搜索结果：Molecular therapy : the journal of the American Society of Gene Therapy

Cystic fibrosis (CF) is a lethal genetic disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The most prevalent disease-causing mutation, F508del, results in the production of misfolded CFTR proteins, which are prematurely degraded. Given the complex pathology of CF, a multimodal therapeutic strategy is essential. This underscores the urgent need to develop adjunctive modulators that synergize with existing therapies. Here, we show that protein kinase C (PKC) activators ingenol-3,20-dibenzoate and 12-deoxyphorbol 13-phenylacetate 20-acetate enhance F508del-CFTR channel function through a mechanism distinct from that of currently FDA-approved CFTR correctors. These agents enhance F508del-CFTR function as monotherapies; in combination with CFTR correctors, they largely restore the channel function in both immortalized human airway epithelial cells and CftrF508del/F508del mouse lungs. Notably, they also attenuate CftrF508del/F508del mouse pulmonary inflammation induced by infection. Furthermore, PKC activators enhance the function of CFTR harboring rare missense mutations that are refractory to existing therapies. Mechanistically, PKCε-mediated phosphorylation of nascent CFTR stabilizes the translating CFTR transcripts, thereby promoting channel synthesis. These findings reveal a previously unappreciated role of PKCε signaling in CFTR biogenesis and suggest a potential combinatorial treatment strategy to achieve a more complete functional rescue of mutant CFTR.

Resmetirom is an oral, liver-targeted medication that selectively activates the thyroid hormone receptor beta (THRB) and thereby targets multiple pathophysiological mechanisms of metabolic dysfunction-associated steatohepatitis (MASH). By activating hepatic THRB, resmetirom promotes fatty acid oxidation, improves mitochondrial function, inhibits de novo lipogenesis and prevents hepatic cell injury and death in cultured cells, liver organoids and mice. Pivotal clinical trials have confirmed that resmetirom markedly reduces liver fat content, ameliorates inflammatory injury, and reverses liver fibrosis while also effectively lowering atherogenic lipid levels. The medication has a favorable safety and tolerability profile. Based on these findings, resmetirom was approved by the US Food and Drug Administration (FDA) in 2024 and by the European Union in August 2025. Further directions in this field will pivot on investigating the cardiovascular benefits of resmetirom, exploring its use in combination with other drugs, and the elucidation of its underlying molecular mechanism networks. This article reviews the pharmacological and clinical evidence regarding the treatment of MASH with resmetirom published by April 2026, with the aim to expanding the pharmacological profile of resmetirom and promoting the development of THRB agonism-based anti-MASH pharmacotherapies.

Chemo-immunotherapy (CI) administrated during the induction phase markedly ameliorates immune responses and improves clinical efficacy in patients with high-risk neuroblastoma (NB), yet the underlying translational mechanisms remain poorly defined. Single-cell transcriptomic analysis revealed selective activation of the NRG3-ERBB4 axis in pretreatment tumor specimens from high-risk NB patients, accompanied by augmented cytotoxic programs in CD8+ T cells and NK cells. During induction therapy, chemotherapy alone suppressed NRG3 and ERBB4 expression, whereas their levels were significantly upregulated upon the addition of naxitamab and positively correlated with NB-reactive immune responses. Functional assays further confirmed that NB cells exposed to CI activated NRG3-ERBB4 signaling, which in turn induced the upregulation of GZMB and GNLY in effector lymphocytes. Integrated analysis of bulk RNA-seq and lipidomics further demonstrated that the NRG3-ERBB4 rewired ganglioside metabolism to limit its intratumoral accumulation, thereby restoring tumor-reactive immune surveillance. Collectively, these findings delineate an NRG3-ERBB4 axis-centered tumor-immune crosstalk that operates across pretreatment, chemotherapy, and CI, uncovering a previously unrecognized mechanism underlying naxitamab-mediated immune activation. Our results also support ERBB4 as a promising predictive biomarker and therapeutic target to optimize CI strategies for high-risk NB.

