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Gene & Protein in Disease Alport syndrome: Genetics, variability, and management

promising results, including reduced proteinuria and serum therapy with bardoxolone methyl analogs, ultimately
urea nitrogen and normalization of GBM morphology. helping mitigate GFR loss over time.
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There are two ongoing clinical trials to evaluate endothelin The CARDINAL clinical trial was conducted to assess
receptor antagonists in glomerular diseases, including AS the effects of bardoxolone methyl in adolescent and adult
patients. 42,43 Preliminary results from the Phase 2 EPPIK patients with AS. After a 2-year study period, treatment
study (NCT05003986) showed that sparsentan safely and with bardoxolone methyl led to a significant preservation of
effectively reduced proteinuria in pediatric patients with eGFR compared to the placebo group. However, a post hoc
various proteinuric glomerular diseases, including AS, analysis of all available eGFR data at week 104 did not
over the first 12 weeks of treatment. Ongoing enrollment achieve statistical significance. 54,55 In addition, treatment
and extended follow-up will assess long-term efficacy, discontinuations were more frequent in the bardoxolone
safety, and pharmacokinetics in children. 42,44 methyl group (10 out of 77 patients), primarily due to

6.4. Lipid-lowering agents protocol-specified increases in serum transaminases.
Ultimately, the U.S. Food and Drug Administration
Recent evidence highlights the significance of disrupted declined to approve this drug, citing insufficient evidence
lipid homeostasis in glomerular cells as a key contributor of efficacy and safety concerns, including a potential risk
and predisposing factor to CKD. 45,46 A study in model mice of hepatotoxicity. 56
showed that administering hydroxypropyl-β-cyclodextrin
(which binds to cholesterol) for 4 weeks to AS mice 6.7. Gene editing therapy
carrying COL4A3 mutations led to reduced kidney lipid Genome editing therapy is a frontier concept in
accumulation, decreased fibrosis, minimized podocyte foot personalized medicine, offering the potential to treat
process effacement in the glomeruli, and lowered urinary incurable genetic diseases by correction of defective genes.
ACR compared to littermate controls. An ongoing clinical At present, it is still an experimental technique for patients
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trial (NCT05267262) that enrolled AS and FSGS patients with AS in pre-clinical stages. Several methods have been
evaluated the efficacy of R3R01, a molecule designed to studied, without strong evidence of a better one so far.
enhance the activity of the ABCA1 transporter, which
facilitates the removal of excess cholesterol from cells. 48 The exon-skipping therapy rationale is based on the use
of antisense oligonucleotides to target and remove exons
6.5. Hydroxychloroquine (HCQ) containing harmful mutations. Creating in-frame deletion
mutations from patients with truncating mutations
HCQ, an antimalarial agent and one of the oldest disease- minimizes disease severity. In AS mouse models with
modifying anti-rheumatic drugs, is widely recognized COL4A5 nonsense mutations, subcutaneous injections of
for its immunomodulatory properties. Its mechanism these oligonucleotides partially restored COL4A5 protein
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of action involves disrupting Toll-like receptor signaling, expression, reduced proteinuria, and delayed kidney
which in turn reduces the activation of innate immunity. failure. 57
In addition, HCQ suppresses cytokine production and
modulates T-cell activation by reducing CD154 expression, A different study introduced a COL4A3 transgene
a molecule involved in T-cell co-stimulation. 50,51 In a specifically in podocytes of COL4A3-deficient mice. This
retrospective study with eight pediatric patients with intervention preserved normal GBM structure, prevented
XLAS, all experienced reduced hematuria after 6 months of albuminuria, and extended survival compared to untreated
treatment with HCQ, and five of them with a concomitant mice, which developed kidney failure by 8 weeks of age.
decrease in proteinuria. Despite the small sample size Some mice presented with normal GBM even at 23 weeks
and the short follow-up period, this study suggested of age, suggesting a lasting effect of this therapy.
the potential therapeutic benefit in XLAS patients. An The clustered regularly interspaced short palindromic
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ongoing phase 2 clinical trial, namely the CHXLAS trial repeat (CRISPR/Cas9) system is a sophisticated genome-
(NCT04937907), aims to further assess the efficacy and editing technology composed of two main components:
safety of this drug in AS patients. 53 the single-guide RNA (sgRNA) and the Cas9 endonuclease.
The sgRNA is a specially designed RNA molecule that
6.6. Bardoxolone methyl
directs the Cas9 protein to a specific location in the
Bardoxolone methyl activates the transcription factor genome by binding to a complementary DNA sequence.
Nrf2, playing a key role in regulating genes involved This high specificity ensures that the system targets only
in inflammation, oxidative stress, and cellular energy the desired genomic site. The Cas9 endonuclease then
metabolism. Several animal studies have shown reduced induces a double-strand break at the identified location,
1
kidney inflammation, fibrosis, and remodeling after initiating the DNA repair process. 50,58 CRISPR/Cas9 has

Volume 4 Issue 2 (2025) 8 doi: 10.36922/gpd.7656