Toward responsible clinical n-of-1 strategies for rare diseases

Defelippe, Victoria; Thiel, Ghislaine J. M. W. van; Otte, Willem M.; Schutgens, Roger E.G.; Stunnenberg, Bas C.; Cross, Helen; O'Callaghan, Finbar; Giorgis, Valentina De; Jansen, Floor E.; Perucca, Emilio; Brilstra, Eva H.; Braun, Kees P.J.

doi:10.1016/j.drudis.2023.103688

Cited by 9 publications

(2 citation statements)

References 46 publications

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“…Personalized medicine is gaining recognition within the field of rare diseases, as it might be the most adequate strategy to develop specific treatments that take into account variability in clinical symptoms and biological responses among affected individuals. Currently, improving the clinical design and evaluation of N-of-1 interventions is an important focus of the field [1][2][3]19,37], but preclinical assessment of the potential therapies must be considered as essential in order to standardize aspects that are required prior to trial initiation. For that reason, this study aimed to initiate preclinical testing for the ultrarare deep-intronic ABCA4 variant c.6817-713A>G, found in one early-onset STGD1 patient, which promotes the insertion of a 122-nt PE between exons 49 and 50 in the final transcript.…”

Section: Discussionmentioning

confidence: 99%

“…As a consequence, the observed heterogeneity may lead to variable responses to treatment, which is a challenging aspect in clinical trials. N-of-1 strategies have been developed over time to speed up tailor-made therapy design for smaller patient groups [1,2]. The main goal for this type of intervention is to properly assess whether it brings significant benefit to the target individual.…”

Section: Introductionmentioning

confidence: 99%

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Preclinical Development of Antisense Oligonucleotides to Rescue Aberrant Splicing Caused by an Ultrarare ABCA4 Variant in a Child with Early-Onset Stargardt Disease

Suárez-Herrera,

Li,

Leijsten

et al. 2024

Cells

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Precision medicine is rapidly gaining recognition in the field of (ultra)rare conditions, where only a few individuals in the world are affected. Clinical trial design for a small number of patients is extremely challenging, and for this reason, the development of N-of-1 strategies is explored to accelerate customized therapy design for rare cases. A strong candidate for this approach is Stargardt disease (STGD1), an autosomal recessive macular degeneration characterized by high genetic and phenotypic heterogeneity. STGD1 is caused by pathogenic variants in ABCA4, and amongst them, several deep-intronic variants alter the pre-mRNA splicing process, generally resulting in the insertion of pseudoexons (PEs) into the final transcript. In this study, we describe a 10-year-old girl harboring the unique deep-intronic ABCA4 variant c.6817-713A>G. Clinically, she presents with typical early-onset STGD1 with a high disease symmetry between her two eyes. Molecularly, we designed antisense oligonucleotides (AONs) to block the produced PE insertion. Splicing rescue was assessed in three different in vitro models: HEK293T cells, fibroblasts, and photoreceptor precursor cells, the last two being derived from the patient. Overall, our research is intended to serve as the basis for a personalized N-of-1 AON-based treatment to stop early vision loss in this patient.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Preclinical Development of Antisense Oligonucleotides to Rescue Aberrant Splicing Caused by an Ultrarare ABCA4 Variant in a Child with Early-Onset Stargardt Disease

Suárez-Herrera,

Li,

Leijsten

et al. 2024

Cells

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Repurposing SGLT2 inhibitors: Treatment of renal proximal tubulopathy in Fanconi‐Bickel syndrome with empagliflozin

Overduin,

Grünert,

Besouw

et al. 2024

J of Inher Metab Disea

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Renal proximal tubulopathy in Fanconi‐Bickel syndrome is caused by impaired basolateral glucose transport via GLUT2 and consequently, intracellular accumulation of glucose and glycogen. SGLT2 inhibitors act on apical glucose reabsorption of renal proximal tubular cells. The purpose of this study was to retrospectively describe the first experiences with repurposing the SGLT2 inhibitor empagliflozin to treat the generalized tubulopathy in Fanconi‐Bickel syndrome. A case series was conducted of seven persons from five families (five males, two females; three children, who were 14y5m, 2y9m, and 1y6m old) with genetically confirmed Fanconi‐Bickel syndrome, off‐label treated with empagliflozin. Median (range) age at start of empagliflozin was 27 years (1y6m – 61y) and duration of follow‐up under empagliflozin treatment was 169 days (57–344). Under empagliflozin (up to 25 mg/d), biochemical parameters of tubular cell integrity (urinary N‐acetyl‐glucosaminidase) and/or tubular functions (including urinary α1‐microglobulin) improved in all persons with Fanconi‐Bickel syndrome, albeit to varying degrees. Clinically, supplementations (i.e., phosphate, alkali, carnitine, and alfacalcidol) could be completely discontinued in the three children, whereas results in the four adult patients were more variable and not as significant. Empagliflozin was well‐tolerated and no symptomatic hypoglycemia was observed. In conclusion, SGLT2 inhibitors such as empagliflozin shift the metabolic block in Fanconi‐Bickel syndrome, that is, they intervene specifically in the underlying pathophysiology and can thus attenuate renal proximal tubulopathy, especially when started in early childhood.

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