Spinal muscular atrophy (SMA) is a severe neurogenetic disorder and the leading inherited cause of infant mortality. Although the available gene therapy has shown substantial efficacy in treating SMA, safety concerns, including hepatotoxicity, underscore the need for optimization. In this study, our findings challenge the prevailing "more-is-better" paradigm, demonstrating that both insufficient and excessive transgene expression are suboptimal. To maximize therapeutic benefit while minimizing risk, we extensively optimized the expression cassette in adeno-associated virus (AAV)-based constructs and selected EXG001-307, an intra-cerebrospinal fluid (intra-CSF)-delivered AAV9 gene therapy engineered for tissue-selective and quantitatively controlled SMN expression. Comparative studies demonstrated that intra-CSF-administered EXG001-307 may offer improved efficacy and safety relative to the other candidates. In subsequent investigational new drug-enabling studies, EXG001-307 demonstrated dose-dependent improvements in survival, body weight gain, and motor function in SMA model mice. Safety evaluations in rats and juvenile nonhuman primates further confirmed a favorable safety profile, with no evidence of systemic toxicity or sustained dorsal root ganglion pathology. Analyses in vector genome biodistribution and transgene expression revealed robust central nervous system transduction consistent with therapeutic benefit. These findings support clinical translation of EXG001-307 and highlight the importance of vector genome engineering and targeted delivery for safe and effective gene therapies.

CDK4/6 inhibitors promote anti-tumor immunity through diverse mechanisms, positioning them as promising adjuvants to cancer immunotherapies. While CDK4/6 inhibitors have demonstrated strong synergy with immune checkpoint inhibitors across numerous preclinical cancer models, their combination with CAR-T cell therapy remains unexplored. In this study, we examined the efficacy of combined CDK4/6 inhibition (trilaciclib) and CAR-T therapy across a range of preclinical blood and solid cancer models. In vitro, trilaciclib enhanced human CAR-T cell cytotoxicity and metabolic fitness while reducing expansion. In vivo, the combination outperformed single agents against retinoblastoma protein (RB)-proficient, trilaciclib-sensitive CD19+ leukemia. However, in an equivalent RB-deficient model, the combination therapy was no more effective than CAR-T cells alone, suggesting that enhanced CAR-T cell function may be offset by reduced expansion. In contrast, in solid cancer models the combination was consistently more efficacious than either monotherapy. Notably, combination effects were most pronounced in immunocompetent mouse models, including a model with poor sensitivity to trilaciclib as a monotherapy. Mechanistically, CDK4/6 inhibition reduced tumor-infiltrating T-regulatory cells while enhancing CD8+ CAR-T cell persistence, tumor trafficking, and cytotoxic function within the tumor. Together, these findings suggest that trilaciclib and CAR-T cell therapy may be an effective combinatorial treatment for solid cancers.

Transplantation of donor hematopoietic stem and progenitor cells (HSPCs) is a well-established curative treatment for various blood and immune diseases, including severe combined immunodeficiency (SCID). However, it comes with significant toxicities, including graft-versus-host disease (GvHD) and tissue damage resulting from the use of genotoxic chemotherapy-containing conditioning regimens. Autologous transplantation using gene-modified HSPCs eliminates GvHD but currently still relies on genotoxic conditioning. Further, gene modification of HSPCs has commonly utilized integrating viruses, which carry the risk of oncogenesis. The ideal therapy would eliminate the risks associated with current hematopoietic stem cell (HSC) gene-modification and conditioning approaches. Here, we combined base editors (BEs), engineered virus-like particles (eVLPs), and non-genotoxic αCD117 antibody-drug conjugate (ADC) conditioning to explore optimal curative treatment of SCID. We generated a Rag2 SCID mouse model with a single point mutation (pm) and corresponding BE. Rag2pm/pm HSPCs were corrected using SpCas9NG-ABE-eVLPs without off-target effects being detected. Even in settings of low editing, transplantation of BE-corrected HSPCs into αCD117-ADC-conditioned mice led to efficient immune cell production in peripheral blood with normal B cell progenitors in the bone marrow. Combining αCD117-ADC conditioning with transplantation of HSPCs that were base edited using eVLPs successfully reversed the SCID phenotype in mice, showcasing a significant advancement in reducing treatment-related toxicities while enabling disease correction.

