A Possible Pathogenic Role for Virus-Carrier Lymphocytes

Nász, I; Kulcsár, G; Peng, Dan; Sallay, K

doi:10.1093/infdis/124.2.214

Cited by 27 publications

(9 citation statements)

References 3 publications

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“…Systemic enzyme replacement therapy (ERT) cannot prevent neurodegeneration in MPS I-H patients because the recombinant enzyme cannot enter the central nervous system (CNS) [13]. In contrast, aminoglycosides enter the CNS at ~10-20% of their serum concentration [14, 15]. We therefore evaluated whether long-term NB84 administration alleviated CNS phenotypes in Idua tm1Kmke mice.…”

Section: Resultsmentioning

confidence: 99%

Long-term nonsense suppression therapy moderates MPS I-H disease progression

Gunn

Dai

et al. 2014

Molecular Genetics and Metabolism

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Nonsense suppression therapy is a therapeutic approach aimed at treating genetic diseases caused by in-frame premature termination codons (PTCs; also commonly known as nonsense mutations). This approach utilizes compounds that suppress translation termination at PTCs, which allows translation to continue and partial levels of deficient protein function to be restored. We hypothesize that suppression therapy can attenuate the lysosomal storage disease mucopolysaccharidosis type I-Hurler (MPS I-H), the severe form of α-L-iduronidase deficiency. α-L-iduronidase participates in glycosaminoglycan (GAG) catabolism and its insufficiency causes progressive GAG accumulation and onset of the MPS I-H phenotype, which consists of multiple somatic and neurological defects. 60-80% of MPS I-H patients carry a nonsense mutation in the IDUA gene. We previously showed that 2-week treatment with the designer aminoglycoside NB84 restored enough α-L-iduronidase function via PTC suppression to reduce tissue GAG accumulation in the Iduatm1Kmke MPS I-H mouse model, which carries a PTC homologous to the human IDUA-W402X nonsense mutation. Here we report that long-term NB84 administration maintains α-L-iduronidase activity and GAG reduction in Iduatm1Kmke mice throughout a 28-week treatment period. Examination of more complex MPS I-H phenotypes in Iduatm1Kmke mice following 28-week NB84 treatment revealed significant moderation of the disease in multiple tissues, including the brain, heart and bone, that are resistant to current MPS I-H therapies. This study represents the first demonstration that long-term nonsense suppression therapy can moderate progression of a genetic disease.

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Section: Resultsmentioning

confidence: 99%

Long-term nonsense suppression therapy moderates MPS I-H disease progression

Gunn

Dai

et al. 2014

Molecular Genetics and Metabolism

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“…Persistence of adenovirus in normal human hosts has also been detected in the gastrointestinal and respiratory tracts for months after the initial infection and immune response [Evans, 1958;Fox et al, 1969;Hillis et al, 1973;Horwitz, 2001] with low levels of replicationcompetent virus remaining in the tonsils, adenoids and intestine [Israel, 1962;Nasz et al, 1971;van der Veen and Lambriex, 1973].…”

Section: Discussionmentioning

confidence: 99%

“…They have been detected in adult human lymphocytes [Horvath et al, 1986;Horwitz, 2001] and persistence or re-isolation of adenovirus from the gastrointestinal and respiratory tracts has been documented for months after the initial infection [Evans, 1958;Fox et al, 1969;Hillis et al, 1973;Horwitz, 2001]. Shedding in these systems may occur for months [Israel, 1962;Nasz et al, 1971;van der Veen and Lambriex, 1973] and low levels of adenovirus persistence have also been demonstrated in peripheral lymphocytes [Abken et al, 1987;Horwitz, 2001].…”

Section: Introductionmentioning

confidence: 99%

Evidence for persistence of adenovirus in the tear film a decade following conjunctivitis

et al. 2005

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Chronic papillary conjunctivitis has been described following adenoviral conjunctivitis. It is unknown however, how long adenovirus is able to persist in the tear film and conjunctiva. To determine if adenovirus persists in the ocular surface following adenoviral conjunctivitis, 304 patients with a history of adenovirus conjunctivitis from whom an adenovirus had been isolated 10 years previously were sent a questionnaire regarding persistent or recurrent symptoms and were invited to attend. Patients were examined and samples of tears and conjunctival cells were collected from both eyes using tear film washes, filter paper, and swabs, the latter for virus isolation. Extracted DNA from the ocular samples was amplified using primers for herpes simplex virus (thymidine kinase) and adenovirus (hexon) genes. Adenovirus amplicons were sequenced and compared to original serotype. Thirty patients attended, 19 of whom had persistent papillary conjunctivitis. Evidence of adenovirus DNA was detected in 17 of 30 patients, 15 of whom also had evidence of a chronic papillary conjunctivitis. Adenovirus DNA was significantly associated with papillary conjunctivitis (P = 0.03). Adenovirus amplicons were successfully sequenced from six patients. Four patients harbored type 3 adenovirus, the same serotype with which they were infected originally 10 years previously. Two patients were infected originally with adenovirus serotype 3 but the current serotype was type 4. Infection of the ocular surface with adenovirus may predispose to the development of a persistent or recurrent conjunctivitis, the presence of which, appears to be associated with evidence of long term persistence of adenovirus DNA.

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“…In particular, ERT is unable to treat MPS I-H neurological defects because the exogenously supplied recombinant protein is unable to cross the blood-brain barrier. Since PTC suppression agents are small molecules that cross the blood-brain barrier to some extent (McCracken et al, 1971, Riff and Jackson, 1971, Smith et al, 1988), suppression therapy may be a suitable approach to alleviate the neurological disease associated with MPS I-H. In addition, numerous drugs are under development to treat cystic fibrosis (CF) by targeting different aspects of CFTR protein localization and function depending upon the type of mutation in the affected individuals (Rogan et al, 2011, Cuthbert, 2010).…”

Section: Efforts To Overcome Suppression Therapy Limitationsmentioning

confidence: 99%

Suppression of premature termination codons as a therapeutic approach

Keeling¹,

Wang²,

Conard³

et al. 2012

Critical Reviews in Biochemistry and Molecular Biology

108

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In this review, we describe our current understanding of translation termination and pharmacological agents that influence the accuracy of this process. A number of drugs have been identified that induce suppression of translation termination at in-frame premature termination codons (PTCs; also known as nonsense mutations) in mammalian cells. We discuss efforts to utilize these drugs to suppress disease-causing PTCs that result in the loss of protein expression and function. In-frame PTCs represent a genotypic subset of mutations that make up ~11% of all known mutations that cause genetic diseases, and millions of patients have diseases attributable to PTCs. Current approaches aimed at reducing the efficiency of translation termination at PTCs (referred to as PTC suppression therapy) have the goal of alleviating the phenotypic consequences of a wide range of genetic diseases. Suppression therapy is currently in clinical trials for treatment of several genetic diseases caused by PTCs, and preliminary results suggest that some patients have shown clinical improvements. While current progress is promising, we discuss various approaches that may further enhance the efficiency of this novel therapeutic approach.

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A Possible Pathogenic Role for Virus-Carrier Lymphocytes

Cited by 27 publications

References 3 publications

Long-term nonsense suppression therapy moderates MPS I-H disease progression

Long-term nonsense suppression therapy moderates MPS I-H disease progression

Evidence for persistence of adenovirus in the tear film a decade following conjunctivitis

Suppression of premature termination codons as a therapeutic approach

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