Whole-body magnetic resonance imaging (WB-MRI) plays a crucial role in the assessment of bone marrow (BM) involvement in Gaucher’s disease (GD), offering both quantitative and semi-quantitative evaluation methods. More than three-quarters of GD patients may exhibit BM abnormalities on WB-MRI despite ongoing treatment. The most commonly used scoring systems for BM assessment include the Bone Marrow Burden Scale (BMB), the Spanish-MRI Scale (S-MRI), and the Vertebra Disc Ratio (VDR). In Poland, experience with MRI assessment includes over 55 patients with GD, providing valuable insights into BM involvement and disease progression. This study showed that 78% of patients had BM abnormalities, with a median BMB score of 6 and an S-MRI score of 5.5. Active bone lesions were present in 57% of cases, particularly in those with elevated chitotriosidase levels and liver enlargement. Patients with non-homogeneous BM morphology were at higher risk for active lesions and avascular necrosis (AVN). Bone pain, evaluated through the visual analog scale (VAS), correlated with bone disease severity. Elevated chitotriosidase levels, liver enlargement, and higher VAS scores may serve as indirect indicators of BM infiltration risk. Given its ability to assess disease severity and skeletal complications, WB-MRI remains an indispensable diagnostic tool for GD. Moreover, its utility extends beyond GD, as it may also be beneficial in evaluating patients with Fabry disease.

Initial Findings from the First In-Vivo, Liver Directed, AAV-Mediated, Gene Integration Clinical Trial for Infants

Gabriel M Cohn²; Julien Baruteau¹; Anil Dhawan³; Anupam Chakrapani¹; Stephanie Grunewald¹; Molly Abbott¹; Helen Ashton¹; Sophie Foxall¹; Ai-Ling Koh¹; Christos Lazaridis¹; Havea Navarro-Kennedy¹; Hamza Patel¹; Siyaminji Sivananthan¹; Eleni Tamvaki¹; Katy Vecchiato¹; Matthew Hall²; Karen Kuhn²; Thomas White²; Barbara Pinho⁴; George A. Diaz²

1-Great Ormond Street Hospital for Children, London, UK; 2- iECURE, Inc., Blue Bell, PA; 3- King’s College Hospital, London, UK; 4- Fortrea, Inc., Princeton, NJ.

Background: Ornithine transcarbamylase deficiency (OTCD) results in impaired ureagenesis and hyperammonemia. Males with severe neonatal onset OTCD typically become hyperammonemic within their first 48-72 hours. Despite aggressive medical management, repeat hyperammonemic events are common and mortality rates are high. ECUR-506 is an in-vivo, liver-directed, gene insertion, investigational treatment for OTCD. Preclinical studies in young animals demonstrated that gene integration, in contrast to gene addition therapy, resulted in durable gene expression.

Methods: OTC-HOPE (NCT06255782) is a global, 24-week, first in human, single arm, Phase 1/2, open-label trial designed to assess the safety and efficacy of ECUR-506 in males <9 months of age with neonatal onset OTCD. Upon completion of OTC-HOPE study, participants will enroll in a 14.5-year follow-up study. Initial data of the first participant to complete the 6-month trial are described.

Results: The participant experienced 2 hyperammonemic events by 3.5 months of age. ECUR-506 was administered at 6.5 months of age. Grade 3 transaminitis was observed between weeks 4-8 post-infusion and resolved with immunosuppression. Reduced glutamine levels prompted nitrogen scavenger medication discontinuation and protein intake liberalization by post-dose weeks 12 and 16, respectively. Over the remainder of the 6-month study, while off scavenger medications and dietary restriction, mean ammonia levels remained normal and no hyperammonemic events were observed.

Conclusion: These data are from the first infant to receive an in-vivo, liver-directed, gene insertion, investigational product (ECUR-506) and complete the OTC-HOPE study. The observed safety profile and complete clinical response, by study definition, support the continued evaluation of ECUR-506.

Background: Fabry disease arises from loss-of-function mutations in the α-galactosidase A (AGAL) coding GLA gene. Since the 2016 approval of pharmacologic chaperone therapy for patients with responsive mutations, about 2000 GLA mutations have been tested in vitro to identify eligible patients.

Objectives: Despite advancements in enzyme activity assays, these tests fail to detect critical splicing defects, which may impact therapy outcomes.

Methods: Unanticipated splicing dysfunctions in exonic GLA mutations can hinder pharmacologic chaperone therapy. To address this, a minigene reporter assay was developed to investigate potential splicing effects undetectable by enzyme activity assays.

Results: Human Splicing Finder (HSF) predicted splicing abnormalities for specific GLA mutations. Minigene assay experiments confirmed alternative splicing for mutations c.194G>T and c.358C>G, resulting in the use of alternative donor splice sites in exon 1 and exon 2. The c.638A>T mutation caused exon 4 skipping, while c.548G>T, despite low predictive probability, also displayed abnormal splicing.

Conclusion: A comprehensive assessment of GLA mutations, including mRNA splicing analysis, is critical to fully understand their mechanistic impact and avoid misguidance in prognosis and treatment.