What is Gaucher's Disease?
 

Gaucher's Disease (GD) is a rare autosomal recessive inherited lysosomal storage disorder. Its core etiology lies in mutations in the glucocerebrosidase (GBA) gene, leading to a significant reduction or complete absence of this enzyme's activity. This enzymatic defect prevents the normal hydrolysis of its substrate, glucosylceramide (GlcCer), causing massive accumulation within lysosomes of the mononuclear phagocyte system and the formation of characteristic "Gaucher cells." These abnormal cells accumulate in organs such as the liver, spleen, and bone marrow, triggering a range of severe clinical symptoms.

Global epidemiological data show a standardized newborn incidence of 0.39-5.80 per 100,000 and a prevalence of 0.70-1.75 per 100,000 for GD, with significant variation across different ethnicities and regions.

Based on neurological involvement and rate of progression, Gaucher's Disease is classified into three types: Type I (non-neuronopathic), Type II (acute neuronopathic), and Type III (chronic or subacute neuronopathic). Type I is the most common, accounting for over 90% of cases, and primarily presents with hepatosplenomegaly, cytopenia, and bone disease without primary neurological symptoms. Type II is the rarest and most severe, with onset typically within the first year of life, rapid neurological deterioration, and death usually before age 3. Type III is characterized by progressive neurological impairment.
 

Pathogenesis
 

The fundamental cause of Gaucher's Disease is mutations in the GBA1 gene, leading to deficient activity of the enzyme glucocerebrosidase (GBA). Under normal conditions, GBA hydrolyzes glucosylceramide into glucose and ceramide. When GBA activity is reduced or absent, glucosylceramide cannot be hydrolyzed and gradually accumulates within macrophage lysosomes, forming "Gaucher cells." These cells aggregate extensively in organs like the liver, spleen, and bone marrow, causing organ enlargement and dysfunction.

 

(Image: PubMed)
 

Recent research has also found that GBA dysfunction not only affects lysosomal metabolism but also triggers multi-organ damage through pathways such as endoplasmic reticulum stress, mitochondrial dysfunction, and impaired autophagy. In the nervous system, abnormal aggregation of alpha-synuclein is closely linked to Gaucher-associated Parkinsonism. In the skeletal system, impaired osteoblast differentiation and an imbalance in osteoclast activation lead to bone disease.
 

(Image: PubMed)

Gene Therapy
 

● AAV-Mediated Gene Therapy: Research teams have used different AAV vector serotypes (e.g., AAV9, AAVrh10) administered intravenously or via the cerebrospinal fluid. These vectors have been shown to effectively transduce the liver and central nervous system. A 2019 study demonstrated that intravenous injection of AAV9-GBA significantly reduced glucosylceramide and Lyso-GL-1 levels in the viscera and brains of a Gaucher disease mouse model, improving neuroinflammation and neuronal damage. Treated animals also showed marked improvement in motor function and cognitive abilities.

● Hematopoietic Stem Cell Gene Therapy: Involves collecting hematopoietic stem cells from the patient, introducing a functional GBA gene using lentiviral vectors ex vivo, and then reinfusing these genetically modified cells. These engineered stem cells engraft in the bone marrow, differentiate into various blood cell lineages, and continuously release the active enzyme protein into the bloodstream.

Mouse Models

● Gba1 KO Mice: Exhibit severe neuronopathic and visceral organ pathology; a foundational model for early mechanistic studies.

● Gba1 D409V/D409V Mice: Model the partial loss of GCase activity seen in human Gaucher disease, exhibiting distinct neuropathological features, including accumulation of glycosphingolipids (such as GlcCer and GlcSph) in the brain.

● 4L/PS-NA Mice: Carry the Gba1 V394L mutation combined with prosaposin gene knockout, leading to severe neuropathy and motor dysfunction.

● Mx1-Cre+ Gba1flox/null Knockout Mice: Present with visceral symptoms (splenomegaly, anemia, elevated glycosphingolipid accumulation) but no central nervous system (CNS) involvement and have a normal lifespan, modeling non-neuronopathic GD (GD1).

● K14-lnl Mice: Retain skin-specific Gba1 expression via a keratin 14 (K14) promoter, develop rapid neurodegeneration (death within 2 weeks), modeling GD2.

● Nestin-Cre+ Gba1flox/flox Mice: Feature neuron- and glial cell-specific knockout of Gba1, leading to motor deficits (abnormal gait, limb stiffness) but retained GCase activity in microglia.

● UBC-CreERT2+ Gba1flox/flox Mice: Show weight loss, motor dysfunction (including gait abnormalities and hyperextension of the neck), and seizures, dying within 7 days after induction.
 

MingCeler Biotech Facilitates Gene Therapy
 

Gene therapy offers hope for rare diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has developed multiple rare disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target gene locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various Gaucher's Disease mouse models according to client needs, such as Gba1 KO mice, Gba1 D409V/D409V mice, 4L/PS-NA mice, Mx1-Cre+ Gba1flox/null knockout mice, K14-lnl mice, Nestin-Cre+ Gba1flox/flox mice, and UBC-CreERT2+ Gba1flox/flox mice. We welcome inquiries!
 

References:

[1] Stirnemann J, Belmatoug N, Camou F, Serratrice C, Froissart R, Caillaud C, Levade T, Astudillo L, Serratrice J, Brassier A, Rose C, Billette de Villemeur T, Berger MG. A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments. Int J Mol Sci. 2017 Feb 17;18(2):441. doi: 10.3390/ijms18020441. PMID: 28218669.

[2] Geard, A.F.; Massaro, G.; Hughes, M.P.; Arbuthnot, P.; Waddington, S.N.; Rahim, A.A. Generation and Treatment of a Novel Severe Model of Visceral Gaucher Disease by Genetic Therapy. Pharmaceutics 2025, 17, 650.

[3] Duan Yanlong. Advances in the Diagnosis and Treatment of Type III Gaucher Disease. Chinese Journal of Internal Medicine, 2023, 62(3): 329-333. DOI: 10.3760/cma.j.cn112138-20220802-00568

[4] Kulkarni A, Chen T, Sidransky E, Han TU. Advancements in Viral Gene Therapy for Gaucher Disease. Genes (Basel). 2024 Mar 15;15(3):364. doi: 10.3390/genes15030364. PMID: 38540423; PMCID: PMC10970163.

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