Nance-Horan Syndrome (NHS)

Nance-Horan Syndrome (NHS) is an X-linked dominant disorder with a prevalence that remains uncertain due to its rarity and underdiagnosis. As a leading service provider in the field of rare genetic disorders, Protheragen is focused on the development of diagnostics and therapeutics for Nance-Horan syndrome.

Overview of Nance-Horan Syndrome (NHS)

Nance-Horan Syndrome (NHS) is a rare X-linked genetic disorder characterized by a spectrum of ocular and dental anomalies, mental retardation, and unusual facial contortion. The syndrome is caused by mutations in the NHS gene located on the X chromosome Xp22.13 and was first described in 1974. The conserved NHS gene in vertebrates is expressed in the brain, retina, lens, tooth primordia, craniofacial mesenchyme, and heart. Congenital cataracts with nystagmus, microcornea, microphthalmia, glaucoma, and developmental delays with dental dysplasia in the form of screwdriver-shaped incisors, supernumerary teeth, and diastema are some of the key features of the disorder.

Fig.1 Pedigrees of three NHS families. (Guven Y., et al., 2023)

Diagnostics Development for Nance-Horan Syndrome

Molecular diagnosis of NHS is critical for the correct classification and therapeutic of the condition. As reported, Sanger sequencing is a frequently applied technique to analyse mutations of the NHS gene. This method enables the detection of point mutations, small deletions, and insertions. For example, a novel nonsense variant, c.2416 C > T; p.(Gln806), was discovered during the clinical diagnosis of a 10-year-old male cases with NHS.

Another highly sensitive technique is chromosomal microarray (CMA) which focuses on more extensive deletions or duplications of the genome containing the NHS gene. For instance, an 1.83-Mb interstitial microdeletion at Xp22.2p22.13 was detected in a 19-year-old male case with NHS which included the NHS gene along with many others. This technique is also applicable to complex genomic rearrangements which are assumed to be responsible for the demerit diversity of NHS.

Therapeutics Development for Nance-Horan Syndrome

Our Services

Protheragen develops complete therapies and diagnostics for Nance-Horan Syndrome and offers various services related to the disease. Using industry-leading technologies, our skilled scientific staff work towards understanding and finding therapeutics for this rare condition. We provide a number of services, for example:

NHS Preclinical Disease Modeling Services

Protheragen provides customized preclinical disease modeling services to generate accurate, physiologically relevant models of NHS, essential for evaluating the efficacy and safety of potential therapies. Our modeling services cover both in vitro and in vivo models, tailored to recapitulate the key phenotypic features of NHS, including congenital cataracts, retinal abnormalities, and neurodevelopmental deficits. For in vitro models, we develop patient-derived induced pluripotent stem cell (iPSC) lines harboring pathogenic NHS gene variants, which are then differentiated into ocular cell types (e.g., lens epithelial cells, retinal photoreceptors) and dental or neural cells to study disease mechanisms and test therapeutic candidates. These iPSC-derived models offer a physiologically relevant alternative to immortalized cell lines, providing insights into the human disease phenotype at the cellular level.

NHS Target Discovery and Validation Services

Protheragen offers target discovery and validation services to identify and characterize actionable therapeutic targets for NHS, focusing on the molecular mechanisms underlying the syndrome's key features. Our team uses a combination of transcriptomic, proteomic, and bioinformatics analyses to identify genes, proteins, and signaling pathways dysregulated in NHS, leveraging data from patient samples, iPSC-derived models, and animal models. For example, RNA-sequencing analyses of retinal tissue from NHS models can reveal changes in metabolic function, photoreceptor signaling, and cellular stress pathways, highlighting potential targets for intervention.

NHS Therapeutic Candidate Screening and Optimization Services

Protheragen provides high-throughput and high-content screening services to identify potential therapeutic candidates for NHS, including small molecules, gene therapies, and protein-based therapies. Our screening platforms are tailored to the specific features of NHS, with assays designed to measure key endpoints such as lens clarity, retinal cell survival, photoreceptor function, and gene expression changes. For small molecule screening, we use iPSC-derived ocular cells or zebrafish models to evaluate thousands of compounds for their ability to mitigate NHS-related phenotypes, such as reducing lens opacity or preserving retinal layer integrity.

NHS Preclinical Efficacy and Safety Evaluation Services

Protheragen conducts comprehensive preclinical efficacy and safety evaluation studies to support the advancement of NHS therapeutic candidates, ensuring they meet regulatory requirements for IND submission. Our efficacy evaluations use a multi-dimensional approach, combining structural, functional, and molecular endpoints to assess the impact of therapies on NHS-related phenotypes. Ophthalmic efficacy assessments include OCT to measure retinal layer thickness and lens opacity, ERG to evaluate photoreceptor function under photopic and scotopic conditions, and confocal microscopy to assess corneal and retinal cell structure. Neurodevelopmental efficacy is evaluated through behavioral testing, while dental efficacy is assessed via histological and imaging analyses of dental tissues.

Diagnostics Development

• Karyotype Analysis Service
• Omics Analysis Service
• Biomarker Development Service
• Artificial Intelligence Service
• Customized Diagnostics Development

Therapeutic Development

• Small Molecule Drug
• Cell Therapy
• Gene Therapy
• Therapeutic Antibody
• Therapeutic Peptide
• Therapeutic Protein
• Customized Therapy Development

Disease Models

Xcat mouse model: The model harbours a massive insertional mutation in the first intron of the Nhs1 gene which causes the expression of an alternative isoform containing exon 1A only. This model is able to reproduce some aspects of the disorder in humans, which includes congenital cataracts and the lens having a lower expression of Nhs1 protein.

Protheragen offers a suite of preclinical research services to support the development of novel therapies for NHS. Our services include:

• Bioinformatics and Data Analysis: Advanced bioinformatics tools to analyze genetic data and identify potential therapeutic targets.
• Genetic Modeling: Development of animal models carrying NHS gene mutations to study disease progression and evaluate therapeutic interventions.
• Pharmacokinetics and Toxicology Studies: Comprehensive preclinical testing to assess the safety and pharmacokinetics of potential therapeutic agents.

If you are interested in our services, please feel free to contact us.

References

• Guven, Yeliz, et al. "Nance-Horan Syndrome: characterization of dental, clinical and molecular features in three new families." BMC oral health 23.1 (2023): 314.
• Li, Huajin, et al. "A novel small deletion in the NHS gene associated with Nance-Horan syndrome." Scientific Reports 8.1 (2018): 2398.