Update on Alport Syndrome: The Report of the 2024 International Workshop on Alport Syndrome

Abstract

The 2024 International Workshop on Alport syndrome brought together people living with Alport Syndrome, clinicians, laboratory scientists, and representatives of pharmaceutical companies to present recent data and discuss issues to advance understanding of this inherited condition. The workshop focused on diagnosis and management of Alport syndrome, with particular attention on genetic variant curation, and treatment strategies across the diverse spectrum of Alport syndrome phenotypes, from hematuria to early kidney failure, with or without hearing loss and eye abnormalities. Advances in genetic testing, especially for non-European populations, were discussed alongside challenges in variant interpretation and misclassification. Novel treatment approaches, including gene therapy, and ongoing trials of medications such as sodium-glucose cotransporter 2 inhibitors and endothelin receptor antagonists, offer hope for prolonging kidney function. Collaboration between high- and low-to-middle-income countries was highlighted, addressing disparities in diagnostic capabilities. In addition, the role of patient advocacy and the need for education in nephrology were emphasized. With ongoing research, Alport syndrome is moving closer to being not only actionable but highly treatable through the prevention of kidney failure.

Introduction

Alport syndrome represents a clinically heterogeneous group of kidney, hearing, and eye phenotypes caused by variants in the collagen IV genes, COL4A3, COL4A4, and COL4A5. Pathogenic variants disrupt the formation of the collagen α3α4α5(IV) heterotrimer that forms an essential part of the glomerular basement membrane (GBM) resulting in a variable clinical phenotype ranging from nonvisible hematuria to proteinuria, and chronic kidney disease (CKD), progressing to kidney failure in those with the most severe forms of the disease. Alport syndrome may also affect the ears, causing bilateral sensorineural hearing loss, and eyes, where anterior lenticonus and perimacular flecks may be manifested.

Since 2014, 8 international workshops on Alport syndrome have taken place because of the concerted efforts of patient groups, bringing together a global group of physicians, geneticists, and scientists from across clinical medicine, academia, and the pharmaceutical industry.1, 2, 3 This 10-year endeavor has mobilized a highly active Alport syndrome community; motivated the enrolment of patients living with the syndrome in registries and biobanks; seen increased awareness of the syndrome among nonspecialists; driven focus on new and old treatments; addressed issues of testing, including variant annotation; widened access to next generation sequencing modalities; and supported basic science research into the structure and function of the GBM using disease models.

The 2024 International Workshop was held in Nicosia, Cyprus from March 14 to 16 and focused on goals for the next 10 years of the community in the following 3 areas of (Figure 1):

• 1.Diagnosis, disease naming, and genetic variant curation
• 2.Building and maintaining basement membranes
• 3.Management, clinical journeys and treatment.

Figure 1.

Priorities and predictions for the next decade in the Alport syndrome community.

Diagnosis, Disease Naming, and Genetic Variant Curation

Alport syndrome has both diverse inheritance patterns and clinical phenotypes (Table 1)⁴ ranging from isolated hematuria,^5,6 and adult onset focal segmental glomerulosclerosis (FSGS)7, 8, 9 to the classic phenotype of kidney failure and deafness reported by Cecil Alport in 1927.¹⁰

Table 1.

The diverse spectrum of Alport syndrome and collagen-associated nephropathies

Inheritance	Prevalence	Gene affected	Collagen (IV) chain–affected	Number of pathogenic variants	Sex	Possible clinical features
X-linked	∼ 2/3 of cases are heterozygous females Affected males a∼ 1 in 5000	COL4A5	ɑ5	1	Men	Hematuria & proteinuria, progressing to kidney failure. Hearing loss. Lenticonus, fleck maculopathy
					Women	Hematuria & proteinuria, potential for loss of eGFR and kidney failure (usually late). Fleck retinopathy
Autosomal recessive	Rarer	COL4A3	ɑ3	2 in a single gene Requires 2 variants in trans (not in cis)	Men & Women	Hematuria and proteinuria progressing to kidney failure, hearing loss, lenticonus, fleck retinopathy
		COL4A4	ɑ4
Digenic		Any 2 of COL4A3-5	ɑ5, ɑ3, ɑ4	2 in different genes	Men & Women	Likely intermediate phenotype
Autosomal dominant	Disease associated variants in 1: 1004	COL4A3 or COL4A4	ɑ3 or ɑ4	1	Men & Women	Hematuria, TBMN is the most common finding on biopsy but FSGS also reported, 5%–20% progress to kidney failure, rarely hearing loss, no eye abnormalities