Preclinical gene therapy studies of mitochondrial diseases remain limited due to the typically multiorgan manifestations and the scarcity of physiologically relevant animal models. Mutations in BCS1L, a nuclear gene encoding an assembly factor for mitochondrial complex III (CIII), are the most common cause of CIII deficiency. The most severe phenotype, GRACILE syndrome, is caused by a homozygous Finnish founder mutation (c.A232G, p.S78G). The corresponding Bcs1lp.S78G knock-in mouse model recapitulates the human disease, with juvenile-onset hepatopathy, tubulopathy, growth restriction, segmental progeria, and short survival. Here, we performed liver-targeted recombinant adeno-associated virus (rAAV)-mediated gene replacement in this model. A single intraperitoneal injection of rAAVs encoding wild-type Bcs1l restored CIII assembly and activity in the liver, preventing hepatopathy. Hepatocyte-specific correction was sufficient to alleviate hypoglycemia, improve growth, normalize systemic metabolism, and extend survival by nearly two-fold, despite persistent CIII deficiency in other tissues. Remarkably, restoring CIII activity in the liver robustly corrected the skeletal muscle transcriptomic changes, particularly those linked to altered energy substrate utilization. These results underscore the central role of the liver in systemic energy homeostasis and growth regulation in multiorgan mitochondrial diseases and demonstrate the therapeutic potential of hepatocyte-directed gene replacement in phenotypes with prominent hepatopathy.

CRISPR/Cas9 has revolutionized genome editing with broad therapeutic applications, yet its repair patterns in vivo remain poorly understood. Here, we systematically profile CRISPR/Cas9 editing outcomes at 95 loci using our established CRISPR/Cas9/AAV9-sgRNA system in skeletal muscle stem cells (MuSCs). Through comprehensive characterization of the repair outcomes, our findings demonstrate that the general rules governing CRISPR/Cas9-mediated editing in vivo largely align with those observed in vitro. Additional to the anticipated small editing indels such as MMEJ mediated deletions and NHEJ mediated templated insertions, we uncover a prevalent occurrence of large on-target modifications, including large deletions (LDs) characterized by microhomology (MH) and large insertions (LIs). Notably, the LIs comprise not only exogenous AAV vector integrations but also endogenous genomic DNA fragments (Endo-LIs). Endo-LIs preferentially originate from active genomic regions, with their integration shaped by three-dimensional chromatin architecture. By disrupting key components of the NHEJ and MMEJ repair pathways in vivo, we identify their distinct roles in regulating the large on-target modifications. Together, our work systematically profiles the CRISPR/Cas9 repair outcomes in vivo and offers valuable guidance for improving the safety of CRISPR/Cas9-based gene therapies.

Mucopolysaccharidosis type I (MPS I), caused by α-L-iduronidase enzyme (IDUA) deficiency, manifests multisystemic symptoms from tissue accumulation of undegraded glycosaminoglycans. Severe MPS I (Hurler syndrome) is associated with developmental delay and loss of neurocognition. Although IDUA enzyme replacement therapy and allogeneic hematopoietic stem cell transplantation (HSCT) are standard therapies for Hurler syndrome, gene therapy represents potential alternative treatment of neurodevelopmental disease. We report more than 5 years of clinical, biochemical, and neurocognitive outcomes following a first-in-human, open-label, single-patient, single administration of intra-cisterna magna (ICM) RGX-111 (AAV9.CB7.hIDUA, 1E-10 vector genomes/g brain mass) in a 20-month-old boy with Hurler syndrome with two older affected siblings deceased from HSCT-related complications. The ICM procedure was safe and well tolerated; treatment-emergent adverse events were mild and self-limiting. Crucially, serial brain imaging has been normal. He has never received an HSCT and continues with weekly IDUA infusions. Neurocognitive testing demonstrates ongoing acquisition of developmental abilities, with cognitive, speech, and motor age equivalents measuring one to two standard deviations below the normative mean. His neurodevelopment is significantly above the natural history of untransplanted Hurler syndrome patients. This single-patient experience of central nervous system-directed gene therapy demonstrates therapeutic potential for severe MPS I and other genetic neurodegenerative diseases.

