BioMarin Pharmaceutical, Inc.

Turner syndrome, a chromosomal disorder, causes short stature, pubertal arrest, amenorrhea, and infertility in females. Prevalence estimates vary widely; however, reliable estimates are important for public health initiatives. Therefore, a meta‐analysis was undertaken. From a total of 875 English‐language studies identified for full‐text screening in MEDLINE and Embase by two independent researchers using predefined criteria, data were extracted from 28 studies, which were also evaluated for quality; 19 and 8 were selected for the birth and point/period prevalence meta‐analyses, respectively (three studies common to both). A random‐effects model was used to calculate a pooled effect size. Heterogeneity was measured using Cochran's Q , Higgins I2 , Tau‐squared, and Tau. The birth prevalence meta‐analysis yielded a pooled estimate of 31.5 (95% CI: 18.2–54.7) per 100,000 female live births. Studies from Europe (compared to Asia) and those with a lifetime case ascertainment period (compared to first year) reported significantly higher birth prevalence. Meta‐regression analysis indicated that studies with lifetime case ascertainment had 2.69 times higher prevalence. Case ascertainment period, diagnostic method, and geography accounted for ~90% of the variation in the birth prevalence estimates across studies. The pooled estimate of point/period prevalence was 23.1 (95% CI: 11.4–46.8) per 100,000 females.

Gene therapies are emerging as a promising strategy for the treatment of rare genetic diseases, for which treatment options are often limited and do not address the underlying disease mechanisms. However, there are significant challenges for gene therapy programs, including defining a suitable first-in-human cohort and selecting endpoints with appropriate variability, sensitivity, reliability, and clinical meaningfulness; a systematic framework for the assessment and approval of these treatments is lacking. In this review, we share insights from 12 clinical development programs that culminated in recent approvals of gene therapies for rare genetic diseases (2016-2023). These approvals highlight useful strategies for navigating the unique challenges of gene therapy trials, including early and frequent engagement with regulatory bodies, incorporating the patient voice, selecting meaningful clinical outcome assessments and suitable controls, and leveraging well-matched real-world data to understand long-term efficacy, durability, and safety. By systematically documenting and analyzing detailed examples in this review, it becomes possible to derive data-driven solutions that can inform the design of future studies. Such solutions may diverge from prior assumptions or preconceptions but can provide a more evidence-based foundation for improving trial efficiency, and ultimately accelerate the development of urgently needed therapies for patients with rare genetic diseases.

Usher syndrome can cause loss of vision, hearing, and balance. There are four clinical subtypes, USH1-4, which are associated with mutations in genes important for structure, function, and survival of photoreceptor cells in the retina and sensory hair cells in the inner ear. Genetic mutations in the USH2A gene, which encodes usherin protein, are the most common cause of Usher syndrome worldwide, with c.2299delG (p.Glu767Serfs∗21) being the most frequent pathogenic variant. An investigational antisense oligonucleotide (ASO) for USH2A c.2299delG, QR-421a, designed to bypass the mutation, has already shown promise in phase 1/2 clinical trials. While recently developed chemistry provides longer ASO half-lives, repeated injection of ASOs may be required to provide long-term efficacy. To overcome this limitation, we screened novel USH2A exon 13 skippers and 20 AAV capsids with the goal of developing a vectorized ASO exon skipping strategy. Optimized vectors and skippers were evaluated in inner ear and retinal organoids derived from human stem cell lines bearing the USH2A c.2299delG mutation. The data revealed enhanced skipping of the pathogenic exon, offering an alternative strategy for treatment of USH2A patients using a single local injection which may prevent progression of vision and hearing loss.