eGFR, estimated glomerular filtration rate; FSGS, focal segmental glomerulosclerosis; TBMN, thin basement membrane nephropathy.

After Judy Savige IPNA Calgary 2022 & Alport Workshop 2024

Increased understanding and awareness of the role of genetic diseases in CKD are likely to lead to a significant increase in genetic testing in both specific phenotypes and in those with CKD of uncertain cause.^11,12 COL4A3-5 variants are likely to be uncovered by this testing in significant numbers,¹¹ suggesting that there is an urgent need to increase understanding of pathogenic variants, relevant phenotypes and the interplay between the 2.

Phenotypic Variability in Individuals With Variants in Collagen IV Genes

Evidence suggests that heterozygous rare, pathogenic, or likely pathogenic variants in COL4A3 or COL4A4¹³ are much more common in the population than are variants associated with other monogenic causes of hematuria or proteinuria. When the Genome Aggregation Database, gnomAD, is examined for known and likely pathogenic variants, heterozygous pathogenic variants in COL4A3/4 occur in up to 1 in 106 individuals, a frequency much higher than that of likely pathogenic variants in genes implicated in other forms of hematuria or proteinuria, such as COL4A5, COL4A1, MYH9, and others associated with podocytopathies and FSGS.⁴ However, it is clear that only a minority of those who carry heterozygous pathogenic variants in COL4A3 or COL4A4 develop serious renal disease.

In this environment, single variant curation remains an obstacle, with misclassification being a major challenge. Roser Torra described how cohorts with CKD of unknown cause who are retrospectively sequenced, and (likely) pathogenic COL4A3-5 variants reported, are enriched for those with kidney disease, so do not allow unbiased assessment of disease risk associated with such variants.¹⁴ Biopsy tissue from patients with (likely) pathogenic COL4A3-5 variants (who may be diagnosed with autosomal dominant Alport syndrome)¹³ frequently shows FSGS, mesangial expansion, thinned GBM, or no glomerular abnormality, contrasting with X-linked and autosomal recessive Alport syndrome, which typically show foam cells and characteristic GBM abnormalities on electron microscopy.¹⁵

Dr Torra reported unpublished observations that at all estimated glomerular filtration rate stages of CKD, patients with X-linked Alport syndrome have significantly greater proteinuria than those with autosomal dominant Alport syndrome; she presented examples demonstrating profound phenotypic variability in those with autosomal dominant Alport syndrome. She concluded that regardless of this, heterozygous pathogenic variants in COL4A3 and COL4A4 are a risk factor for CKD and should motivate nephrological follow-up. An advantage of the term autosomal dominant Alport syndrome over “Alport carrier” is that it may facilitate patients' access to specialists.

Improving Genetic Diagnosis

The ClinGen variant curation project for Alport genes, which was summarized at the workshop by Mary-Beth Roberts, aims to improve the current criteria for variant classification in the Alport genes using the best evidence available and following medical genetic guidelines (https://clinicalgenome.org/affiliation/50146/). In addition, this project seeks to define the types and characteristic clinical features of Alport syndrome and how often each clinical feature is found with each genetic type. A “minimal state of disease” of microhematuria has been agreed upon, and the findings from this variant curation group will be published in due course.

