL inhibition promotes cell death in ovarian cancer cells treated with chemotherapy. Clinical use of BCL-XL inhibitors has been limited by thrombocytopenia due to platelet dependency on BCL-XL. DT2216 is a proteolysis targeting chimera (PROTAC) degrader of BCL-XL, comprised of a VHL E3 ubiquitin ligase ligand and an ABT-263 moiety based BCL-XL binder that targets BCL-XL to VHL for ubiquitination and proteasomal degradation. Because VHL expression is low in platelets, DT2216 causes less thrombocytopenia than BCL-XL inhibitors. A phase I safety and tolerability trial in 20 patients with solid tumors (Dialectic Therapeutics) established a recommended DT2216 dose of 0.4 mg/kg intravenously (IV) twice weekly and showed BCL-XL degradation in peripheral white blood cells. Single-agent DT2216 was well tolerated; the most common toxicity was thrombocytopenia that was typically transient and did not require cessation of DT2216. In pre-clinical models, DT2216 combined with paclitaxel showed significant growth inhibition and apoptosis induction in high-grade serous ovarian cancer in vitro and in vivo. Methods: This is a phase 1b study of twice weekly DT2216 combined with weekly paclitaxel in platinum-resistant ovarian cancer (clinicaltrials.gov NCT06964009). It is a dose-escalation study with a BOIN design and a dose level 0 of 0.32 mg/kg DT2216 (DT) IV twice weekly and 70 mg/m2 paclitaxel (Pac) IV weekly, with possible escalation to a maximum of 0.4 mg/kg DT and 80 mg/m2 Pac or de-escalation to 0.24 or 0.2 mg/kg DT and 70 mg/m2 Pac. Participants will be treated with DT2216 IV twice weekly (D1,4,8,11,15,22,25) and paclitaxel IV weekly (D1,8,15) in a 28-day cycle. Key inclusion criteria include a diagnosis of relapsed or refractory platinum-resistant epithelial ovarian cancer and four or fewer lines of prior systemic therapy. Key exclusion criteria include prior weekly paclitaxel in the recurrent setting or prior treatment with a BCL-XL inhibitor, and complications including recent surgery or bowel obstruction, clinically significant ascites or pleural effusion, and dependency upon parenteral nutrition or IV fluids. The primary endpoint is to determine the maximum tolerated dose and the recommended phase 2 dose of the combination of twice weekly DT2216 plus weekly paclitaxel. Secondary endpoints include evaluating the safety of DT2216 combined with paclitaxel based on the frequency and type of adverse events during treatment, and assessing the efficacy of DT2216 combined with paclitaxel based on overall response rate, median progression-free survival and duration of response. Translational objectives include measuring the pharmacokinetics of DT2216 and paclitaxel when given in combination; quantitating BCL-XL levels in peripheral white blood cells to measure DT2216-mediated degradation of BCL-XL; and evaluating candidate biomarkers of response to DT2216 plus paclitaxel. Approximately 30 patients are expected to enroll. Citation Format: Elizabeth H. Stover, Xingping Qin, Martin Hayes, Caroline Barabell, Su-Chun Cheng, Brendan Shay, Oyku E. Sumer, Atomu Yamaguchi, Stacy N. Suberg, Joshua Sills, Larry Tremaine, Robert Hromas, James Strauss, Michael Kurman, Joan S. Brugge, Meghan E. Shea, Daohong Zhou, Kristopher A. Sarosiek, Nabihah Tayob, Ursula A. Matulonis, Joyce F. Liu. Phase 1b trial of BCL-XL degrader DT2216 and weekly paclitaxel in recurrent platinum-resistant ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B004.

The determination of RNA secondary structure (RSS) could help understand RNA's functional mechanisms, guiding the design of RNA-based therapeutics, and advancing synthetic biology applications. However, traditional methods such as NMR for determining RSS are typically time-consuming and labor-intensive. As a result, the accurate prediction of RSS remains a fundamental yet unmet need in RNA research. Various deep learning (DL)-based methods achieved improved accuracy over thermodynamic-based methods. However, the over-parameterization nature of DL makes these methods prone to overfitting and thus limits their generalizability. Meanwhile, the inconsistency of RSS predictions between these methods further aggravated the crisis of generalizability. Here, we propose TrioFold to achieve enhanced generalizability of RSS prediction by integrating base-pairing clues learned from both thermodynamic- and DL-based methods by ensemble learning and convolutional block attention mechanism. TrioFold achieves higher accuracy in intra-family predictions and enhanced generalizability in inter-family and cross-RNA-types predictions. Additionally, we have developed an online webserver equipped with widely used RSS prediction algorithms and analysis tools, providing an accessible platform for the RNA research community. This study demonstrated new opportunities to improve generalizability for RSS predictions by efficient ensemble learning of base-pairing clues learned from both thermodynamic- and DL-based algorithms.

