Envisioning treating genetically-defined urinary tract malformations with viral vector-mediated gene therapy

Lopes, Filipa; Woolf, Adrian S.; Roberts, Neil

doi:10.1016/j.jpurol.2021.07.002

Cited by 7 publications

(2 citation statements)

References 68 publications

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“…Moreover, surgery to refashion the LUT in UFS is either ineffective or even worsens symptoms ( Ochoa, 2004 ). Given that some REOLUT disorders have defined monogenic causes, it has been reasoned that gene therapy might be a future option, but the strategy must first be tested on genetic mouse models that mimic aspects of the human diseases ( Lopes et al, 2021 ). The results presented in the current study constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.…”

Section: Discussionmentioning

confidence: 99%

Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

Lopes,

Grenier,

Jarvis

et al. 2024

eLife

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Rare early onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants of HPSE2 , encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts of Hpse2 mutant mice display impaired neurogenic relaxation. We hypothesized that HPSE2 gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral ( AAV ) vector-based approach. AAV9/HPSE2, carrying human HPSE2 driven by CAG , was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, and ex vivo myography was undertaken to measure bladder function. In mice administered AAV9/HPSE2 , the transduced genome was detected in pelvic ganglia, where human HPSE2 was also expressed. Moreover, heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, untreated mutant mice had distended urinary bladders, consistent with bladder outflow obstruction, but AAV9/HPSE2 - administered mice did not, thus resembling wild-type mice. AAV9/HPSE2 significantly ameliorated impaired neurogenic relaxation of Hpse2 mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly ameliorated by AAV9/HPSE2 . These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.

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Section: Discussionmentioning

confidence: 99%

Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

Lopes,

Grenier,

Jarvis

et al. 2024

eLife

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“…Atualmente, as terapias gênicas mediadas por vetores virais são muito caras, o Zolgensma, licenciado pelo FDA, é um tratamento sistêmico de dose única para crianças com AME, possuindo um custo de 2 milhões de dólares 30 . de reais e os anos seguintes 750 mil reais; enquanto o uso do Risdiplem demanda um investimento de mais de 630 mil reais por mês e o uso do Zolgensma cerca de 11 milhões de reais 33,34 .…”

Section: Changing Respiratory Expectations With the New Disease Traje...unclassified

The Strategies for the Treatment of Spinal Muscular Atrophy

De Castro Meira,

De Oliveira Ferreira Júnior,

Sasseron Agostinho

et al. 2024

RECIMA21

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A Atrofia Muscular Espinhal (AME) é uma doença neuromuscular congênita causada pela deleção ou mutação nos genes SMN1 e SMN2 do cromossomo 5q13, o que causa fraqueza muscular progressiva. O objetivo desta revisão de literatura é compreender as principais estratégias para o tratamento da AME, buscando analisar os estudos mais relevantes sobre o tema. Trata-se de uma revisão integrativa da literatura, sendo utilizados artigos de 2017 a 2022 dos bancos de dados: PubMed e BVS. Resultados: Os tipos de terapias para o tratamento da AME abordados nos artigos selecionados foram: 58,8% terapia de modulação de splicing; 47% estudos de novas terapias; 35,3% terapia direcionada a genes; 5,9% terapia neuroprotetora; 5,9% terapia de estabilização de proteínas e 5,9% terapia de substituição celular. A partir desta pesquisa verificamos que a AME ainda é uma doença sem cura. Os tratamentos farmacológicos existentes, principalmente o Nusinersen, retardam a evolução da doença para quadros mais graves, mas não recuperam a degeneração sofrida pelos neurônios motores. Assim, o objetivo principal dessas terapias é melhorar a qualidade de vida dos pacientes, aumentando e preservando a função muscular residual a fim de prolongar a expectativa de vida dos doentes.

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Narrowing the chromosome 22q11.2 locus duplicated in bladder exstrophy–epispadias complex

Beaman

Woolf

Lopes

et al. 2022

Journal of Pediatric Urology

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Envisioning treating genetically-defined urinary tract malformations with viral vector-mediated gene therapy

Abstract: mice to treat non-urinary tract diseases. If similar strategies were successful in animals with urinary tract malformations, this would pave the way for personalized and potentially curative treatments for people with urinary tract malformations.

Cited by 7 publications

References 68 publications

Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

Human HPSE2 gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome

The Strategies for the Treatment of Spinal Muscular Atrophy

Narrowing the chromosome 22q11.2 locus duplicated in bladder exstrophy–epispadias complex

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