Medical genetics societies such as the American College of Medical Genetics and Genomics have recommendations on how to categorize rare variants into benign and pathogenic¹⁶; however, many detected variants are categorized as “variants of uncertain significance,” particularly missense variants. Pathogenic and likely pathogenic variants are currently best defined in Europeans, with variants of uncertain significance more common in those of mixed race or who are non-European. This may pose problems for genetic counselling.

Heterozygous females with pathogenic COL4A5 variants follow variable clinical courses. This has been presumed to be at least partly because of unequal inactivation of the X-chromosomes with and without the pathogenic variant¹⁷; however, this and other factors, including the likely coinheritance of genetic modifiers that could predict progression¹⁸ remain unclear, so all patients should be followed-up with.³ Work in polygenic risk scores may become relevant in this population and in individuals heterozygous for COL4A3 and COL4A4 variants, because these patients also follow a variable clinical course.¹⁹

Challenges in Genetic Testing in Alport Syndrome

Another challenge is patients who have persistent hematuria but in whom COL4A3-5 testing is negative. At least 10% of pathogenic variants in patients diagnosed with Alport syndrome are not detected by whole exome sequencing. Many of these, possibly 90%, result from deep intronic variants that are identified with RNA sequencing (from a urinary podocyte pellet) and minigene assays,20, 21, 22 and work in this area was presented at the Workshop by Guillaume Dorval. Data was presented in which a common variant rs11898094 (minor allele frequency 13%) predicted to cause COL4A4 exon 27 skipping, is associated with hematuria and/or albuminuria in the UK Biobank, Geisinger and in a CKD Gen meta-analysis.²³ Because these variants are not located in the protein coding region of the gene, they are not readily amenable to predicted classification.

Functional approaches to investigate the impact of intronic variants on the encoded mRNA using urine specimens and RT-PCR/minigene assay/targeted RNA sequencing are available but are currently used only in research laboratories.²⁴ Considering existing challenges in evaluating variants of uncertain significance, an alternative approach might be to pursue family studies involving healthy and affected family members and performing cascade testing and segregation analysis. Such a strategy might enhance or annul the likely pathogenicity of certain variants.

The Workshop acknowledged that genetic kidney disease is understudied in non-Caucasian populations, including those in Asia. Steps to redress this were reported from Singapore, a multiethnic city state, and a center for collaboration with neighboring countries of lower income such as the Philippines, Myanmar, Vietnam, and Cambodia. Alport syndrome can be diagnosed using electron microscopy in only a small proportion of patients (because of technique availability) in many of these countries. Genetic testing is increasingly used; but is still not widely accessible.

The DRAGoN study examined children with steroid-resistant nephrotic syndrome in Asian countries and found a high rate of genetic diagnoses (> 60%) in children even with subnephrotic proteinuria but with a family history of renal disease or extrarenal manifestations. One-third of this cohort had a pathogenic variant in an Alport gene.²⁵ Furthermore, results from large scale whole genome sequencing study in Singapore²⁶ has demonstrated that pathogenic Alport variants are more common in Chinese than in Malays in the Singapore population, further suggesting the importance of inclusive investigation across diverse populations.²⁷

Individuals and families with phenotypes suggestive of Alport syndrome but who carried variants in genes other than COL4A3-5 were discussed. Recent work has identified prolyl 3-hydroxylase 2 (P3H2), which is involved in collagen chain assembly, stability and cross-linking, as a regulator of GBM homeostasis. In experimental animals, loss of P3H2 resulted in thin GBMs and development of nonvisible hematuria and albuminuria at the age of 36 weeks.²⁸ Three kindreds with homozygous truncating variants in P3H2 were studied; 1 had nephrotic syndrome and FSGS, 1 had microhematuria, and 1 showed both microhematuria and microalbuminuria. These data suggest that P3H2 variants may be relevant in patients with phenotypes similar to Alport syndrome, either as a phenocopy or as a genetic modifier in patients who have COL4A3–5 variants. Furthermore, pathogenic variants in LAMB2, which encodes laminin β2, a major noncollagenous component of the GBM, cause Pierson syndrome or isolated nephropathy.²⁹ Awareness of phenocopies is important for clinical practice because it may require broader genetic testing aside from just targeted sequencing of the collagen genes if a molecular diagnosis is necessary.