Self-replicating RNA (srRNA) technology has received its first approval with Kostaive and Emergency Use Authorization for GEMCOVAC COVID-19 vaccines. The effective doses for srRNA vaccines are far lower than for conventional mRNA, as srRNA drives greater protein expression and has attributes of viral vectors that can potentiate immunogenicity. Importantly, srRNA encodes for a viral replicase, frequently derived from non-structural proteins (nsP) from Venezuelan equine encephalitis virus (VEEV), that helps amplify the encoded transgene. nsPs also influence critical cellular processes, including protein translation and processing, inflammation, and autophagy, that can impact downstream performance. Here, we show that a next-generation srRNA vector derived from Eastern equine encephalitis virus, identified from a wider screen of alphaviruses, has high potency in two immunotherapeutic applications, RBI-1000 and RBI-2000. RBI-1000, a multigenic vaccine targeting acquired resistance mutations in breast cancer, was able to elicit antigen-specific immune responses to tumor-associated antigens and neoantigens. In addition, RBI-2000, a combination interleukin-12 and IL-1 receptor antagonist biotherapeutic, resulted in therapeutic levels of protein expression that bolstered anti-tumor immune responses in vivo. Both RBI-1000 and RBI-2000 successfully demonstrated efficacy in preclinical tumor models. These data show the importance of empirically evaluating new srRNA vectors for the development of fit-for-purpose therapies.

CAR-T cell therapies are revolutionizing the treatment of refractory or relapsed hematological malignancies, but many patients do not achieve durable responses, and these therapies remain ineffective against solid tumors. Therapeutic failure is closely associated with a poor persistence of CAR-T cells in patients, highlighting the need to identify strategies promoting in vivo expansion. Although numerous gene-editing strategies have been proposed, comparative studies to identify the most effective ones are still lacking. Here, using a focused CRISPR-knockout library targeting 50 selected gene candidates, we developed a competitive screening that revealed ZC3H12A, SOCS1, PTPN2, and CDKN2A as the most robust targets to improve persistence of EGFR CAR-T cells in human lung tumor-bearing mice. Surprisingly, disruption of other genes previously reported to improve CAR-T cell efficacy in other preclinical models-MED12, PRDM1, and BATF-had a detrimental effect in this context. These results suggest that some gene-editing strategies can yield beneficial, neutral, or even deleterious effects on CAR-T cell persistence, depending on specific conditions. Altogether, these findings highlight the importance of performing context-specific evaluations of genetic modifications to accelerate the clinical translation of the most promising editing strategies for optimizing CAR-T cell therapies.

Although immune checkpoint blockade (ICB), including in combination with neoadjuvant regimens, has shown encouraging efficacy in lung cancer, a substantial fraction of patients remains resistant, and the underlying mechanisms are not fully understood. Here, we performed single-cell RNA sequencing of lung squamous cell carcinoma (LUSC) samples collected before and after ICB, stratified by therapeutic outcome. In responders, ICB promoted the expansion of B cells and T follicular helper (Tfh) cells, supporting the formation of tertiary lymphoid structure. In contrast, non-responders exhibited persistent type I interferon (IFN-I) signaling driven by CD36+SPP1+ tumor-associated macrophages, which disrupted lymphoid organization. At baseline, dysfunctional T cells were characterized by aberrant nuclear factor of activated T cells (NFAT) signaling. Mechanistically, IFN-I induced the expression of the phosphatase dual-specificity phosphatase 2 (DUSP2) in pre-exhausted T cells, promoting NFAT dephosphorylation and nuclear accumulation. Nuclear NFAT upregulated inhibitory receptors and antagonized Bcl6-dependent transcriptional programs, thereby reinforcing T cell exhaustion and impairing Tfh differentiation. Genetic ablation of Dusp2 restored CD8+ T cell function and Tfh-B cell interaction, enhancing responsiveness to ICB. These findings identify a pathogenic IFN-I-DUSP2-NFAT axis that limits immunotherapy efficacy in LUSC.

Bone remodelling is essential for maintaining skeletal integrity by preserving the balance between bone formation and resorption, with excessive osteoclast activity contributing to osteoporosis. Osteocytes act as central regulators of osteoclastogenesis through mechanically sensitive paracrine signals, yet the influence of osteoblasts and their mesenchymal precursors remains less defined. Extracellular vesicles (EVs) have recently emerged as mediators of bone cell communication, although their role in osteoclast regulation are still underexplored. This study demonstrates that mesenchymal-derived bone cells inhibit osteoclastogenesis through an EV-dependent mechanism shaped by their differentiation stage and mechanical environment. Mechanically stimulated osteocyte-derived EVs showed the strongest anti-catabolic response. Notably, we identify miR-150-5p as a mechano-responsive miRNA enriched within osteocyte EVs, capable of inducing a dose-dependent reduction in osteoclastogenesis. Transcriptomic analyses reveal that EV treatment and miR-150-5p delivery induce substantial transcriptional changes in osteoclast precursors, including downregulation of shared target genes linked to bone remodelling. Overall, we highlight mechanically activated osteocytes as key regulators of osteoclastogenesis through an EV-mediated mechanism, in which miR-150-5p represents a promising candidate contributor within the broader EV cargo landscape, highlighting their potential for future cell-free therapeutic strategies.

