Madhumita Saha

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder arising predominantly from de novo loss-of-function mutations in MECP2, affecting approximately 1 in 10,000 live female births. MECP2 is a dosage-sensitive epigenetic regulator acting through its methyl-CpG-binding (MBD) and transcriptional-repression (TRD) domains; isoform-specific expression and X-chromosome-inactivation mosaicism drive the wide phenotypic variability, with mutation type broadly correlating with severity. Although historically viewed as neuron-centric, RTT is a multisystem disorder: beyond psychomotor regression, stereotypic hand movements, gait apraxia, and loss of spoken language, MECP2 deficiency contributes to brainstem-mediated breathing dysrhythmia, QTc prolongation, enteric dysmotility, low bone density, and mitochondrial/metabolic deficits, amplified by glial–neuronal crosstalk. Preclinical models, MECP2 rodents, patient iPSC-derived neurons, and cerebral organoids, reveal synaptic and dendritic deficits that improve substantially when MECP2 is reactivated in these systems, indicating that MECP2-deficient neurons remain viable rather than degenerating; whether comparable improvement can be achieved in affected individuals is not yet established. The therapeutic landscape now spans multidisciplinary supportive care, the first approved pharmacotherapy trofinetide, AAV-mediated MECP2 gene replacement (now in pivotal trials, with an important gene-therapy safety signal), antisense oligonucleotides for dosage normalisation, and emerging metabolic agents; validated biomarkers and objective outcome measures remain a major unmet need. Conclusion: RTT is a multisystem monogenic disorder whose management is shifting from symptom control toward disease modification. Phenotypic rescue after MECP2 restoration in rodent models provides the rationale for this shift but does not establish that RTT is reversible in patients; progress now depends on validated biomarkers, dose-controlled disease-modifying therapies, long-term outcome data, and equitable global access. Graphical abstract Integrated overview of Rett syndrome (RTT) from molecular cause to equitable translation. 1 MECP2 as a dosage-sensitive epigenetic reader encoded at Xq28, where a loss-of-function MECP2 variant impairs methylated-DNA binding and chromatin regulation and disrupts transcriptional, splicing, and synaptic gene networks; the MECP2-E1 (492 amino acids) and MECP2-E2 (486 amino acids) isoforms differ in distribution, and severity is modified by mutation type, residual function, and X-chromosome-inactivation mosaicism. Because too little MECP2 causes RTT while too much is also pathogenic, restoration must be dose-controlled, cell-aware, and brain-wide. 2 RTT extends well beyond the central nervous system, direct peripheral effects combining with brainstem autonomic dysfunction to involve brain and glia, breathing, cardiac, gastrointestinal, skeletal and metabolic systems, across the characteristic four-stage clinical trajectory. 3 A therapeutic landscape moving from whole-person supportive care toward controlled gene restoration, spanning trofinetide (modest symptom-level benefit), AAV gene replacement (milestone gains in uncontrolled single-arm programmes, with expression control and immune safety critical after a fatal high-dose event in 2024), and earlier-stage antisense, X-reactivation, editing, and small-molecule approaches. No approach has yet demonstrated reversal of established deficits in humans. 4 Translation, safety, and equitable access as the rate-limiting step, from earlier genetic diagnosis through registry-based natural-history data and biomarker-guided trials to equitable access What is Known: • More than 90–95% of classic Rett syndrome is caused by de novo loss-of-function mutations in MECP2, a dosage-sensitive epigenetic reader whose isoform distribution, residual function and X-chromosome-inactivation mosaicism together account for much of the phenotypic variability. • Reactivating MECP2 in symptomatic adult rodents substantially improves many disease features, establishing that MECP2-deficient neurons are functionally impaired rather than lost and providing the rationale for disease-modifying therapy. What is New: • This review integrates isoform-specific and non-neuronal (glial, respiratory, cardiac, gastrointestinal, skeletal and metabolic) mechanisms with a literature base updated to 15 August 2026, and identifies the continuing absence of any validated biomarker or surrogate endpoint, rather than target identification, as the principal obstacle to efficient trials. • It critically appraises the post-trofinetide landscape — divergent FDA and EMA assessments of the same trial data, a fatal high-dose AAV hyperinflammatory event, and single-arm registrational gene-therapy programmes reported largely outside peer review — and concludes that the demonstrated outcome to date is gain or re-acquisition of developmental milestones, not reversal of established disease.