Constantinos Deltas presented unpublished data regarding the presence of renal cysts in patients heterozygous for COL4A3/A4 pathogenic variants, an observation that was previously reported by several groups.^9,30 He reported on a Cypriot patient with hematuria and a pathogenic variant in the COL4A3 gene, who had bilateral renal cysts, suggesting polycystic kidney disease. He was found heterozygous for ALG8:c.1090C>T (p.Arg364Ter). Variants in the ALG8 gene are known to cause polycystic liver disease, with or without renal cysts. Considering the high frequency of heterozygous COL4A mutations in the general population, it is not surprising that occasionally, there are patients with digenic inheritance.

Building and Maintaining Basement Membranes

Distinct heterotrimeric forms of type IV collagen occur in mammalian GBMs. α1α1α2(IV) is seen predominantly in developing GBM, before being mostly replaced by an α3α4α5(IV) network, which accounts for > 70% of the mass of the mature GBM.³¹ A thin layer of collagen α1α1α2(IV) remains at the endothelial aspect of the GBM at maturity.

Basic Science to Aid Clinical Diagnosis

Work of diagnostic relevance was presented by Jeffrey Miner. His group has developed a technique to quantitatively assess GBM collagen α5(IV) and α1/2(IV) in paraffin sections of kidney biopsies. Intensity and thickness ratios of the α5 and α1/2 components of GBM showed significant reduction in biopsy tissue from patients with FSGS carrying pathogenic or likely pathogenic Alport syndrome gene variants.³² As a result, measurements of relative α5 and α1/2 components in GBM using this technique may serve both to identify patients who may benefit from genetic testing, and investigate the pathogenicity of variants of uncertain significance.

Improving Understanding of Pathophysiology

Our understanding of the biological functions and properties of all type IV collagen chains and their roles in basement membrane formation is limited but growing; such knowledge is likely key to further development of targeted therapies for Alport syndrome. In this regard, study of diverse animal species has recently provided new insights into the role of type IV collagen chains in the GBM. Work from the laboratory of Billy Hudson presented at the meeting used in silico analysis to pinpoint the evolutionary emergence of the COL4A3, COL4A4, COL4A5, and COL4A6 genes.³³ Subsequent comparative analysis across organisms demonstrated that GBM morphology evolved from a thick and disordered extracellular matrix in hagfish and shark, to a uniform and compact matrix in bony fish and mammals, suggesting that the evolution of the collagen α3α4α5(IV) heterotrimer scaffold underlies the formation of a compact GBM able to act as the kidney ultrafilter.³¹

In the kidney, the podocytes and the vascular endothelium synthesize separate basement membranes that fuse to form the GBM. Thickening and splitting or layering of the GBM is a cardinal sign of Alport syndrome, suggesting a role for α3α4α5(IV) in maintaining GBM integrity, and illustrating the importance of understanding what underlies stable linkages between adjacent basement membranes. Caenorhabditis elegans has proven particularly tractable for studying GBM linkage and its interaction with collagen. David Sherwood showed how use of C elegans may help elucidate the network of distinct matrix proteins required to form a functioning GBM,³⁴ and flag potentially druggable targets.

The importance of turnover and maturation in the GBM was discussed and may be important for future targeted therapies. Maturing organisms show decreased solubility of basement membrane fractions and increased abundance of proteins necessary for GBM integrity,³⁵ suggesting slower turnover, which may imply less potential for successful protein replacement by gene therapy in older individuals. Use of kidney organoids has demonstrated similar findings and abnormal GBM maturation in the presence of a pathogenic α5(IV) chain variant associated with Alport syndrome, suggesting organoids may be useful for designing and evaluating future therapies in vivo.³⁶ Brian Stramer talked about measuring basement membrane turnover in Drosophila by imaging fluorescent tags fused to collagen IV and other matrix proteins.³⁷ Basement membrane components are highly conserved and it is therefore possible to study turnover in Drosophila to gain insights into GBM assembly in the kidney.

