Fate Therapeutics (United States)

Headache disorders are prevalent and disabling conditions. Despite the recent introduction of modern therapies, a large portion of patients are still sub-optimally treated, resulting in a minor or no decrease in health loss nor disability. The Global Burden of Disease (GBD) study classifies 88 risk factors which impact several conditions, thus enabling the estimation of the potential health gain due to addressing these risk factors, but such analysis is not available for headache disorders yet. To address which risk factors, as intended by the taxonomy of the GBD study, are associated to disability in primary headaches. Primary research studies addressing primary headache disorders and disability were searched in PubMed, Web of Science and SCOPUS, in the period between 2000 and 2025. The GBD taxonomy, which classifies risk factors into environmental and occupational, behavioural, and metabolic factors, was used. A descriptive analysis was employed to report the associations between disability measures and the presence/absence of specific risk factors, accounting for diagnoses and the age of patients. A total of 64 studies (97,846 patients) were included, and a total of 86 single associations were found. Metabolic risk factors (high BMI, high fasting plasma glucose, and LDL cholesterol), and behavioural risk factors (low physical activity, inadequate dietary habits, tobacco smoking, and alcohol consumption) were the most frequently reported. Our results suggest that it is possible to address headache-related disability by acting on a set of modifiable factors, with interventions tailored to the specific needs of patients or addressing the exposed populations as a whole. In particular, targeting dietary aspects and exercise is reasonably expected to promote weight loss, and might have an impact on the reduction in fasting plasma glucose and LDL cholesterol, ultimately improving patients’ overall health status and reducing headache-related disability.

Cisplatin-based chemotherapy causes hearing loss in 40-60 % of all patients, yet effective preventative options remain limited. Building on prior animal studies, we demonstrate that oral administration of AZD5438, a potent and selective CDK2 inhibitor, provides dose-dependent protection against hearing loss in a clinically relevant multi-dose cisplatin mouse model. Protective doses (4.7 and 9.4 mg/kg b.i.d.) fall within the human-equivalent maximum tolerated dose range established in AstraZeneca trials, and exhibit plasma pharmacokinetics comparable to those in humans. Importantly, AZD5438 at 9.4 mg/kg b.i.d. does not reduce cisplatin's anti-tumor efficacy in a testicular cancer xenograft model, consistent with in vitro findings. These results support AZD5438 as a promising candidate for clinical trials to prevent cisplatin-induced hearing loss while preserving cancer treatment efficacy.

IPF is a progressive lung disease requiring precision medicine approaches and novel therapeutic targets to improve patient quality of life and outcomes. Our hypothesis was that therapeutic-relevant PUlmonary Fibrosis-Induced lncRNA (PUFINs), specifically overexpressed in lung myofibroblasts, define cell-states that drive fibrosis. An <italic>in silico</italic> network analysis of our pulmonary regulatory genome atlas, integrating IPF patient and multi-omics data, allowed identification and prediction of the cell state reprogramming potential of PUFINs enriched in IPF patients. Machine learning was used to generate gene signatures to assess on-target efficacy and potential therapeutic effects. Antisense oligonucleotides (ASOs) were designed and used to knockdown PUFINs <italic>in vitro</italic> and <italic>in vivo</italic>. PUFIN1 <italic>in vivo</italic> efficacy was studied utilizing a novel humanized murine model and bleomycin challenge. PUFIN1 and PUFIN7 were mapped to separate co-expression networks associated with pro-fibrotic and IPF-relevant pathways. PUFIN2 and 7 knockdown demonstrated anti-fibrotic on-target effects and cell-state reprogramming at single-nuclei resolution. A genetic variant associated with IPF patient outcomes was identified in the PUFIN1 locus. We mapped PUFIN1 and PUFIN7 downstream dose-responsive genes into an IPF-associated transcriptional regulatory network. PUFIN1 ASO-targeting suppressed IPF-relevant genes, including an IPF mortality risk signature, and induced anti-fibrotic and on-target activity <italic>in vivo</italic>. A multi-omics-based precision medicine approach leveraging disease-specific gene signatures identified and predicted that suppression of novel PUFIN lncRNAs results in anti-fibrotic activity with the potential to improve IPF patient care.

