Biology subjects

Rechtzigel, M. J.

Publications and source records attributed to Rechtzigel, M. J..

4 recordsLinked to original sources

bioRxiv2025

Therapeutic antisense oligonucleotide mitigates retinal dysfunction in a pig model of CLN3 Batten disease

CLN3 Batten disease is a lethal pediatric autosomal recessive neurodegenerative disease caused by mutations in the CLN3 gene. Typically, the disease manifests as vision loss early in life and progresses to neurological dysfunction and death in young adulthood. Therapeutic development has focused on treating the central nervous system. However, such therapies may not protect against vision loss, which has a significant impact on quality of life. We have shown that a splice-switching antisense oligonucleotide (ASO) delivered to the central nervous system can reduce neurological disease burden in mouse models of CLN3 disease. Here, we report on a similar ASO approach for treating CLN3 Batten disease retinal dysfunction in a pig model of the disease, which is more representative of human vision. A single intravitreal injection of ASO induces robust exon skipping in the retina for up to 12 months. The ASO treatment resulted in higher amplitudes on electroretinograms, suggesting mitigation of retinal dysfunction at early timepoints of disease. One ASO that efficiently induces exon skipping in vivo was well-tolerated and targets a region of CLN3 that is conserved in humans, making it a promising candidate for treating the disease in humans. Our findings demonstrate the potential utility of an ASO-based approach to treat retinal dysfunction in CLN3 Batten disease and generally supports the use of ASOs for treating eye diseases. One Sentence SummarySplice-switching antisense oligonucleotides delivered by intravitreal injection are safe and show efficacy in preventing early retinal dysfunction in a pig model of CLN3 Batten disease.

molecular biology↗

bioRxiv2024

Mutation in Wdr45 leads to early motor dysfunction and widespread aberrant axon terminals in a beta-propeller protein associated neurodegeneration (BPAN) patient-inspired mouse model

Beta-propeller Protein Associated Neurodegeneration (BPAN) is a devastating neurodevelopmental and neurodegenerative disease linked to variants in WDR45. Currently, there is no cure or disease altering treatment for this disease. This is, in part, due to a lack of insight into early phenotypes of BPAN progression and WDR45s role in establishing and maintaining neurological function. Here we generated and characterized a mouse model bearing a c52C>T BPAN patient variant in Wdr45. We show this mutation ablates WDR45 protein expression and alters autophagy in the brain. Behavioral analysis of these mice revealed characteristic signs of BPAN including cognitive impairment, hyperactivity, and motor decline. We show these behaviors coincide with widespread neuroinflammation and development of axonal spheroids in multiple neuron subclasses throughout the brain. Several lines of evidence suggest these spheroids arise from axon terminals. Transcriptomic analysis uncovered multiple disrupted pathways in the cortex including genes associated with synapses, neurites, endosomes, endoplasmic reticulum, and ferroptosis. This is supported by accumulation of the iron regulating transferrin receptor 1 (TFRC) and the endoplasmic reticulum resident calreticulin (CALR) in the cortex as these animals age. CALR forms spheroid structures similar to the axonal spheroids seen in these animals. Taken together, our data demonstrate that WDR45 is necessary for healthy brain function and maintenance of axon terminals. This model opens the door to therapeutics targeting BPAN and further exploration of the role of WDR45 in neuronal function.

neuroscience↗

bioRxiv2023

Longitudinal Deep Multi-Omics Profiling in a CLN3Δex7/8 Minipig Model Reveals Novel Biomarker Signatures for Batten Disease

Development of therapies for CLN3 Batten disease, a rare pediatric lysosomal storage disorder, has been hindered by the lack of etiological insights and translatable biomarkers to clinics. Here, we used a deep multi-omics approach to discover new biomarkers using longitudinal serum samples from a porcine model of CLN3 disease. Comprehensive metabolomics was combined with a nanoparticle-based LC-MS-based proteomic profiling coupled with TMTpro 18-plex to generate quantitative data on 769 metabolites and 2,634 proteins, collectively the most exhaustive multi-omics profile conducted on serum from a porcine model, which was previously impossible due a to lack of efficient deep serum proteome profiling technologies compatible with model organisms. The presymptomatic disease state was characterized by elevations in glycerophosphodiester species and lysosomal proteases, while later timepoints were enriched with species involved in immune cell activation and sphingolipid metabolism. Cathepsin S, Cathepsin B, glycerophosphoinositol, and glycerophosphoethanolamine captured a large portion of the genotype-correlated variation between healthy and diseased animals, suggesting that an index score based on these analytes could have great utility in the clinic.

neuroscience↗

bioRxiv2021

Transmembrane Batten disease proteins interact with a shared network of vesicle sorting proteins to regulate synaptic composition and function.

Batten disease is unique among lysosomal storage disorders for the early and profound manifestation in the central nervous system, but little is known regarding potential neuron-specific roles for the disease-associated proteins. We demonstrate substantial overlap in the protein interactomes of three transmembrane Batten proteins (CLN3, CLN6, and CLN8), and that their absence leads to synaptic depletion of key partners (i.e. SNAREs and tethers) and aberrant synaptic SNARE dynamics in vivo, demonstrating a novel shared etiology.

neuroscience↗