Lessons Learned From Other Collagen Genes

Lessons from disorders arising from distinct type IV collagens were considered at the meeting. Douglas Gould presented his work on pathogenic variants in COL4A1 and COL4A2. This work has shown the importance of interaction between gene variants and mouse genetic background, with the same pathogenic variants on different genetic backgrounds resulting in diverse clinical and laboratory phenotypes. Conversely, different pathogenic variants on the same genetic background may show similar phenotypes, thus suggesting domain specific, subdomain specific, position specific, and allele-specific effects of genetic variants.³⁸ This seems highly relevant to Alport syndrome, because the presentation of the disease often varies greatly from patient to patient, even if they carry the same initiating variant in a COL4A gene.

Hearing problems in Alport syndrome were widely acknowledged by the workshop to be understudied, largely because of the inaccessibility of inner ear structures both in life and in postmortem samples. Dan Jagger, from the UCL Ear Institute, summarized what is currently known. At a macroscopic level, a characteristic "zone of separation" is seen between the basilar membrane and overlying cells of the organ of Corti, likely altering cochlear micromechanics to cause sensorineural hearing loss.³⁹ At a molecular level, α3(IV) and α5(IV) collagen are absent from basement membranes on immunostaining.⁴⁰ Increased understanding of the mechanisms underlying hearing loss in Alport syndrome remains an unmet research need.

Clinical Considerations

The patient journey has always been a central focus of the Alport workshops. Particular attention was paid to reducing unwarranted variation in patient management through guidelines, and considering those with Alport syndrome previously underrepresented in the conversation, such as those from low- and middle-income countries and pregnant women.

The importance of patient advocacy groups was stressed by Hannah Russell who spoke on behalf of Alport UK (http://www.alportuk.org/) about the challenges that the disease poses to patients every day. Specific challenges discussed were the burden of diagnosis and possible mental health problems due to symptoms such as kidney failure or deafness, which often occur at the most difficult and unstable times of life such as the transition from adolescence to adulthood. She showed all the activities by which Alport UK responds to patients and their families (Email or telephone availability, young adult groups, constant presence of the ALPORT UK team alongside patients). Further details of which can be viewed at http://www.alportuk.org/support-alport.

Heidi Zealey, the current Alport syndrome patient representative within European Rare Kidney Disease Network (ERKnet) (ePAG), introduced the “Patient Journey” dedicated to Alport syndrome. Patient journeys are an ERKnet initiative for patients, and represent the journey through diagnosis, treatment, and monitoring of various rare kidney diseases. These educational tools are created by the ePAG and reviewed by medical experts who are members of ERKNet. Because they are created by patients and formulated from a patient's point of view, they can help health care providers to address the specific needs of patients throughout the disease journey. The draft of this document was presented in Cyprus for the first time and is currently under revision (https://www.erknet.org/patients/your-kidney-disease/patient-journeys).

There was a prevalent feeling, at the workshop, of a need to move beyond diagnosis and management being focused in high income countries with recognized preexisting experts. Dr Kar Hui Ng described difficulties in diagnosis in low- and middle-income countries, where sometimes even dipstick urinalysis is unavailable. Electron microscopic study of kidney biopsies and genetic testing are rarely possible, and therefore Alport syndrome is probably underdiagnosed in these countries. In contrast, Dr. Ng and colleagues in Singapore have commenced a program of weekly meetings with different Asian low- and middle-income countries to discuss clinical cases, and teams in Singapore are offering clinical and laboratory support for genetic testing.

Several presentations addressed another group previously understudied in Alport syndrome—pregnant women. Magriet Gosselink presented evidence from 192 pregnancies in 116 women with mild disease entering pregnancy.⁴¹ Autosomal recessive Alport syndrome (12 of the pregnancies in this study) was an independent predictor for both reduced gestational age and low birth weight even in the “mild CKD” group; however, pregnancy did not seem to alter maternal estimated glomerular filtration rate slope. This group seemed more likely to develop nephrotic-range proteinuria, as previously reported. Women with either X-linked Alport syndrome or heterozygous autosomal variants had much better overall outcomes.

