SEARCHSYSTEMATIC_REVIEWneurology, pediatrics

systematic_review·neurology, pediatrics, genetics, neuroscience, developmental_medicine·PMC10219055

Evidence Synthesis of Gene Therapy and Gene Editing from Different Disorders—Implications for Individuals with Rett Syndrome: A Systematic Review

International Journal of Molecular Sciences · 3 authors, 3 centres

AI SUMMARY

FIDELITY 68%

POPULATIONPatients with genetic disorders including metachromatic leukodystrophy, cerebral adrenoleukodystrophy, Duchenne muscular dystrophy, spinal muscular atrophy type 1, hemophilia A, β-thalassemia, sickle cell disease, Tay-Sachs disease, mucopolysaccharidosis type IIIA, neuronal ceroid lipofuscinosis 7, Fabry disease, Rett syndrome, Angelman syndrome, retinal dystrophies, Wiskott-Aldrich syndrome, amyotrophic lateral sclerosis, and Huntington's disease

INTERVENTIONGene therapy (lentiviral or AAV vectors) or gene editing (CRISPR/Cas9, antisense oligonucleotides)

COMPARISONNatural history cohorts, placebo controls, or untreated control groups where available

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AGENT 01 · STRUCTURED SUMMARY

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TL;DR

This systematic review of 29 gene therapy studies across multiple disorders (leukodystrophies, neuromuscular diseases, hemoglobinopathies, and others) identified four key themes: therapeutic time window, administration/dosing strategies, methods of gene therapeutics, and future clinical considerations. The most prominent finding was that early intervention before significant neurological deterioration predicts better outcomes, with 80% of studies supporting a critical therapeutic window. For Rett syndrome specifically, the review suggests gene therapy would be optimal before Stage 1 regression, with intracranial administration routes potentially more effective, though challenges remain regarding MeCP2 dosage sensitivity, biodistribution, and lack of early biomarkers.

Full summary

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**Background:** Rett syndrome (RTT) is caused by pathogenic loss-of-function of the MECP2 gene, leading to impaired chromatin modulation and disruption of long genes critical for neuronal development. Currently, no transformative therapies exist for RTT, with management focused on symptoms. While mouse models show neurological defects can be reversed, gene therapy in RTT is complicated by functional mosaic expression of MeCP2 due to X-chromosome inactivation, requiring precise dosing to avoid MECP2 duplication syndrome. This systematic review aimed to synthesize evidence from gene therapy studies across multiple disorders to identify themes applicable to future RTT gene therapy trials.

**Methods:** Following PRISMA guidelines, two authors independently searched PubMed, Scopus, Cochrane, PsycINFO, Embase, and Web of Science from December 2022. Primary search terms targeted RTT and MECP2; secondary searches covered Angelman syndrome, MECP2 duplication syndrome, and tuberous sclerosis complex. A snowballing approach identified additional articles. Inclusion criteria: full-text peer-reviewed articles from 2012 onward, human studies. Exclusion criteria: non-English articles, animal models, reviews, preprints, conference abstracts. Data extraction and thematic analysis were performed independently by two authors with consensus agreement.

**Key Results:** From 473 initial records, 29 articles were included in the final analysis. Four themes emerged: (1) Therapeutic time window (12 articles, most prominent theme) — 80% of these studies supported early intervention for optimal outcomes. In metachromatic leukodystrophy (MLD), infants entering rapid disease progression did not benefit from arsa-cel treatment. In cerebral adrenoleukodystrophy, neurological deterioration occurred in all but the youngest patient treated at 4.4 years. In Tay-Sachs disease, patient A (treated at 30 months) remained seizure-free at 5 years, while patient B (treated at 7 months) showed clinical stabilization for 3 months then deteriorated. In mucopolysaccharidosis type IIIA, neurocognitive improvements were mainly observed in the youngest child (2 years 8 months). However, evidence against a strict time window included an Angelman syndrome model not dependent on critical timing, and Leber's Congenital Amaurosis patients aged 17-23 years showing greatest improvement. (2) Administration and dosing strategies (4 articles) — high-dose AAV avoided dose escalation in Duchenne muscular dystrophy; isolated limb infusion replaced systemic delivery in limb-girdle muscular dystrophy; intrathecal AAV provided sustained single-dose effect in ALS; dose-dependent HTT protein reduction was seen in Huntington's disease CSF. (3) Methods of gene therapeutics (3 articles) — antisense oligonucleotide (Milasen) personalized within 1 year for CLN7 reduced seizure frequency; CRISPR/Cas9 corrected MECP2 c.473C>T hotspot with high precision in RTT primary cells; AAV-CRISPR/Cas9 corrected FOXG1 variants in RTT patient-derived cells. (4) Future clinical interest (2 articles) — pre-treatment MRI could facilitate gene transfer in Becker muscular dystrophy; glucocorticoid regimens and lifestyle factors may influence host response variability in hemophilia A.

