A single combination gene therapy treats multiple age-related diseases

Davidsohn, Noah; Pezone, Matthew J.; Vernet, Andyna; Graveline, Amanda; Oliver, Daniel; Slomovic, Shimyn; Punthambaker, Sukanya; Sun, Xiaoming; Liao, Ronglih; Bonventre, Joseph V.; Church, George M.

doi:10.1073/pnas.1910073116

Cited by 73 publications

(49 citation statements)

References 52 publications

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“…In a recent pioneering study, Davidsohn et al [132] showed in mice that a single delivery of three longevity associated genes, including fibroblast growth factor 21 (FGF21), αKlotho, and a soluble form of mouse transforming growth factor-β receptor 2 (sTGFβR2) using adeno-associated viruses can mitigate four age-related diseases: obesity, type 2 diabetes, heart failure, and renal failure. These results emphasize the promise of gene therapy for the treatment of diverse age-related ailments.…”

Section: Future Directionsmentioning

confidence: 99%

Presbycusis: An Update on Cochlear Mechanisms and Therapies

Wang

Puel

2020

JCM

156

125

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Age-related hearing impairment (ARHI), also referred to as presbycusis, is the most common sensory impairment seen in the elderly. As our cochlea, the peripheral organ of hearing, ages, we tend to experience a decline in hearing and are at greater risk of cochlear sensory-neural cell degeneration and exacerbated age-related hearing impairments, e.g., gradual hearing loss, deterioration in speech comprehension (especially in noisy environments), difficulty in the localization sound sources, and ringing sensations in the ears. However, the aging process does not affect people uniformly; nor, in fact, does the aging process appear to be uniform even within an individual. Here, we outline recent research into chronological cochlear age in healthy people, and exacerbated hearing impairments during aging due to both extrinsic factors including noise and ototoxic medication, and intrinsic factors such as genetic predisposition, epigenetic factors, and aging. We review our current understanding of molecular pathways mediating ARHL and discuss recent discoveries in experimental hearing restoration and future prospects.

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Section: Future Directionsmentioning

confidence: 99%

Presbycusis: An Update on Cochlear Mechanisms and Therapies

Wang

Puel

2020

JCM

156

125

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“…In fact, three-fold overexpression of TGFβ in mice caused glomerulosclerosis and albuminuria (59). More recently, administration of a soluble TGFβ receptor II by a gene therapy protocol to mice with renal fibrosis, where TGFβ contributes to the pathology, showed significant beneficial effects (60). These results conclusively demonstrate a significant pathologic role of TGFβ in renal diseases, suggesting blocking of TGFβ may be beneficial in renal fibrosis.…”

Section: Discussionmentioning

confidence: 91%

TGFβ acts through PDGFRβ to activate mTORC1 via the Akt/PRAS40 axis and causes glomerular mesangial cell hypertrophy and matrix protein expression

Maity

Das

Kasinath

et al. 2020

Journal of Biological Chemistry

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Interaction of TGFβ-induced canonical signaling with the noncanonical kinase cascades regulates glomerular hypertrophy and matrix protein deposition, which are early features of glomerulosclerosis. However, the specific target downstream of TGFβ receptor involved in the noncanonical signaling is unknown. Here, we show that TGFβ increased the catalytic loop phosphorylation of platelet-derived growth factor receptor beta (PDGFRβ), a receptor tyrosine kinase expressed abundantly in glomerular mesangial cells. TGFβ increased phosphorylation of the PI 3 kinase-interacting Tyr-751 residue of PDGFRβ, thus activating Akt. Inhibition of PDGFRβ using a pharmacological inhibitor and siRNAs blocked TGFβ-stimulated phosphorylation of PRAS40, an intrinsic inhibitory component of mTORC1, and prevented activation of mTORC1 in the absence of any effect on Smad 2/3 phosphorylation. Expression of constitutively active Myr-Akt reversed the siPDGFRβ-mediated inhibition of mTORC1 activity; however, co-expression of phospho-deficient mutant of PRAS40 inhibited the effect of Myr-Akt, suggesting a definitive role of PRAS40 phosphorylation in mTORC1 activation downstream of PDGFRβ in mesangial cells. Additionally, we demonstrate that PDGFRβ-initiated phosphorylation of PRAS40 is required for TGFβ-induced mesangial cell hypertrophy and, fibronectin and collagen I (α2) production. Increased activating phosphorylation of PDGFRβ is also associated with enhanced TGFβ expression and mTORC1 activation in the kidney cortex and glomeruli of diabetic mice and rat, respectively. Thus, pursuing the TGFβ noncanonical signaling, we identified how TGFβ receptor I achieves mTORC1 activation through PDGFRβ-mediated Akt/PRAS40 phosphorylation to spur mesangial cell hypertrophy and matrix protein accumulation. These findings provide support for targeting PDGFRβ in TGFβ-driven renal fibrosis.

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“…Whilst the modulation of Klotho expression in transgenic mice has been shown to extend lifespan by up to 30%, it is increasingly recognised that prevention or treatment of these diseases may involve the perturbation of multiple genetic pathways [2,139,140]. Taking this in to consideration, Davidsohn and colleagues undertook an in vivo study to evaluate gene therapies based on three longevity associated genes (fibroblast growth factor 21 [FGF21], Klotho, the soluble form of the mouse transforming growth factor receptor 2 [sTGFβR2]) delivered individually and in combination using AAV, and explored their ability to alleviate four age-related diseases-obesity, type II diabetes, heart failure, and renal failure [141]. They observed that a single formulation combining two separate gene therapies into a single agent was able to treat all four diseases.…”

Section: Therapeutic Approaches To Klotho Deliverymentioning

confidence: 99%

Klotho and the Treatment of Human Malignancies

Sachdeva

Gouge

Kontovounisios

et al. 2020

Cancers

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Klotho was first discovered as an anti-ageing protein linked to a number of age-related disease processes, including cardiovascular, renal, musculoskeletal, and neurodegenerative conditions. Emerging research has also demonstrated a potential therapeutic role for Klotho in cancer biology, which is perhaps unsurprising given that cancer and ageing share similar molecular hallmarks. In addition to functioning as a tumour suppressor in numerous solid tumours and haematological malignancies, Klotho represents a candidate therapeutic target for patients with these diseases, the majority of whom have limited treatment options. Here, we examine contemporary evidence evaluating the anti-neoplastic effects of Klotho and describe the modulation of downstream oncogenic signalling pathways, including Wnt/β-catenin, FGF, IGF1, PIK3K/AKT, TGFβ, and the Unfolded Protein Response. We also discuss possible approaches to developing therapeutic Klotho and consider technological advances that may facilitate the delivery of Klotho through gene therapy.

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A single combination gene therapy treats multiple age-related diseases

Cited by 73 publications

References 52 publications

Presbycusis: An Update on Cochlear Mechanisms and Therapies

Presbycusis: An Update on Cochlear Mechanisms and Therapies

TGFβ acts through PDGFRβ to activate mTORC1 via the Akt/PRAS40 axis and causes glomerular mesangial cell hypertrophy and matrix protein expression

Klotho and the Treatment of Human Malignancies

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