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Developing Gene Therapy for Mitigating Multisystemic Pathology in Fabry Disease: Proof of Concept in an Aggravated
Natalia Boukharov, Shipeng Yuan, Wanida Ruangsirluk
1Takeda Pharmaceuticals USA, Inc., Cambridge, Massachusetts, USA.
Abstract:
Fabry disease (FD) is a multisystemic lysosomal storage disorder caused by the loss of α-galactosidase A (α-Gal) function. The current standard of care, enzyme replacement therapies, while effective in reducing kidney pathology when treated early, do not fully ameliorate cardiac issues, neuropathic manifestations, and risk of cerebrovascular events. Adeno-associated virus (AAV)-based gene therapies (AAV-GT) can provide superior efficacy across multiple tissues owing to continuous, endogenous production of the therapeutic enzyme and lower treatment burden. We set out to develop a robust AAV-GT to achieve optimal efficacy with the lowest feasible dose to minimize any safety risks that are associated with high-dose AAV-GTs. In this proof-of-concept study, we evaluated the effectiveness of an rAAV9 vector expressing human GLA transgene under a strong ubiquitous promoter, combined with woodchuck hepatitis virus posttranscriptional regulatory element (rAAV9-hGLA). We tested our GT at three different doses, 5e10 vg/kg, 2.5e11 vg/kg, and 6.25e12 vg/kg in the G3Stg/GLAko Fabry mouse model that has tissue Gb3 substrate levels comparable with patients with FD and develops several early FD pathologies. After intravenous injections of rAAV9-hGLA at 11 weeks of age, we observed dose-dependent increases in α-Gal activity in the key target tissues, reaching as high as 393-fold of WT in the kidneys and 6156-fold in the heart at the highest dose. Complete or near-complete substrate clearance was observed in animals treated with the two higher dose levels tested in all tissues except for the brain. We also found dose-dependent improvements in several pathological biomarkers, as well as prevention of structural and functional organ pathology. Taken together, these results indicate that an AAV-GT under a strong ubiquitous promoter has the potential to address the unmet therapeutic needs in patients with FD at relatively low doses.
Insights
Adeno-associated virus gene therapy (AAV-GT) shows promise for Fabry disease (FD). This study demonstrates AAV-GT effectively reduces substrate buildup and improves pathology in a mouse model, suggesting potential for treating FD patients.
Area of Science:
- Gene Therapy
- Lysosomal Storage Disorders
- Molecular Medicine
Background:
- Fabry disease (FD) is a severe genetic disorder caused by deficient α-galactosidase A (α-Gal) enzyme activity.
- Current enzyme replacement therapies for FD have limitations in addressing cardiac, neurological, and cerebrovascular complications.
- Adeno-associated virus gene therapy (AAV-GT) offers a potential alternative for sustained therapeutic enzyme production across multiple tissues.
Purpose of the Study:
- To develop and evaluate a novel adeno-associated virus gene therapy (AAV-GT) for Fabry disease (FD).
- To determine the efficacy and optimal dosage of an rAAV9-hGLA vector in a preclinical FD mouse model.
- To assess the potential of AAV-GT to address unmet therapeutic needs in FD with minimized safety risks.
Main Methods:
- An rAAV9 vector expressing the human GLA gene under a strong ubiquitous promoter was constructed (rAAV9-hGLA).
- The rAAV9-hGLA vector was administered intravenously at three different doses (5e10, 2.5e11, and 6.25e12 vg/kg) to the G3Stg/GLAko Fabry mouse model.
- Enzyme activity, substrate levels, pathological biomarkers, and organ pathology were assessed post-treatment.
Main Results:
- Dose-dependent increases in α-Gal activity were observed in target tissues, with significant elevations at higher doses.
- Complete or near-complete clearance of the Gb3 substrate was achieved in most tissues (except the brain) at the two higher dose levels.
- Significant improvements in pathological biomarkers and prevention of organ damage were noted in a dose-dependent manner.
Conclusions:
- AAV-GT utilizing an rAAV9 vector with a strong ubiquitous promoter demonstrates significant therapeutic potential for Fabry disease.
- This AAV-GT approach can achieve substantial substrate reduction and ameliorate pathology in a preclinical model at relatively low doses.
- The findings support the potential of AAV-GT to overcome limitations of current therapies and address critical unmet needs in FD management.
