Advances and unmet needs in genetic, basic and clinical science in Alport syndrome: report from the 2015 International Workshop on Alport Syndrome

Abstract

Alport syndrome (AS) is a genetic disease characterized by haematuric glomerulopathy variably associated with hearing loss and anterior lenticonus. It is caused by mutations in the COL4A3, COL4A4 or COL4A5 genes encoding the α3α4α5(IV) collagen heterotrimer. AS is rare, but it accounts for >1% of patients receiving renal replacement therapy. Angiotensin-converting enzyme inhibition slows, but does not stop, the progression to renal failure; therefore, there is an urgent requirement to expand and intensify research towards discovering new therapeutic targets and new therapies. The 2015 International Workshop on Alport Syndrome targeted unmet needs in basic science, genetics and diagnosis, clinical research and current clinical care. In three intensive days, more than 100 international experts including physicians, geneticists, researchers from academia and industry, and patient representatives from all over the world participated in panel discussions and breakout groups. This report summarizes the most important priority areas including (i) understanding the crucial role of podocyte protection and regeneration, (ii) targeting mutations by new molecular techniques for new animal models and potential gene therapy, (iii) creating optimal interaction between nephrologists and geneticists for early diagnosis, (iv) establishing standards for mutation screening and databases, (v) improving widespread accessibility to current standards of clinical care, (vi) improving collaboration with the pharmaceutical/biotech industry to investigate new therapies, (vii) research in hearing loss as a huge unmet need in Alport patients and (viii) the need to evaluate the risk and benefit of novel (including 'repurposing') therapies on an international basis.

Keywords: Alport syndrome; chronic kidney disease; guidelines; hereditary kidney disease; nephroprotection.

FIGURE 1

Extract of some of the most important clinical topics discussed at the workshop. Some of the most relevant clinical aspects and unmet needs were addressed by Clifford Kashtan (clinician's view) and Sharon Lagas (patient's view): (i) the value of a new, easier classification of the AS to enable earlier diagnosis and treatment; (ii) the role of biomarkers, international registries and open access to data; (iii) possible risks (and pricing) of new therapies; (iv) combined effort of researchers, clinicians, patients and the pharmaceutical/biotech industry to find better therapies; and (v) the role of patient organizations. XLAS, X-linked Alport syndrome; ADAS, autosomal dominant Alport syndrome; TBMN, thin basement membrane nephropathy; ARAS, autosomal recessive Alport syndrome.

FIGURE 2

Poster prizes and young investigator awards of the 2015 International Workshop on Alport Syndrome.

FIGURE 3

Extract of urgent unmet needs validated in panel discussions. Some of the most relevant unmet needs were: (i) the need for a multi-target, flexible, patient-specific individual approach for lifelong therapy of AS to minimize the progress of disease; (ii) the need for a less complicated, straight forward diagnosis; (iii) the need to scientifically evaluate the outcome of treating young patients on a broad international basis; (iv) chances to spread the standard of care to developing countries; and (v) the urgent need for new therapies, as industry will make a difference in the awareness of AS as a treatable disease that requires early diagnosis.