**Clinical Implications:** For RTT, the evidence synthesis suggests gene therapy would be optimal before Stage 1 regression but should be avoided during the regression phase (Stage 2) when worsening symptoms could mask treatment side effects. Treatment may still benefit patients past the plateau stage (Stage 3) for clinical stabilization. Intracranial administration routes targeting specific brain regions may be more effective but riskier. Lower doses could be used with earlier treatment. Key challenges include: no established molecular or developmental biomarkers for early detection, MeCP2 dosage sensitivity (1.6-2.4 times normal expression causes MDS symptoms, 3.8-fold is lethal), immune responses, transduction efficiencies, and biodistribution limitations. Current RTT gene therapy trials use modified AAVs with miRARE or EXACT technology to regulate MECP2 dosage. The review recommends wearable sensor-based biomarkers and the Multi-system Profile of Symptoms Scale for patient stratification and longitudinal monitoring. Pharmacogenomics could minimize drug reactions from long-term immunosuppressant use. The prevalence of RTT is 5-10 cases per 100,000 females.

PICO

PPOPULATION

Patients with genetic disorders including metachromatic leukodystrophy, cerebral adrenoleukodystrophy, Duchenne muscular dystrophy, spinal muscular atrophy type 1, hemophilia A, β-thalassemia, sickle cell disease, Tay-Sachs disease, mucopolysaccharidosis type IIIA, neuronal ceroid lipofuscinosis 7, Fabry disease, Rett syndrome, Angelman syndrome, retinal dystrophies, Wiskott-Aldrich syndrome, amyotrophic lateral sclerosis, and Huntington's disease

IINTERVENTION

Gene therapy (lentiviral or AAV vectors) or gene editing (CRISPR/Cas9, antisense oligonucleotides)

OOUTCOME

Safety, tolerability, efficacy (motor function, cognitive function, biomarker levels, survival), and clinical improvement across disorders

STUDY TYPE

systematic_review

SPECIALTY

neurology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

68% · C

ORIGINAL PAPER

PMC10219055

Evidence Synthesis of Gene Therapy and Gene Editing from Different Disorders—Implications for Individuals with Rett Syndrome: A Systematic Review

International Journal of Molecular Sciences

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ABSTRACT

Abstract This systematic review and thematic analysis critically evaluated gene therapy trials in amyotrophic lateral sclerosis, haemoglobinopathies, immunodeficiencies, leukodystrophies, lysosomal storage disorders and retinal dystrophies and extrapolated the key clinical findings to individuals with Rett syndrome (RTT). The PRISMA guidelines were used to search six databases during the last decade, followed by a thematic analysis to identify the emerging themes. Thematic analysis across the different disorders revealed four themes: (I) Therapeutic time window of gene therapy; (II) Administration and dosing strategies for gene therapy; (III) Methods of gene therapeutics and (IV) Future areas of clinical interest. Our synthesis of information has further enriched the current clinical evidence base and can assist in optimising gene therapy and gene editing studies in individuals with RTT, but it would also benefit when applied to other disorders. The findings suggest that gene therapies have better outcomes when the brain is not the primary target. Across different disorders, early intervention appears to be more critical, and targeting the pre-symptomatic stage might prevent symptom pathology. Intervention at later stages of disease progression may benefit by helping to clinically stabilise patients and preventing disease-related symptoms from worsening. If gene therapy or editing has the desired outcome, older patients would need concerted rehabilitation efforts to reverse their impairments. The timing of intervention and the administration route would be critical parameters for successful outcomes of gene therapy/editing trials in individuals with RTT. Current approaches also need to overcome the challenges of MeCP2 dosing, genotoxicity, transduction efficiencies and biodistribution. Keywords: gene therapy, gene editing, genetic disorders, neurodevelopment, brain, Rett syndrome

CITATION EXPORT

Jatinder Singh, Ella Goodman-Vincent, Paramala Santosh. Evidence Synthesis of Gene Therapy and Gene Editing from Different Disorders—Implications for Individuals with Rett Syndrome: A Systematic Review. International Journal of Molecular Sciences. (2023). https://doi.org/10.3390/ijms24109023

AUTHORS

3 · 3 CENTRES

Jatinder Singh, Ella Goodman-Vincent, Paramala Santosh

1Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK; [email protected] (J.S.); [email protected] (E.G.-V.)
2Centre for Interventional Paediatric Psychopharmacology and Rare Diseases (CIPPRD), South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK
3Centre for Interventional Paediatric Psychopharmacology (CIPP) Rett Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London and South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK