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Project Description

Please note that we are a research service provider, not a pharmacy or clinic, so we are unable to see patients and do not offer diagnostic and treatment services for individuals.

Alport Syndrome (AS)

Alport syndrome (AS) is a seldom-seen hereditary condition that predominantly involves the kidneys, hearing, and vision. It involves the following abnormalities: kidney failure, hearing loss, and ocular abnormalities. We at Protheragen offer full-spectrum diagnostic and therapeutic service development for Alport syndrome (AS).

Overview of Alport Syndrome (AS)

Alport Syndrome (AS) is an uncommon hereditary ailment noted for worsened chronic kidney disease, sensorineural hearing impairment, and several eye issues. It occurs mostly due to mutations in the genes that code for collagen IV proteins; in particular, COL4A5 (X-linked form), COL4A3, and COL4A4 (autosomal forms). The prevalent-to-rare ratio for forms of AS is approximately 80% to 20% for X-linked and autosomal dominant or recessive forms, respectively. Males are usually more severely affected, while females with exon-heterozygous mutations are less symptomatic or experience slower progression of the disease.

Comparison of ocular manifestations in Pierson syndrome, Alport syndrome, and normal males.

Fig. 1 Comparison of ocular manifestations in Pierson syndrome and Alport syndrome. (Gooley K., et al., 2023)

Pathogenesis of Alport Syndrome

Alport Syndrome is caused by the disturbance of the collagen IV network, which forms an important part of the structural framework of the basement membranes in the kidney, ear, and eye. Mutations in COL4A5, COL4A3, or COL4A4 cause collagen IV to be synthesized abnormally, which demolishes the architecture of the basement membrane. This disruption results in:

Kidney Disease: The progressive glomerular basement membrane (GBM) thinning, splitting and subsequent fibrosis contributes to chronic kidney disease and end-stage renal failure.
Hearing Loss: Cochlear basement membrane degeneration results in progressive sensorineural hearing loss.
Ocular Abnormalities: The abnormal transformations of the basement membranes of the lens capsule, cornea, and retina cause lenticonus, retinopathy, and macular thinning along with cataracts.

Diagnostics Development for Alport Syndrome (AS)

Genetic Diagnostics: Molecular genetics has positioned itself at the front line for diagnosing Alport syndrome, employing techniques like Whole Exome Sequencing (WES) and targeted gene panels for discovering pathogenic variants within COL4A5, COL4A3, and COL4A4 genes. One study, for example, described a milder variant of Pierson syndrome, which has some overlapping ocular features with Alport syndrome. The study also described a homozygous missense variant (p.Arg1719Cys) in LAMB2, which was also detected through WES, underlining the significance of extensive genetic tests in the dispute of diagnosing such syndromes.
Ophthalmological Examination: Ophthalmological examinations are fundamental for the assessment of Alport Syndrome. The identification of changes involving the retina, lens, and cornea structures can be performed using Optical Coherence Tomography (OCT) as well as slit lamp examination.

Therapeutics Development for Alport Syndrome (AS)

Gene Therapy

Certain procedures like exon-skipping therapy are tried for X-linked Alport Syndrome associated with truncating COL4A5 mutations. Research is ongoing to develop gene therapies that can correct the underlying genetic mutations, thereby restoring normal collagen IV production and improving basement membrane integrity.

Cell-Based Therapies

Research is underway regarding cell-based therapies to repair damaged kidney tissue. The transplantation of stem cells may be able to improve renal function and restore the glomerular basement membrane. Starting with animal models, preclinical research has shown considerable promise, readying the path for human trials.

Small Molecule Drugs

The development of small molecule drugs which target specific pathways involved in the pathogenesis of Alport Syndrome are at various stages. An example of this is the ongoing research of TGF-β signaling inhibitors aimed at reducing inflammation and fibrosis in the kidneys. These compounds hope to slow down the progression of the disease and enhance the quality of life.

Our Services

Protheragen's diagnostic services include genetic testing using state-of-the-art NGS technology, ocular examination, and hearing evaluation. Our therapeutic development services encompass gene therapy, small-molecule drug therapies, and cell therapy, with a focus on preclinical research and development.

Diagnostics Development

Therapeutic Development

Preclinical Research

Disease Models

COL4A3 Knockout Mouse Models
COL4A5 Knockout Mouse Models
COL4A4 Knockout Mouse Models
COL4A5 Knockout Rat Models

Recognizing that each research program is unique, Protheragen provides customized services to meet specific client needs. Our flexibility and expertise allow us to adapt our protocols and methodologies to address the particular challenges and objectives of any Alport Syndrome research project. If you are interested in our services, please feel free to contact us.

References

Gooley, Kieran, et al. "A comparison of the ocular features in Pierson and Alport syndrome: a case report and literature review." Ophthalmic Genetics 44.5 (2023): 417-422.
Ramakrishnan, Rahul, Atira Shenoy, and Damon Meyer. "Ocular manifestations and potential treatments of Alport syndrome: a systematic review." Journal of Ophthalmology 2022.1 (2022): 9250367.