The Treatment Landscape in Alport syndrome

Notwithstanding these unmet needs, it is an exciting period for the treatment of Alport syndrome. Evidence now exists for treatment using existing medications, and this has been consolidated in formal guidance, for example by ERKNet (https://www.erknet.org/guidelines-pathways). These documents have examined previous guidelines and, in some cases endorsed their recommendations but incorporate new evidence. The 2024 guideline on behalf of ERKNet, ERA, and ESPN has recently been published.⁴²

Studies of Existing Medicines

Beyond standard of care with early angiotensin-converting enzyme inhibition, Alport syndrome is now seen as a disease in which clinical trials are feasible and able to deliver answers to important questions about treatment. Many sessions, talks, and posters at the Workshop explored ongoing trials of new and existing therapies, and the development of novel treatment approaches. A summary of ongoing and completed but unpublished trials in Alport syndrome is presented in Table 2.

Table 2.

Ongoing clinical trials in Alport syndrome involving existing treatments, novel agents and gene therapy

Trials of existing medicines
Name & ID	Design	Primary Outcome
DOUBLE PROTECT Alport Study (NCT05944016)	Multicenter randomized placebo-controlled trial of dapagliflozin in Alport syndrome for: adolescents aged ≥ 10 to < 18 yrs with albuminuria (uACR ≥ 300 mg/g creatinine) & eGFR ≥ 30 ml/min per 1.73 m2 OR Adults aged ≥ 18 to < 40 yrs with albuminuria (uACR ≥ 500mg/g creatinine) & eGFR ≥ 60 ml/min per 1.73 m2	Change from baseline uACR at 48 wks
Treatment with Metformin in Chinese Children with Alport syndrome (NCT05655728)	Single-center randomized placebo-controlled trial of metformin in Alport syndrome for children aged > 10 yrs with uACR > 30 mg/g, eGFR > 45 ml/min per 1.73 m2 and on maximum tolerated dose of renin-angiotensin-aldosterone blockade	Change in albuminuria and eGFR slope over 24 mos
FIONA (NCT05196035)	Multicenter randomized placebo controlled double blind trial of finerenone for children aged > 6 mos and < 18 yrs old with CKD and proteinuria	Proportion of participants achieving a > 30% reduction in uPCR after 6 mos
EPPIK (NCT05003986)	A phase 2, open-label, single-arm, cohort study of sparsentan in 27 patients with Alport syndrome and IgA nephropathy aged > 2 yrs and < 18 yrs and with uPCR > 0.6 g/g	Change from baseline uPCR at 6 months
AFFINITY (NCT04573920)	A phase 2 open-label to evaluate the efficacy and safety of atrasentan in patients with proteinuric glomerular disease across various indications, including Alport syndrome, IgA nephropathy, and FSGS	Change from baseline in uPCR at 12 wks
Trials of novel molecules
Setanaxib in patients with Alport syndrome (NCT06274489)	A phase 2a, randomized, double-blind, placebo-controlled study. Ages 12 to 50 yrs with eGFR > 30 and uPCR > 0.8g/g	Percentage of patients with serious adverse events
ALPESTRIA-1 (NCT0642055)	A single arm, fixed dose escalation, open label, nonrandomized study of Vonafexor	Number of treatment-emergent adverse events
R3R01 in patients with Alport Syndrome (NCT05267262)	A phase 2, multicenter, open-label study to assess safety, tolerability, efficacy, and pharmacokinetics of R3R01 in patients with Alport syndrome with uncontrolled proteinuria on renin-angiotensin-aldosterone blockade	Percentage change from baseline in uPCR at 12 wks
Trials of gene therapy
ELX-02 in patients with Alport syndrome (NCT05448755)	Phase 2 open label pilot study in patients with UAG or UGA nonsense mutations with eGFR > 60 and uPCR > 500 mg/g	The incidence and characteristics of adverse events

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; FSGS, focal and segmental glomerulosclerosis; uACR, urine albumin-to-creatinine ratio; uPCR, urine protein-to-creatinine ratio.

Sodium-glucose cotransporter 2 inhibitors have changed treatment of progressive CKD, and now have an emerging evidence base in patients with Alport syndrome.⁴³ This is likely to be augmented by the ongoing DOUBLE PROTECT Alport Study (NCT05944016), although concerns over potential inequities in access for pediatric patients remain.⁴⁴ Ongoing trials of other existing treatments include those using metformin (NCT05655728), finerenone (FIONA, NCT05196035), and the endothelin A receptor antagonists, sparsentan (EPPIK, NCT05003986) and atrasentan (AFFINITY, NCT04573920). Recent high-quality data from a mouse model of Alport syndrome presented by Dr. Hans-Joachim Anders suggests that “triple therapy” with finerenone added to renin-angiotensin-aldosterone system and sodium-glucose cotransporter 2 inhibition improves outcomes when initiated after disease onset.⁴⁵

Emerging Novel Molecules

In terms of novel molecules, a preclinical study of a NRF2 activator added to renin-angiotensin-aldosterone system inhibition presented by Dr. Hirofumi Kai revealed marked attenuation of a progressive phenotype in experimental Alport syndrome. In addition, 2 novel molecules targeting kidney fibrosis are currently the subject of phase 2 studies: setanaxib, which targets NADPH-oxidase (NOX) enzymes 1 and 4 (NCT06274489); and vonafexor, which targets the farnesoid X receptor (NCT06425055). Despite the interest generated by such novel molecules demonstrating efficacy in preclinical models and early phase trials, generally, translation into human benefit remains limited. Only about 5% of promising therapeutic interventions in animals achieve regulatory approval,⁴⁶ and approximately 70% of investigational drugs fail to advance beyond phase 2 clinical trials.

Dr Christoforos Odiatis from the Deltas group in Cyprus presented new data on preclinical studies of their Alport mouse, which is homozygous for a knock-in pathogenic variant that substitutes COL4A3 glycine 1332 with glutamate. The administration of 4-phenylbutyrate, a repurposed synthetic chaperone, improved the histology and the biochemistry of affected animals. The idea of using repurposed US Food and Drug Administration–approved drugs is attractive, and combining them with existing approved medications (i.e., renin-angiotensin-aldosterone system inhibitors) may drastically improve disease outcomes.

Gene Therapy

People living with Alport syndrome, clinicians and researchers in the field, and relevant pharmaceutical companies, all have considerable hope about future treatments using gene therapy, and the prospects for such therapies are expanding much more quickly than expected.

One form of gene therapy already being trialed is the translational readthrough inducing drug, ELX-02. This is an aminoglycoside analogue designed to lead to continuation of protein translation despite a premature termination codon in patients with such variants and is currently being evaluated in a phase 2 open label study (NCT05448755).

Reaching the components of the glomerular filtration barrier (glomerular endothelial cells, the GBM, and podocytes) early enough in the disease process remains a major hindrance to success in gene therapy. Lessons from COL4A1/2-associated diseases have clearly defined that potential gene therapies must be thought of in terms of a potential therapeutic window (the “when”), the most efficacious site to deliver gene therapy (the “where”), and the relevant form of gene delivery (the “how”).

Reliable targeting of the glomerular filtration barrier in the kidney is likely to be necessary for delivery of relevant gene therapies. Therefore, the recent development of an adeno-associated virus gene delivery platform, presented by Dr. Tobias Huber, that targets the glomerular endothelial cells, a component of the barrier, may be of future use in Alport syndrome.⁴⁷ An alternative adeno-associated virus technology that targets podocytes, presented by Dr. Hiroyuki Nakai, is also under evaluation.⁴⁸ In addition, unpublished work presented at the Alport Workshop by Yupeng Chen reported podocyte-specific expression of a miniCol4a5 gene with resulting restoration of type 4 collagen expression and assembly in a mouse model of Alport syndrome.

