Vertex Pharmaceuticals

Use of adeno-associated virus (AAV)-mediated transfer of functional microdystrophins to address Duchenne muscular dystrophy (DMD) has been established. RGX-202, an AAV8 vector encoding a novel, optimized human microdystrophin with an extended C-terminal domain, expressed under the Spc5-12 muscle-specific promoter, was evaluated for tolerability and efficacy in dystrophin-deficient mdx mouse in 12- and 26-week studies at vector doses ranging from 3 × 1013 to 5 × 1014 gc/kg. A single intravenous administration of RGX-202 was well tolerated and led to robust, dose-dependent expression of microdystrophin in skeletal and cardiac muscles at 12 weeks, which persisted to 26 weeks post-administration. Increased microdystrophin was associated with recruitment of the dystrophin-associated protein complex to the sarcolemma, particularly at doses ≥1 × 1014 gc/kg. Histologic and magnetic resonance imaging examinations revealed marked and sustained suppression of dystrophic pathology in all RGX-202-treated mice. Functionally, gains were observed in the in vitro specific force of extensor digitorum longus muscle, in vivo grip strength, and the rescue of treadmill and gait deficits. These findings provide preclinical evidence for the therapeutic efficacy of RGX-202 at a minimum effective dose (MED) of 1 × 1014 gc/kg in the murine DMD model. This MED served as the starting dose for the RGX-202 clinical study (NCT05693142), which has currently completed phase III enrollment.

Research suggests the effects of combined (containing both estrogen and progestin) hormonal contraception (CHC) can negatively affect insulin sensitivity. This study aims to better understand the associations between hormonal contraceptive (HC) use, prevalence of existing CFRD, and incidence of developing CFRD in females with CF. Between January 2021 to April 2022, we recruited females ages 18-45 years with CF from 10 CF centers to complete a retrospective online questionnaire regarding contraceptive use from 2008 to survey completion year. We linked survey responses to the CF Foundation's Patient Registry (CFFPR) covering the same years as the survey. We examined potential associations with CFRD, incidence of new CFRD, and CFRD's association with HC using Cox regression adjusted for age, body mass index, CF modulator use, and educational level. In our observational cohort of 551 persons completing the survey and with information in the CFFPR, the incidence of reported CFRD was low at 145 cases per 3674 person-years (p-y). Neither BMI nor age were found to be associated with CFRD incidence. Elevated plasma glucose, 2-hour oral glucose tolerance test, and HbA1c were all significantly associated with CFRD. Compared to no modulator use, CF modulator use was associated with a similar rate of CFRD (HR 1.04, 95% CI 0.50 to 2.17). Among non-modulator users, CFRD incidence was significantly associated with CHC use (HR = 1.53, 95% CI 1.03 to 2.27). In this retrospective observational study, CHC was associated with a higher incidence of CFRD among non-modulator users.

Although type 1 diabetes (T1D) technology has improved health outcomes for many, some people continue to experience severe hypoglycemic events (SHEs). This study reviews the history of SHEs and impaired awareness of hypoglycemia (IAH) compound risk for future SHEs, and describes the lived experiences of SHEs among adult people with T1D (pwT1D) with recurrent SHEs (≥ 2/year) and IAH who use continuous glucose monitors (CGMs). In this online survey study with eligible CGM-users from the T1D Exchange Registry, participants were asked open-ended questions on the impact of SHEs on their lives, then responses were analyzed thematically. Participants reporting ≥ 2 SHEs in the last year and IAH were included in the analytic sample. Participant (n = 158) responses were coded into 12 thematic categories. A total of 82% of participants reported one or more of the following themes: Emotional and Psychological Impact of SHEs, Social/Relationships Impacts, and Attempts to Prevent and Cope. Specifically, nearly half of participants described the Emotional and Psychological Impact of SHEs (49.4%), with fear around hypoglycemia being especially prominent (e.g., "I worry I might pass out and not wake up…"). Over one-third of participants described impacts of SHEs on their Social Relationships (33.5%), including increased distress from their loved ones. Remaining themes described impacts on numerous other domains of life. Adult pwT1D using CGMs who had recurrent SHEs and IAH experience substantial burden in their daily lives. New therapeutic options to help this population eliminate SHEs and meet T1D treatment goals would be especially beneficial. With modern technological advances in the field of diabetes, more people with type 1 diabetes use devices such as continuous glucose monitors, insulin pumps, and hybrid closed-loop systems to help manage blood sugar levels and lower the risk of dangerous low blood sugar events. These technologies can improve glucose management, but they do not completely eliminate the risk of severe hypoglycemic events. This risk is particularly higher for those with impaired awareness of hypoglycemia, where they do not feel early warning signs of low blood sugar. This study aimed to better understand the lived experiences of adults with type 1 diabetes who use continuous glucose monitors in combination with insulin pumps, hybrid closed-loop systems or multiple daily injections but still experience recurrent severe hypoglycemic events and impaired awareness of hypoglycemia. The study involved an online survey that asked 158 participants to describe the impact of severe hypoglycemic events on their everyday lives. The most common impacts were seen in relationships, attempts to prevent and cope, and emotional or psychological health. Almost half of participants were concerned about severe hypoglycemic events, and over one-third said that these events added worry and stress to their relationships with friends and family. Other areas in life, such as work, independence, and well-being were also disrupted by these occurrences. Even when using advanced glucose management technology, participants felt a heavy burden from diabetes on their daily lives. These findings show that new treatment approaches could benefit the quality of life for this group.

Nanobodies are emerging as attractive biopharmaceuticals due to their small size, stability and target specificity. However, their therapeutic use has largely been restricted to extracellular targets because of a lack of efficient delivery methods. This limitation is particularly relevant for diseases caused by dysfunctional intracellular proteins, such as cystic fibrosis. Here we show that cell-permeable nanobodies can modulate an intracellular disease-relevant target: the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel carrying the common F508del mutation. By combining a CFTR-binding nanobody with cell-penetrating peptides, we achieved intracellular delivery in cystic fibrosis bronchial epithelial cells. The delivered nanobody stabilizes misfolded F508del-CFTR, promotes its maturation and trafficking to the apical membrane and restores chloride channel activity. Moreover, the cell-permeable nanobody enhances the efficacy of approved CFTR modulator drug combination in primary airway epithelial cultures from patients with cystic fibrosis. These findings establish cell-permeable nanobodies as promising biopharmaceuticals for intracellular protein targeting and therapeutic modulation.

Despite the promise of engineered tissue implants for the treatment of organ failure, scaling of these constructs to sizes of therapeutic relevance remains a barrier to clinical translation. Here, we propose a strategy to circumvent this limitation: to instead implant a small-scale construct and then induce it to grow in situ after its engraftment into a host. Using engineered liver tissue as a proof-of-concept application, we integrated synthetic biology and tissue engineering tools to build liver tissues that can be expanded on-demand after implantation in vivo. To achieve this goal, we first identified the combination of Yes-associated protein (YAP) and growth factor (GF) signaling as sufficient to drive human hepatocyte proliferation in dense, three-dimensional engineered tissues. We then engineered control of these signaling axes using synthetic biology tools to drive human liver tissue expansion both in vitro and in vivo. As such, this work establishes a genetic strategy for generating large organ implants through bioengineered on-demand outgrowth via synthetic biology triggering (BOOST).