Alagille syndrome (ALGS) is a rare genetic disorder that affects multiple organ systems, especially the liver, leading to life-threatening complications. In most cases, ALGS is caused by haploinsufficient mutations in the JAG1 gene, resulting in impaired liver bile duct development during early childhood. Therefore, increasing JAG1 protein levels in ALGS patients offers a potential therapeutic approach. In this study, we designed antisense oligonucleotides (ASOs) targeting the JAG1 mRNA to enhance translation through different mechanisms. We found that certain ASOs targeting the upstream open reading frame (uORF) increased JAG1 protein levels in various cell lines and ALGS patient-derived cells. Optimized ASOs also increased Jag1 protein levels in normal mouse liver for up to 2-fold, accompanied by elevated levels of cleaved Notch1 protein, suggesting that the increased Jag1 protein was functionally active. Importantly, ASO treatment increased Jag1 protein in Jag1+/− mouse model. When newborn Jag1+/− mice were treated with ASO, improved bile duct development was observed, along with trends of reduced plasma bile acids, bilirubin, and triglyceride levels, implying improved liver function. Together, these results suggest that ASO-induced JAG1 upregulation may provide a promising therapeutic opportunity for ALGS patients, especially when treated at an early age.

SummaryAlthough chimeric antigen receptor (CAR) T cells have demonstrated therapeutic activity in hematopoietic malignancies, tumor heterogeneity has impeded the efficacy of CAR T cells and their extension into successful solid tumor treatment. To address these challenges, induced pluripotent stem cell (iPSC)-derived T (iT) cells are engineered to uniformly express CAR and T cell receptor (TCR), enabling targeting of both surface and intracellular antigens, respectively, along with a high-affinity, non-cleavable variant of CD16a (hnCD16) to support antibody-dependent cellular cytotoxicity (ADCC) when combined with therapeutic antibodies. Co-expression of each antitumor strategy on engineered iT cells enables independent and antigen-specific targeting across a diverse set of liquid and solid tumors. In heterogeneous tumor models, coactivation of these modalities is required for measurable antitumor efficacy, with activation of all three modalities displaying maximal efficacy. These data highlight the therapeutic potential of an off-the-shelf engineered iPSC-derived trimodal T cell expressing CAR, TCR, and hnCD16 to combat difficult-to-treat heterogeneous tumors.

Recently there has been a surge in interest involving the application of oligonucleotides, including small interfering RNA (siRNA) and antisense oligonucleotides (ASOs), for the treatment of chronic diseases that have few available therapeutic options. This emerging class of drugs primarily operates by selectively suppressing target genes through antisense and/or RNA interference mechanisms. While various commercial medications exist for delivering oligonucleotides to the hepatic tissue, achieving effective delivery to extra hepatic tissues remains a formidable challenge. Here, we review recent advances in oligonucleotide technologies, including nanoparticle delivery, local administration, and 2'-O-hexadecyl (C16)-conjugation that work to extend the applicability of siRNAs and ASOs to nerve tissues. We discuss critical factors pivotal for the successful clinical translations of these modified or engineered oligonucleotides in the context of treating neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis.

Developing knee osteoarthritis (OA) treatments is challenging due to assessing pain and joint structure outcomes within a highly heterogeneous disease. Lorecivivint (LOR), an intra-articular CLK/DYRK inhibitor, modulates Wnt and inflammatory pathways. This review analysis of LOR 0.07 mg trial data aims to describe the potential impact of baseline joint structure on OA pain response. Two Phase 2 and two Phase 3 trials enrolled knee OA patients with Kellgren-Lawrence (KL) Grades 2-3 and Pain Numeric Rating Scale [NRS (0-10)] ≥ 4 to ≤8 in their target knee. Cumulative frequency distribution plots by KL grade summarized the percentages of patients with medial joint space width (medial JSW) < 3 mm. Osteoarthritis Research Society International Joint Space Narrowing grades and treatment responses in trials capturing Pain NRS were similarly summarized. Pain outcome changes were estimated using baseline adjusted ANCOVA. Compared with phase 2 trials, the phase 3 trials had an increased proportion of patients with baseline medial JSW <3 mm. LOR demonstrated beneficial treatment effects vs placebo in KL 2 subgroups, which were found to have higher proportions of baseline medial JSW >3 mm, apart from one Phase 3 trial with advanced structural knee OA. Baseline medial JSWs were heterogeneous across trials despite KL inclusion criteria. LOR demonstrated greater symptomatic improvements in patients with less structurally advanced disease, indicative of an association between OA structural damage and pain. Early treatment interventions may improve outcomes and provide insight for future OA trial inclusion criteria development. OA-02, NCT02536833; OA-04, NCT03122860; OA-10, NCT04385303; OA-11, NCT03928184.