A single combination gene therapy treats multiple age-related diseases.
Proc Natl Acad Sci U S A
; 116(47): 23505-23511, 2019 11 19.
Article
em En
| MEDLINE
| ID: mdl-31685628
ABSTRACT
Comorbidity is common as age increases, and currently prescribed treatments often ignore the interconnectedness of the involved age-related diseases. The presence of any one such disease usually increases the risk of having others, and new approaches will be more effective at increasing an individual's health span by taking this systems-level view into account. In this study, we developed gene therapies based on 3 longevity associated genes (fibroblast growth factor 21 [FGF21], αKlotho, soluble form of mouse transforming growth factor-ß receptor 2 [sTGFßR2]) delivered using adeno-associated viruses and explored their ability to mitigate 4 age-related diseases obesity, type II diabetes, heart failure, and renal failure. Individually and combinatorially, we applied these therapies to disease-specific mouse models and found that this set of diverse pathologies could be effectively treated and in some cases, even reversed with a single dose. We observed a 58% increase in heart function in ascending aortic constriction ensuing heart failure, a 38% reduction in α-smooth muscle actin (αSMA) expression, and a 75% reduction in renal medullary atrophy in mice subjected to unilateral ureteral obstruction and a complete reversal of obesity and diabetes phenotypes in mice fed a constant high-fat diet. Crucially, we discovered that a single formulation combining 2 separate therapies into 1 was able to treat all 4 diseases. These results emphasize the promise of gene therapy for treating diverse age-related ailments and demonstrate the potential of combination gene therapy that may improve health span and longevity by addressing multiple diseases at once.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Envelhecimento
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Terapia Genética
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Diabetes Mellitus Experimental
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Fator de Crescimento Transformador beta1
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Fatores de Crescimento de Fibroblastos
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Receptor do Fator de Crescimento Transformador beta Tipo II
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Glucuronidase
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Insuficiência Cardíaca
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Falência Renal Crônica
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Obesidade
Tipo de estudo:
Etiology_studies
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Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article