The cardiac autonomic nervous system is central to various cardiac diseases, yet its regulation in the human heart remains poorly understood due to the lack of reliable models. Here, we report the development of a neurocardiac co-culture system using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and sympathetic neurons (hiPSC-SNs). Both cell types were characterized molecularly and electrophysiologically and subsequently used for the establishment of the co-culture model in a two-well chambers insert, forming a dense axonal network connected with hiPSC-CMs. The co-culture demonstrated robust functional interactions: hiPSC-CMs maintained a stable beating rate, while hiPSC-SNs exhibited significantly increased firing activity after 7 days. Nicotine stimulation enhanced hiPSC-SN activity, resulting in an increased beating rate in co-cultured hiPSC-CMs, an effect that is absent in monoculture. This rise in the beats was abolished by nicotinic acetylcholine receptor blockade through α-bungarotoxin on hiPSC-SNs in co-culture. The β-blocker propranolol mitigated isoproterenol or nicotine effects on hiPSC-CMs. Using a fluorescent tracer, functional exocytosis and norepinephrine release was confirmed in hiPSC-SNs in co-culture. This novel neurocardiac model replicates neuronal control of cardiomyocytes and provides a new and robust platform for studying neuro-cardiac interactions. It represents a promising tool for advancing disease modeling and pharmacologic research in cardiac pathophysiology.

Cutaneous gene therapy has the potential to treat a wide range of skin disorders, but effective delivery remains limited by the skin's barrier properties and immune surveillance. Here, we identify AAVrh32.33 as a potent vector for targeting dermal stromal compartments. Following systemic administration in mice, AAVrh32.33 mediated robust and durable transgene expression, with preferential targeting of dermal fibroblasts and hair follicle bulge cells. Expression peaked at one month and persisted for up to two years, highlighting its suitability for chronic conditions. To reduce immunogenicity, a dominant CD8+ T cell epitope was disrupted, generating the IDPΔ variant. This modification attenuated peptide-specific T cell responses while preserving stromal transduction. In human skin explants, IDPΔ achieved high levels of gene expression, primarily in dermal fibroblasts and precursors, confirming translational relevance. Finally, vectors encoding CCL17, CCL20, and CCL22 demonstrated localized targeted therapeutic gene delivery in both healthy and inflamed skin, underscoring the feasibility of using this platform to reshape local immune responses. Together, these findings establish AAVrh32.33 and IDPΔ as promising platforms for durable cutaneous gene therapy, with direct applications in diseases such as vitiligo where long-term modulation of the dermal microenvironment is essential.

Angiogenesis is a key function of vascular endothelial cells and becomes aberrant in pathologies such as preeclampsia. An important mediator of angiogenesis is vascular endothelial growth factor (VEGF) receptor FLT1; however, alternative splicing of FLT1 can generate soluble FLT1 (sFLT1), a decoy receptor that inhibits VEGF signaling. While some long non-coding RNAs (lncRNAs) are known to regulate splicing, their roles in endothelial biology remain poorly defined. Here, we identify lncRNA LINC00607 as a critical regulator of FLT1 alternative splicing. Loss of LINC00607 increased the formation of the anti-angiogenic sFLT1. CRISPR-mediated knockout of LINC00607 promoted exon 15 inclusion in FLT1, elevating sFLT1 levels and blunting VEGF-driven angiogenesis-a defect reversed by sFLT1-neutralizing antibodies. LINC00607 interacted with U2 small nuclear RNA (snRNA) to regulate exon 15 inclusion in FLT1, an interaction dependent on the chromatin-remodeler BRG1. A splice-blocking morpholino targeting the FLT1 intron14/exon15 junction specifically inhibited sFLT1 production by interacting with LINC00607 and U2 snRNA, and its application increased VEGF-A-mediated sprouting. LINC00607 expression inversely correlated with sFLT1 levels in vascular diseases. In preeclampsia, a multisystem pregnancy disorder involving hypertension and proteinuria, LINC00607 was downregulated in early and late-stage preeclampsia compared with healthy pregnancies. LINC00607 therefore fine-tunes VEGF signaling and might contribute to the pathophysiology of preeclampsia.

