bims-raghud 2025-03-09 papers

Issue of 2025–03–09
two papers selected by
Irene Sambri, TIGEM

Brain. 2025 Mar 03. pii: awaf081. [Epub ahead of print]

TSC2 loss in neural progenitor cells suppresses mRNA translation of neurodevelopmental genes.

Pauline Martin, Krzysztof J Szkop, Francis Robert, Srirupa Bhattacharyya, Roberta L Beauchamp, Jacob Brenner, Nicholas E Redmond, Sidong Huang, Serkan Erdin, Ola Larsson, Vijaya Ramesh.

Tuberous sclerosis complex (TSC) is an inherited multi-system neurocutaneous disorder where patients often present with neurodevelopmental manifestations such as epilepsy and TSC-associated neuropsychiatric disorder (TAND) that includes autism spectrum disorder (ASD). TSC is caused by inactivating mutations in TSC1 or TSC2 tumor suppressor genes, with encoded proteins hamartin (TSC1) and tuberin (TSC2) forming a functional complex inhibiting mechanistic target of rapamycin complex 1 (mTORC1) signaling. This has led to treatment with allosteric mTORC1 inhibitor rapamycin analogs ("rapalogs") for TSC tumors; however, rapalogs are ineffective for treating neurodevelopmental manifestations. mTORC1 signaling controls protein synthesis by regulating formation of the eIF4F complex, with further modulation by MNK1/2 kinases via phosphorylation of the eIF4F subunit eIF4E. While both these pathways modulate translation, comparing their impact on transcriptome-wide mRNA translation, as well as effects of inhibiting these pathways in TSC has not been explored. Employing CRISPR-modified, isogenic neural progenitor cells (NPCs) derived from a female TSC2 patient, we have examined alterations in early neurodevelopmental phenotypes including proliferation and neurite outgrowth, as well as ability of bi-steric mTORC1-specific inhibitor RMC-6272 to rescue these phenotypes. Further, we utilized polysome-profiling to examine transcriptome-wide changes in mRNA translation upon TSC2 loss and tested effects of treatment with RMC-6272 or MNK1/2-specific inhibitor eFT-508. Our results reveal that altered early neurodevelopmental phenotypes can be rescued upon treatment with RMC-6272, but not rapamycin. We also discovered dysregulated mRNA translation in TSC2-Null NPCs, which significantly overlaps with the translatome from TSC1-Null NPCs. Interestingly, numerous non-monogenic ASD-, NDD- and epilepsy-associated genes identified in patients harboring putative loss-of-function mutations, were translationally suppressed in TSC2-Null NPCs. Importantly, translation of these ASD- and NDD-associated genes was reversed upon inhibition of either mTORC1 or MNK1/2 signaling using RMC-6272 or eFT-508, respectively. This study establishes the importance of mTORC1-eIF4F- and MNK-eIF4E-sensitive mRNA translation in TAND, ASD and other neurodevelopmental disorders laying the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for these disorders.

Keywords: 4E-BP1; 5’UTR; CNS; S6K1; protein synthesis; rapalogs

DOI: https://doi.org/10.1093/brain/awaf081

Nephrol Dial Transplant. 2025 Mar 07. pii: gfaf046. [Epub ahead of print]

Rationale and design of the Renal Lifecycle Trial assessing the Effect of Dapagliflozin on Cardiorenal Outcomes in Severe Chronic Kidney Disease.

Renal Lifecycle Trial Investigators

BACKGROUND: Several clinical trials have shown beneficial effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on kidney disease progression and cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD) with and without type 2 diabetes mellitus. However, some subgroups of patients with CKD have been excluded from participation in these trials, such as patients with severely impaired kidney function, patients on dialysis, and kidney transplant recipients.
METHODS: The Renal Lifecycle trial (NCT05374291) is a pragmatic, international, multicenter, investigator-initiated, randomized, placebo-controlled, clinical trial planned to enroll approximately 1500 patients with 1) an estimated glomerular filtration rate (eGFR) ≤25 ml/min/1.73m2, 2) on hemo- or peritoneal dialysis 3) a kidney transplant and an eGFR ≤45 ml/min/1.73m2, who will be randomized 1:1 to receive either dapagliflozin 10 mg once daily or matching placebo.
RESULTS: The primary endpoint is a composite of heart failure hospitalization, all-cause mortality or, for those not on dialysis, kidney failure (start of dialysis longer than 1 month, receiving a kidney transplantation or death due to kidney failure). The trial is event-driven, indicating that it will end after 468 first primary endpoint events have occurred with a power of 80% and an alpha of 0.05 to detect a 25% relative risk reduction assuming an annual 12.5% incidence of the primary outcome. The secondary endpoints include a separate analysis of the incidence of each component of the primary endpoint in the overall trial population as well as the incidence of the combined primary endpoint in each of the three subgroups of patients. Other (exploratory) endpoints are efficacy, safety, tolerability, health-related quality of life and cognition.
CONCLUSION: The Renal Lifecycle trial aims to investigate the effects of the SGLT2 inhibitor dapagliflozin compared to placebo on the incidence of kidney failure, heart failure, mortality, and safety in three subgroups of patients with advanced CKD.

Keywords: SGLT2 inhibitor; chronic kidney disease; dialysis; heart failure; kidney failure; kidney transplantation; mortality; safety

DOI: https://doi.org/10.1093/ndt/gfaf046