Respiratory syncytial virus (RSV) causes the most common type of severe lower respiratory tract infection worldwide, and the fusion (F) protein is a target for neutralizing antibodies and vaccine development. This study aimed to investigate the immunogenicity and efficacy of an mRNA-based RSV vaccine with an F protein sequence. We designed an mRNA construct encoding a modified RSV F protein, which was further developed into an LNP-encapsulated mRNA vaccine (LVRNA007). LVRNA007 was administered to mice and cotton rats, followed by immunogenicity analysis and viral challenge studies. Protection of rodents from the viral infection was evaluated based on the presence of the virus in the lung and pathological examination of respiratory tissues. LVRNA007 induced robust humoral and cellular immune responses in both mice and cotton rats, with neutralization antibody levels in the immunized animals maintained at high levels for over one year. Vaccination of LVRNA007 also protected the rodents from RSV challenge, judged by the much decreased virus titer and the pathological score in the lung tissue. In addition, no vaccine-enhanced disease (VED) phenomenon was observed with LVRNA007 vaccination. Based on the preclinical immunogenicity and efficacy data, LVRNA007 could be a potential promising vaccine for prophylaxis of RSV infection.

Abstract The transmembrane fusion (F) protein of RSV plays important roles in RSV pathogenesis as it mediates the fusion between virus and the target cell membrane. During the fusion process, F protein transits from a metastable state (prefusion, preF) to a stable state after merging of virus and cell membranes (postfusion, postF). The majority of highly neutralizing antibodies induced by natural infection or immunization targets the preF form, making it the preferred antigen for vaccine development. Here, we evaluate the mRNA vaccine candidate, STR-V003, which encapsulates the modified mRNA encoding the preF protein in lipid nanoparticles (LNPs). This vaccine demonstrated robust immunogenic in both mice and cotton rats. STR-V003 induced high levels of neutralizing antibodies and RSV preF-specific IgG antibodies, and significantly reduced the RSV viral loads in the lung and nose tissue of challenged animals. In addition, STR-V003 did not have obvious enhancement of lung pathology without causing vaccine enhanced disease (VED). The repeated dose general toxicology studies and local tolerance studies of STR-V003 were evaluated in rats. Therefore, STR-V003 has an acceptable safety profile and robust protective immunity against RSV, and has been approved by the FDA to enter phase I clinical study ( NCT06344975 ).

Rabies is a lethal disease caused by the rabies virus (RABV), which causes acute neurological infections in mammals, including human beings. We previously reported that an mRNA vaccine (LVRNA001) encoding the rabies virus’s glycoprotein induced strong protective immune responses to rabies in mice and dogs. Here, we further evaluate the safety of LVRNA001. First, we performed a confirmative efficacy study in dogs, which showed that LVRNA001 fully protected the animals from the virus, both pre- and post-infection. Moreover, using pre- and post-exposure prophylaxis murine models, we showed that LVRNA001, built from the CTN-1 strain, was able to protect against various representative RABV strains from the China I–VII clades. To evaluate the safety of the vaccine, chronic and reproductive toxicity studies were performed with cynomolgus macaques and rats, respectively. In a repeated-dose chronic toxicity study, vaccinated monkeys displayed no significant alterations in body weight, temperature, or hematological and biochemical markers. Lymphocyte subset measurement and histopathological examination showed that no toxicity was associated with the vaccine. The immunogenicity study in cynomolgus macaques demonstrated that LVRNA001 promoted the generation of neutralizing antibodies and Th1-biased immune response. Evaluation of reproductive toxicity in rats revealed that administration of LVRNA001 had no significant effects on fertility, maternal performance, reproductive processes, and postnatal outcomes. In conclusion, LVRNA001 can provide efficient protection against rabies virus infection in dogs and mice, and toxicity studies showed no significant vaccine-related adverse effects, suggesting that LVRNA001 is a promising and safe vaccine candidate for rabies prophylaxis and therapy.

Rationale: While rodent lung fibrosis models are routinely used to evaluate novel antifibrotics, these models have largely failed to predict clinical efficacy of novel drug candidates for Idiopathic Pulmonary Fibrosis (IPF). Moreover, single target therapeutic strategies for IPF have failed and current multi-target standard of care drugs are not curative. Caveolin-1 (CAV-1) is an integral membrane protein, which, via its caveolin scaffolding domain (CSD), interacts with caveolin binding domains (CBD). CAV-1 regulates homeostasis, and its expression is decreased in IPF lungs. LTI-03 is a seven amino acid peptide derived from the CSD and formulated for dry powder inhalation; it was well tolerated in normal volunteers ( NCT04233814 ) and a safety trial is underway in IPF patients ( NCT05954988 ). Objectives: Anti-fibrotic efficacy of LTI-03 and other CSD peptides has been observed in IPF lung monocultures, and rodent pulmonary, dermal, and heart fibrosis models. This study aimed to characterize progressive fibrotic activity in IPF PCLS explants and to evaluate the antifibrotic effects of LTI-03 and nintedanib in this model. Methods: First, CBD regions were identified in IPF signaling proteins using in silico analysis. Then, IPF PCLS (n=8) were characterized by COL1A1 immunostaining, multiplex immunoassays, and bulk RNA sequencing following treatment every 12hrs with LTI-03 at 0.5, 3.0, or 10 μM; nintedanib at 0.1 μM or 1 μM; or control peptide (CP) at 10 μM. Measurements and Main Results: CBDs were present in proteins implicated in IPF, including VEGFR, FGFR and PDGFR. Increased expression of profibrotic mediators indicated active fibrotic activity in IPF PCLS over five days. LTI-03 dose dependently decreased COL1A1 staining, and like nintedanib, decreased profibrotic proteins and transcripts. Unlike nintedanib, LTI-03 did not induce cellular necrosis signals. Conclusion: IPF PCLS explants demonstrate molecular activity indicative of fibrosis during 5 days in culture and LTI-03 broadly attenuated pro-fibrotic proteins and pathways, further supporting the potential therapeutic effectiveness of LTI-03 for IPF.

Abstract The Fanconi anemia (FA) and translesion synthesis (TLS) are DNA damage tolerance and repair pathways that have been found to be regulated by reversible ubiquitination in which ubiquitin-specific protease 1 (USP1) plays a key role. Numerous studies have indicated that USP1 inhibitors have therapeutic effects on tumors with homologous recombination deficiency (HRD), including mutations in BRCA1/2. Due to the emergence of resistance to PARP inhibitors in clinical applications, new strategies are needed to address this issue. Here we present LAE120, a novel, allosteric and highly potent USP1 inhibitor, displayed monotherapy potency and combination activity with PARP inhibitor in HRD cancers. LAE120 has a unique tail group distinct from all the published USP1 inhibitors and is predicted to induce a different conformational change at the USP1 allosteric site. In the biochemical assay, LAE120 strongly inhibited USP1 enzymatic activity with IC50 of 5.6 nM. LAE120 potently inhibited proliferation of BRCA-mutated MDA-MB-436 breast cancer cell (IC50:19 nM) and exhibited anti-proliferative activity in NCI-H1792 (IC50: 69 nM) and K562 (IC50: 38 nM) cell lines. In the xenograft model of MDA-MB-436 cells with BRCA mutations, LAE120 demonstrated robust single-agent tumor inhibitory activity (TGI: 88%, 10 mg/kg BID) and a favorable dose-dependent response (TGI: 106%, 25 mg/kg BID). We also observed strong tumor-inhibition efficacy of LAE120 as a single agent in the K562 xenograft model with Bcr-Abl expression (TGI: 86%, 10 mg/kg BID). Current research indicates that USP1 inhibitors exhibit synergistic activity in combination with PARP inhibitors and re-sensitizes PARP refractory tumors. Similar results have been confirmed in the xenograft model of BRCA-mutated MDA-MB-436 cells. The combination of LAE120 and Olaparib (PARP inhibitor) yielded a more robust and durable anti-tumor efficacy at low dose (TGI: 110%, LAE120, 5 mg/kg BID + Olaparib, 50 mg/kg QD). LAE120 also displayed favorable ADME properties and PK profiles. Preclinical-tox studies indicated the molecule was well tolerated without significant toxicities and hematological observations. Both in vitro and in vivo data strongly support further investigation of LAE120, whether as a single agent or in combination therapy. Citation Format: Jintao Wang, Yan Chen, Junyan Chen, Ling Jiang, Xiaofen Lin, Chaojun Cai, Minhua Zhang, Ming Li, Justin Gu. Preclinical candidate LAE120, a novel selective USP1 inhibitor shows effective anticancer and combination activity with PARP inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 670.

Abstract Current PARP inhibitors primarily target PARP1/2 and demonstrate high efficacy against tumors with deficiencies in homologous recombination repair, such as those with BRCA mutations. However, these inhibitors are also associated with significant hematological toxicities. Studies have indicated that the synthetic lethality observed with BRCA mutations is mainly driven by PARP1, while PARP2 is not essential in this context. PARP2 has been shown to be crucial for the survival of hematopoietic stem/progenitor cells in animal models. Therefore, selective inhibition of PARP1 could potentially reduce toxicity and improve therapeutic outcomes. Here we introduce LAE119, a potent and selective PARP1 inhibitor and PARP1-DNA trapper. It demonstrates more than a 1000-fold selectivity for PARP1 DNA trapping compared to PARP2. In comparison to most PARP inhibitors including AZD5305, LAE119 exhibits extremely long residence time on PARP1 in both biochemical and cellular assays. It demonstrates robust anti-proliferation activity against BRCA2−/− DLD-1 cells and MDA-MB-436 cells, with IC50 value of 0.6 nM in both cell lines. In CAL51 cells, which has a BRCA2 mutation but with low PARP1 expression level and are much less sensitive to AZD5305, LAE119 demonstrates much better activity than AZD5305, particularly when PARP1 level is increased with transgene expression. LAE119 demonstrated substantial tumor inhibition in MDA-MB-436 and Capan-1 xenograft models. LAE119 also displays favorable ADME properties and PK profiles. It has high tumor/plasma ratio which is beneficial for sustainable anti-tumor effect and reduction of off-target effects. In rat hematologic toxicity study, LAE119 at 10 mpk QD dose was well tolerated and had minimal effects on hematologic parameters. Both in vitro and in vivo data strongly support the further clinical investigation of LAE119. Citation Format: Ming Li, Yan Chen, Junyan Chen, Ling Jiang, Xiaofen Lin, Justin Gu. Preclinical characterization of LAE119, a novel PARP1 selective inhibitor and trapper [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7132.

Simple SummaryAlthough mRNA injection-based protein supplementation has emerged as a feasible strategy for treating Fabry disease, whether the administration of lipid nanoparticle-encapsulated mRNA results in the alteration of the metabolome in the in vivo system remains largely unknown. In the present study, an mRNA encoding α-Gal A was developed and exhibited efficient therapeutic effects. Moreover, metabolomics analysis revealed significant alterations in metabolites related to arachidonic acid metabolism, amino acid metabolism, and glycolysis/gluconeogenesis pathways.mRNA injection-based protein supplementation has emerged as a feasible treatment for Fabry disease. However, whether the introduction of LNP-encapsulated mRNA results in the alteration of metabolomics in an in vivo system remains largely unknown. In the present study, α-galactosidase A (α-Gal A) mRNA was generated and injected into the Fabry disease mouse model. The α-Gal A protein was successfully expressed. The level of globotriaosylsphingosine (Lyso-Gb3), a biomarker for Fabry disease, as well as pro-inflammatory cytokines such as nuclear factor kappa-B (NF-κB), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α), were greatly decreased compared to the untreated control, indicating the therapeutic outcome of the mRNA drug. Metabolomics analysis found that the level of 20 metabolites was significantly altered in the plasma of mRNA-injected mice. These compounds are primarily enriched in the arachidonic acid metabolism, alanine, aspartate and glutamate metabolism, and glycolysis/gluconeogenesis pathways. Arachidonic acid and 5-hydroxyeicosatetraenoic acid (5-HETE), both of which are important components in the eicosanoid pathway and related to inflammation response, were significantly increased in the injected mice, possibly due to the presence of lipid nanoparticles. Moreover, mRNA can effectively alter the level of metabolites in the amino acid and energy metabolic pathways that are commonly found to be suppressed in Fabry disease. Taken together, the present study demonstrated that in addition to supplementing the deficient α-Gal A protein, the mRNA-based therapeutic agent can also affect levels of metabolites that may help in the recovery of metabolic homeostasis in the full body system.