In humans, but away from the kidney, Vassili Valayannopoulos described positive progress in intracochlear gene therapy using an adeno-associated virus platform, which is undergoing evaluation in other genetic diseases affecting hearing (NCT05788536). This route could be relevant in Alport syndrome.

Expectations in Alport syndrome must be tempered by an understanding that previous gene therapy approaches targeting kidney disease have achieved limited translation from preclinical success to meaningful clinical outcomes. Only a small number of candidates have advanced from animal studies to early-phase clinical trials, with persistent challenges observed with model predictability and immune compatibility.⁴⁹ Furthermore, the field faces complex regulatory oversight, manufacturing and delivery constraints, and long-term uncertainties regarding vector persistence and off-target effects.⁵⁰

Summary

The 2024 International Workshop on Alport syndrome has confirmed that the spectrum of Alport syndrome is expanding beyond expectations. Achievements in basic science, drug trials, and clinical management are coming closer to patients, whose leadership in this disease space seems unique in nephrology. Educating the world’s nephrologists about this expanded scope of disease and its treatment will be a significant but necessary undertaking and will ensure that as many patients as possible are identified and properly classified. This will ensure that they can receive useful treatments, can know what condition they have, and can help their potentially affected family members prolong their own kidney function.

Controversies remain about aspects of naming the condition, largely because of the diverse phenotypes observed in patients with heterozygous variants in COL4A3 and COL4A4, and equity of access to testing and treatment. Increased understanding of relevant genetic variants and their relationship to clinical phenotypes is required to personalize clinical pathways. This will be increasingly relevant as the outcomes of clinical trials of new and existing therapies are reported. Focus in such areas may result in Alport syndrome moving from an actionable disease to a curable disease.

Disclosure

CD reports research support from CY-Biobank, funded by the EU Horizon 2020 Research and Innovation Programme (grant agreement no. 857122), the Republic of Cyprus, and the University of Cyprus; and a grant from the Alport Syndrome Foundation Inc., the Pedersen Family, and the Kidney Foundation of Canada to his institution for Alport syndrome research. DG reports consulting fees from Bayer, Calliditas, Novartis, SOBI, CSL Vifor, Otsuka, GSK, Alnylam, Britannia, STADA, and Alexion; honoraria from CSL Vifor and Sanofi; support for travel from Alexion; participation on an advisory board for Bayer; and leadership roles as AlportUK Trustee and Chair of the UKKA Rare Diseases Committee. NT reports consulting fees from Purespring (2021–present), Enyo Pharma (2022), and Calliditas Therapeutics (2023); and honoraria from Chiesi (2022). TO reports support for travel from Alport UK, which paid for his flight and accommodation at the Workshop described in the manuscript. OG reports a grant from the German Research Foundation; consulting fees from Bayer AG; honoraria from AstraZeneca; and participation on an advisory board for Bayer AG. JHM reports research support from Keros Therapeutics (payments to institution) and the Alport Syndrome Foundation (gift for research); royalties/licensing payments from Sintra Therapeutics and SonoThera to himself and Washington University; consulting fees from Eloxx Therapeutics, Visterra, Bayer AG, Sintra Therapeutics, and SonoThera; participation on an advisory board for Bayer AG; an unpaid leadership role in the Alport Syndrome Foundation Scientific Advisory Research Network; and equity in Sintra Therapeutics. RL reports grants from the Wellcome Trust (226804/Z/22/Z and 227417/Z/23/Z), the National Institute for Health Research (NIHR–Manchester BRC), Four Points Innovation/Deerfield Management, Novo Nordisk, and Kidney Research UK/Stoneygate Trust (Alport Research Hub); and planned Alport gene therapy patents. All the other authors declared no competing interests.