Dataset Information

Non-viral in situ gene editing effectively and safely rescues congenital ichthyosis-causing mutations in human skin

ABSTRACT: Autosomal recessive congenital ichthyosis (ARCI) refers to a group of rare, highly debilitating skin disorders which significantly impair patients’ quality of life and lack any effective treatment options. Here, we report clinically-relevant in situ correction of the most common ARCI-causing mutation TGM1 c.877-2A>G, a splice-site aberration, in human disease models. Targeted skin barrier modulation followed by topical application of the cytosine base editor eTD packaged into lipid nanoparticles yielded functional restoration of ~30% of wild-type transglutaminase 1 activity in skin tissue. Toxicity studies and comprehensive off-target analysis demonstrated an excellent safety profile even after repeated application, without systemic distribution of the lipid nanoparticles or the genetic cargo as determined via highly-sensitive methods including DESI metabolic imaging. This study presents comprehensive preclinical data on the feasibility of in situ gene correction of genodermatoses-causing mutations showcasing its therapeutic potential and paving the way for curative next-generation treatments for severe genetic skin diseases.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin

DISEASE(S): Autosomal Recessive Congenital Ichthyosis

SUBMITTER: Fabian Coscia

LAB HEAD: Fabian Coscia

PROVIDER: PXD072230 | Pride | 2026-01-23

REPOSITORIES: Pride

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			Action	DRS
	Bluto_20250702_FCo_Evo2_40SPDzoom_Elena_B02_S6-A1_1_12816.d.zip	Other
	Bluto_20250702_FCo_Evo2_40SPDzoom_Elena_B04_S6-A2_1_12817.d.zip	Other
	Bluto_20250702_FCo_Evo2_40SPDzoom_Elena_B06_S6-A3_1_12818.d.zip	Other
	Bluto_20250702_FCo_Evo2_40SPDzoom_Elena_B10_S6-A4_1_12819.d.zip	Other
	Bluto_20250702_FCo_Evo2_40SPDzoom_Elena_B14_S6-A5_1_12820.d.zip	Other

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Project description:Mitochondrial disorders show remarkable clinical and genetic heterogeneity, and result from genetic variants in either mitochondrial-encoded or nuclear-encoded genes. CHCHD4 is a component of the mitochondrial import and assembly (MIA) pathway that imports small cysteine-containing substrates such as TIM proteins, complex I and IV subunits and/or assembly factors. We report a child subject with biallelic CHCHD4 variants who presented with severe lactic acidosis, psychomotor and neurological regression. Western blot analysis in subject-derived fibroblasts showed decreased steady-state levels of CHCHD4 and a severe oxidative phosphorylation (OXPHOS) defect. Moreover, diminished assembly of both complexes I and IV was also observed. To demonstrate that the segregating CHCHD4 variants were responsible for the observed biochemical phenotype, we overexpressed wild-type CHCHD4 in control and subject fibroblasts, restoring steady-state levels of complex I and IV proteins and the associated OXPHOS assembly defects. Proteomic studies and Reactome enrichment of the altered proteins pointed to respiratory electron transport and complex I biogenesis as the main dysregulated pathways. More detailed analyses revealed a severe loss of several complex I and IV subunit proteins and/or assembly factors, that were rescued by overexpression of wild-type CHCHD4. CHCHD4 is involved in the import of several other mitochondrial proteins, has numerous targets and interacting factors and has been shown to be involved in the export of iron-sulfur clusters synthesized inside mitochondria, suggesting involvement in several mitochondrial and non-mitochondrial functions. Surprisingly, few of these interacting factors or non-mitochondrial functions were impacted by the observed CHCHD4 defect. In conclusion, our work establishes CHCHD4 deficiency as a new cause of dysregulated mitochondrial protein import, and suggests this gene should be investigated in subjects with this rare form of mitochondrial disease.

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Non-viral in situ gene editing effectively and safely rescues congenital ichthyosis-causing mutations in human skin

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