Rett syndrome (RTT), an X-linked neurodevelopmental disorder predominantly arising from de novo MECP2 mutations, manifests with psychomotor regression, stereotypic hand movements, gait apraxia, and expressive aphasia, driven by dosage-sensitive epigenetic dysregulation via MeCP2's methyl-CpG-binding domain (MBD) and transcriptional repression domain (TRD). Isoform-specific expression (MeCP2-E1 neuronal predominance) and X-chromosome inactivation mosaicism underpin phenotypic variability, with missense (R133C, T158M) and nonsense (R168X, R255X) variants correlating to severity gradients. Multisystem pathophysiology encompasses brainstem-mediated respiratory dysrhythmias, QTc prolongation via ion channel perturbations, enteric hypomotility, osteopenic fractures, and mitochondrial bioenergetic deficits, exacerbated by glial-neuronal crosstalk and oxidative stress. Preclinical platforms, including Mecp2-null rodents, patient-derived iPSCs, and cerebral organoids, elucidate synaptic hyperexcitability, dendritic arborization deficits, and reversibility upon Mecp2 reactivation. Therapeutic modalities span supportive multidisciplinary interventions, FDA-approved trofinetide (IGF-1 analog modulating neurotrophic cascades), AAV-mediated gene replacement (NGN-401, TSHA-102 with miRARE autoregulation), ASOs for dosage normalization, and emerging PPAR-γ agonists targeting metabolic homeostasis. Prioritized research agendas emphasize validated biomarkers (BDNF/IGF-1 axes, miRNA signatures), combinatorial regimens, and equitable global access to mitigate caregiver burden and phenotypic heterogeneity.

Autism Spectrum Disorder (ASD) is a genetically heterogeneous neurodevelopmental condition driven by rare de novo variants, copy number variations, and polygenic risk. SFARI-curated genes show high mutational constraint and enriched expression in cortical neurons and glia. This review highlights recent advances in CRISPR-based functional genomics using human pluripotent stem cells and induced pluripotent stem cells differentiated into neural progenitors, excitatory and inhibitory neurons, astrocytes, microglia, and brain organoids. CRISPR modalities including knockouts, CRISPRi and CRISPRa, base and prime editing, and Cas13 enable pooled and arrayed screens with high coverage at low multiplicity of infection. Integration of multimodal readouts such as Perturb-seq, single-cell and spatial transcriptomics, proximity labeling proteomics, and functional assays including microelectrode arrays and calcium imaging provides system-level insights into ASD gene function. Computational frameworks like MIMOSCA and SCEPTRE facilitate network reconstruction and pseudo-time inference. Case studies reveal Wnt and BAF complex dysregulation, microglial pruning deficits, and non-cell autonomous effects. Translational approaches target haplo-insufficient genes such as CHD8 and SCN2A using AAV or antisense oligonucleotides supported by isogenic iPSC models. Remaining challenges include model immaturity and scalability, while future directions focus on spatial perturb-omics, AI-driven causal inference, and standardized biobanks for precision ASD therapeutics.

Biomineralization processes in terrestrial ecosystems facilitate durable carbon dioxide removal (CDR) by transforming atmospheric CO₂ into stable inorganic phases via interconnected biogeochemical pathways. This review elucidates the oxalate–carbonate pathway (OCP), wherein oxalogenic angiosperms biosynthesize calcium oxalate (CaC₂O₄) crystals, metabolized by rhizospheric oxalotrophs through oxalyl-CoA decarboxylase (oxc/frc)-mediated decarboxylation, generating alkalinity and bicarbonate for pedogenic CaCO₃ precipitation. Complementary mechanisms include microbially induced carbonate precipitation (MICP) via ureolysis (ureC), denitrification, sulfate reduction, and cyanobacterial photosynthetic CO₂ drawdown, nucleating calcite polymorphs with extracellular carbonic anhydrase catalysis; phytolith-occluded organic carbon (PhytOC) encapsulation in amorphous SiO₂ matrices exhibiting millennial recalcitrance; and enhanced rock weathering (ERW) accelerating silicate (e.g., basalt) dissolution to liberate Ca²⁺/Mg²⁺ for secondary carbonates. Empirical δ¹³C, radiocarbon, and clumped isotope (∆₄₇) analyses from iroko and basaltic fig systems quantify sequestration rates of 0.5–5 t CO₂ ha⁻¹ yr⁻¹, with permanence spanning 10³–10⁶ years. Proposed monitoring, reporting, and verification (MRV) frameworks integrate mineralogical speciation, functional metagenomics, and biomarkers to ensure additionality and mitigate risks. Translational strategies—agroforestry, microbial augmentation, ERW integration—harness co-benefits for edaphic fertility and biodiversity, positioning biomineralization as a gigaton-scale CDR paradigm bridging biogenic transience with geological stability.

