2026-07-08 | Precision therapeutic tRNA rescue of nonsense mutation R166X in KCNJ13 to restore K+ channel function.

The KCNJ13 gene encodes the Kir7.1 protein, and mutations cause Leber's Congenital Amaurosis (LCA) and Snowflake Vitreoretinal Degeneration (SVD), leading to early-onset vision loss. One such nonsense mutation, R166X, results in nystagmus, poor night vision, and visual impairment. We examined therapeutic options for the R166X nonsense point mutation. Unlike missense genetic mutations, which can be rectified by gene augmentation and genome editing, nonsense mutations provide an opportunity to test additional readthrough therapies. Attempts to produce human induced pluripotent stem cells (hiPSCs) with the R166X mutation (CGA to TGA) were unsuccessful. This may be due to challenges in chromatin structure and folding that hinder access to the targeted loci. Therefore, we constructed an open reading frame (ORF) stably integrated HEK293T line by inserting the wild type (WT) or R166X-KCNJ13 gene using the FLP-FRT recombinase technique. While genome editing strategies did not repair the R166X mutation efficiently in this cell line, an arginine anticodon-engineered tRNA (ACE-tRNAArg.UGA) restored K+ channel expression and function. This study provides an example in precision medicine where translational readthrough strategies can rescue channel function at a mutation that is difficult to correct via genome editing.

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2026-06-25 | Programmed axon degeneration gene variants in human disease.

Programmed axon degeneration (PAD; also known as Wallerian degeneration) is a conserved pathway controlling axon breakdown following injury or metabolic stress. PAD is driven by the depletion of nicotinamide adenine dinucleotide (NAD) through loss of the pro-survival enzyme NMNAT2 and activation of the pro-degenerative NADase SARM1. Recent genetic studies have identified pathogenic variants in PAD pathway enzymes associated with severe neurodegenerative phenotypes. Pathogenic variants in NAMPT, NMNAT1, NMNAT2, and SARM1 have been identified and will be discussed in this review. NAMPT variants cause sensory and motor neuropathy with neurodevelopmental symptoms. NMNAT1 variants are well-characterized causes of Leber Congenital Amaurosis type 9, while NMNAT2 variants result in peripheral neuropathies with childhood onset. SARM1 gain-of-function variants with constitutively active NADase activity are enriched in amyotrophic lateral sclerosis patients. These findings demonstrate that maintaining proper NAD homeostasis is crucial for axon survival, and disruption through genetic variants leads to distinct neurodegenerative outcomes. Understanding these rare variants provides insight into PAD mechanisms and supports development of broad-spectrum neuroprotective therapies targeting this pathway. Current therapeutic approaches include SARM1 inhibitors in clinical trials, gene therapy, and NAD precursor supplementation, offering hope for treating multiple neurodegenerative diseases.

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2026-06-25 | Ora visual navigation course™ mobility test results in two individuals with CEP290 LCA after intravitreal injection of antisense oligonucleotide.

This study aimed to report the longitudinal Ora Visual Navigation Course (Ora VNC™) mobility test results in two individuals, with CEP290 LCA following intravitreal injections of an antisense oligonucleotide, sepofarsen. Two individuals were enrolled in the Illuminate Phase 3 trial and subsequently in the Post-Trial Access (PTA) program, undergoing Ora VNC™ across 12 visits. Subject 1 was initially randomized to the control (sham) group and switched to treatment from control group from the month 12 visit onwards. This individual passed only a few courses but demonstrated signs of enhanced spatial perception (defined by, among others, the ability to perceive objects' shapes and sizes). FST (full-field stimulus threshold) supported the light sensitivity gain in this subject. In contrast, subject 2, who received treatment since baseline visit, successfully completed mobility tests in all visits with progressive improvement, reaching lower luminance and more challenging contrast settings over time. According to the technicians' report, both subjects demonstrated an increase in perceived obstacle recognition during iterations, which may reflect improvement of mobility-based visual function outcomes. The Ora VNC™ mobility test captured mobility-based visual function gains, including subtle spatial improvements, but may lack sensitivity in individuals with extremely low vision, potentially overlooking small but patient-relevant changes.

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