Clinical evidence regarding chimeric antigen receptor (CAR) therapy for systemic lupus erythematosus (SLE) remains limited. Here, we report a phase 1/2 trial evaluating the safety and efficacy of autologous CD19 CAR-T therapy. This study includes dose escalation and expansion stages, utilizing time-to-event Bayesian optimal interval phase 1/2 design for assigning doses based on benefit-risk trade-off. Primary endpoints were dose-limiting toxicity (DLT) within 28 days and adverse events (AEs) within 30 days in phase 1 and overall response rate at months 3 and 6 in phase 2. Eighteen patients, predominantly pediatric (n = 15), including 15 with Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) &#x2265;4 were enrolled. No DLT occurred, and the recommended dose for phase 2 was 1 &#xd7; 106 CAR-T cells/kg. AEs included grade 1 cytokine release syndrome in 72%, neurotoxicity in 17%, and grade 1-2 infections in 17%. At months 3 and 6, of 15 patients with baseline SLEDAI-2K &#x2265;4, 9 and 12, respectively, achieved SRI-4 response, 1 achieved lupus low disease activity state at 6 months, and 2 were non-responders. Three with baseline SLEDAI-2K <4 achieved definition of remission in SLE. With a median follow-up of 10.2 months, all responders maintained response without immunosuppressants, except for 1 relapse. CAR-T cells persisted for a median of 56 days and ablated B cells transiently. This approach shows safety and preliminary efficacy.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene, which leads to a mutant protein that destroys neurons in the brain. Despite intense effort, there remains no approved disease-modifying therapy for HD. Here we develop a pan-HTT-targeting CRISPR-Cas9 system that, when delivered to the striatum of R6/2 and YAC128 mice by AAV5, lowered mutant HTT mRNA and protein by 55-80% via its induction of frameshift-inducing indel mutations in HTT exon 1. Cas9 targeting improved motor coordination and locomotor activity, decreased anxiety-like deficits, reduced clasping and weight loss, limited striatal atrophy, and decreased the formation of intranuclear inclusions immunoreactive for the mutant HTT protein. In Hu21/21 mice, which carry the wild-type human HTT gene in lieu of the mouse ortholog, Cas9 lowered the HTT protein by 44% but induced no measurable behavioral deficits and had no adverse effect on neuronal viability, though its targeting was associated with neuroinflammation. Altogether, our results demonstrate the ability for a newly developed pan-HTT-targeting Cas9 system to affect HD-related phenotypes across models and provide insights into its tolerability.

Immune responses against the adeno-associated virus (AAV) vector capsid and transgene product pose significant hurdles to the efficacy and safety of gene therapy. Antibodies to the capsid can cause complement activation and prevent redosing, while T cell responses can mediate liver toxicity. Furthermore, responses against the transgene product can negatively impact therapy and cause tissue toxicities. Here, we investigated transient prophylactic immunosuppression at the time of AAV dosing as a means of mitigating immune responses, employing two clinically approved but mechanistically distinct drugs: abatacept, a CTLA-4-Ig fusion blocking T cell costimulation, and dasatinib, a small-molecule SRC kinase inhibitor that targets T cell receptor signaling. Results in mouse models demonstrate that both drugs can fully block neutralizing antibody formation against capsid, enable redosing by the systemic route, and suppress CD8+ T cell responses against capsid, albeit abatacept showed overall greater efficacy. Furthermore, both drugs inhibited adaptive responses against transgene products such as human Factor IX and ovalbumin. These findings identify two clinically viable strategies for managing both humoral and cellular immunity to AAV and its cargo. Due to its selectivity, pharmacokinetics/pharmacodynamics, and safety properties, abatacept appears particularly promising as an immunosuppressant that could critically improve the clinical translatability of AAV gene therapy.