Fungal ribosomally synthesized and post-translationally modified peptides (F-RiPPs) embody a paradoxical duality, transitioning from lethal mycotoxins to precision oncology payloads via antibody-drug conjugates (ADCs). This review portrays the biosynthetic logic of canonical families - amatoxins/phallotoxins, dikaritins, epichloëcyclins, and emergent asperigimycins, emphasizing PTMs like macrocyclization, N-methylation, and oxidative cross-links that confer proteolytic stability, membrane permeability, and target affinity. Genome mining pipelines integrating antiSMASH, seq2ripp, HypoRiPPAtlas, and GNPS molecular networking accelerate cryptic BGC decryption, heterologous expression in yeast/filamentous fungi, and combinatorial refactoring for analog libraries. Pharmacologically, F-RiPPs inhibit RNA Pol II (amatoxins), disrupt microtubules (dikaritins), perturb membranes (borosins), and induce lipid-mediated apoptosis (asperigimycins), with preclinical IC50s of 1–50 nM/μM and therapeutic indices >100 in xenografts. Translational exemplars include Heidelberg Pharma's ATACs, achieving Phase I/IIa remissions in myeloma/NHL via BCMA/CD37-targeted amanitin delivery. Addressing bottlenecks in silent cluster activation, enzyme mechanistics, and GMP-scaleup, a roadmap proposes ML-driven prioritization and automated heterologous platforms to harness untapped RiPP diversity for MDR-evasive, bystander-active therapeutics.

Neurodevelopmental and neurodegenerative disorders arise from intricate disruptions in brain architecture and function, often rooted in early development. Traditional models have limited capacity to replicate human neural complexity, prompting the emergence of advanced in vitro systems. This review discusses the evolution of brain organoids, assembloids, and organ-on-chip technologies derived from human pluripotent stem cells, highlighting their transformative impact on modeling Alzheimer’s and Parkinson’s diseases. Recent innovations—such as region-specific organoids, vascularized constructs, microfluidic systems, and integration of neuronal diversity—have enhanced the fidelity of these models in replicating human brain physiology and pathology. Organoid-based platforms have revealed novel insights into disease mechanisms, drug discovery, and therapeutic interventions, offering unprecedented windows into amyloid aggregation, neuroinflammation, dopaminergic neuron degeneration, and gut-brain axis interactions. Despite their promise, challenges persist, including limited vascularization, cellular stress, variability, and high production costs in organ-on-chip systems. Advances in standardization, vascularization, and immune system integration are critical for improving reproducibility and translational relevance. By bridging key gaps between basic neuroscience and clinical application, brain organoid technologies represent a new frontier in understanding and treating complex neurological diseases.

Circular RNA (circRNA) vaccines are emerging as a revolutionary strategy in cancer immunotherapy, offering novel mechanisms for inducing robust and durable immune responses. Unlike traditional linear mRNA vaccines, circRNAs exhibit exceptional stability, enhanced translational efficiency, and resistance to exonuclease degradation, making them ideal candidates for vaccine development. This review delves into the fundamental principles underlying circRNA biology, highlighting their unique structural advantages and translational potential. We examine recent advancements in circRNA vaccine design, focusing on their application in oncology. As the circRNA-based cancer vaccine is a relatively novel approach, accounts of all the major studies describing the efficacy have been discussed. To maximize the anti-cancer effects of circRNA vaccines, we also investigate their combination with other immunotherapeutic modalities such as immune checkpoint inhibitors and adoptive cell therapies. Large-scale manufacturing, immunogenicity optimization, delivery systems, and other challenges and future directions in the sector are also discussed. This study aims to thoroughly analyse the state-of-the-art and potential future applications of circRNA vaccines in cancer immunotherapy, highlighting them as exciting possibilities for next-generation cancer therapies.