QR-1011 / ProQR - LARVOL DELTA

Major role of dolutegravir in the emergence of the S147G integrase resistance mutation. (PubMed, J Antimicrob Chemother) - "In this French study, S147G emerged principally in patients on dolutegravir regimens, in association with up to five other INSTI resistance mutations. This accumulation of mutations suggests a replicative advantage on HIV strains under dolutegravir selection pressure, suggesting that caution is required when interpreting dolutegravir resistance in the presence of such S147G resistance patterns, even in patients prescribed dolutegravir twice daily."

Journal • Human Immunodeficiency Virus • Infectious Disease • CD4

Role of Dolutegravir in the Emergence of the S147G Integrase Resistance Mutation (CROI 2024) - "While S147G RM confers high resistance to elvitegravir (EVG) in the Stanford and ANRS resistance algorithms, only STANFORD included it in the set of DTG resistance mutations...The median viral load and CD4 cell count were 5860 copies/mL (IQR 1011-24525) and 412 cells/ mm3 (228-560), respectively. The INSTI included in the ongoing treatment was DTG (n=42, 48%), EVG (n=32, 36%), raltegravir (n=9, 10%), bictegravir (n=2) and cabotegravir (n=1).Two patients were not receiving INSTI: one drug-naive patient infected with a multi-resistant virus, another had received previous INSTI regimens...In this study, the S147G mutation is mainly identified during DTG regimen failures. In such a context it can be associated with up to 6 other INSTI-RM, including T97A and/or N155H in the majority of cases. Thus the S147G mutation needs to be added to the DTG resistance profile in the ANRS algorithm."

Human Immunodeficiency Virus • Infectious Disease • CD4

QR-1011 restores defective ABCA4 splicing caused by multiple severe ABCA4 variants underlying Stargardt disease. (PubMed, Sci Rep) - "Overall, QR-1011, initially developed for a single ABCA4 variant, exhibited potent splice correction capabilities for two additional severe NCSS variants nearby. This suggests the possibility of a broader therapeutic impact of QR-1011 extending beyond its original target and highlights the potential for treating a larger population of STGD1 patients affected by multiple severe ABCA4 variants with a single AON."

Journal • Age-related Macular Degeneration • Inherited Retinal Dystrophy • Macular Degeneration • Ophthalmology • Retinal Disorders

Antisense oligonucleotide therapy corrects splicing in the common Stargardt disease type 1-causing variant ABCA4 c.5461-10T>C. (PubMed, Mol Ther Nucleic Acids) - "Furthermore, western blot and immunohistochemistry analyses identified restoration of ABCA4 protein after treatment. Collectively, we identified QR-1011 as a potent splice-correcting AON and a possible therapeutic intervention for patients harboring the severe ABCA4 c.5461-10T>C variant."

Journal • Inherited Retinal Dystrophy • Macular Degeneration • Ophthalmology • Retinal Disorders

QR-1011 corrects splicing in the Stargardt disease type 1-causing variant ABCA4 c.5461-10T>C (ARVO 2022) - "QR-1011 treatment resulted in splice correction in both midigene and organoid models. Moreover, when administered to ROs, QR-1011 restored the production of ABCA4 protein. These results show the ability of QR-1011 to correct aberrant splicing caused by the c.5461-10T>C mutation in ABCA4 and highlight its therapeutic potential for STGD1."

Inherited Retinal Dystrophy • Ophthalmology • Retinal Disorders