Tyrosinemia type III in an asymptomatic girl

Szymańska, Edyta; Średzińska, Małgorzata; Ciara, Elżbieta; Piekutowska‐Abramczuk, Dorota; Płoski, Rafał; Rokicki, Dariusz; Tylki‐Szymańska, Anna

doi:10.1016/j.ymgmr.2015.10.004

Cited by 16 publications

(20 citation statements)

References 14 publications

(19 reference statements)

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“…Patients with mutations in the HPD gene are considered to have Type III Tyrosinemia and exhibit high level of tyrosine in blood, but otherwise appear to be largely asymptomatic [ 55 , 56 ]. HPD acts upstream of FAH in the tyrosine catabolism pathway and Hpd disruption ameliorates HT-I symptoms by preventing the toxic metabolite build-up that results from loss of FAH.…”

Section: Discussionmentioning

confidence: 99%

All-in-one adeno-associated virus delivery and genome editing by Neisseria meningitidis Cas9 in vivo

et al. 2018

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BackgroundClustered, regularly interspaced, short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) have recently opened a new avenue for gene therapy. Cas9 nuclease guided by a single-guide RNA (sgRNA) has been extensively used for genome editing. Currently, three Cas9 orthologs have been adapted for in vivo genome engineering applications: Streptococcus pyogenes Cas9 (SpyCas9), Staphylococcus aureus Cas9 (SauCas9), and Campylobacter jejuni (CjeCas9). However, additional in vivo editing platforms are needed, in part to enable a greater range of sequences to be accessed via viral vectors, especially those in which Cas9 and sgRNA are combined into a single vector genome.ResultsHere, we present in vivo editing using Neisseria meningitidis Cas9 (NmeCas9). NmeCas9 is compact, edits with high accuracy, and possesses a distinct protospacer adjacent motif (PAM), making it an excellent candidate for safe gene therapy applications. We find that NmeCas9 can be used to target the Pcsk9 and Hpd genes in mice. Using tail-vein hydrodynamic-based delivery of NmeCas9 plasmid to target the Hpd gene, we successfully reprogram the tyrosine degradation pathway in Hereditary Tyrosinemia Type I mice. More importantly, we deliver NmeCas9 with its sgRNA in a single recombinant adeno-associated vector (rAAV) to target Pcsk9, resulting in lower cholesterol levels in mice. This all-in-one vector yielded > 35% gene modification after two weeks of vector administration, with minimal off-target cleavage in vivo.ConclusionsOur findings indicate that NmeCas9 can enable the editing of disease-causing loci in vivo, expanding the targeting scope of RNA-guided nucleases.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1515-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

All-in-one adeno-associated virus delivery and genome editing by Neisseria meningitidis Cas9 in vivo

et al. 2018

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“…Patients with mutations in the HPD gene are considered to have Type III Tyrosinemia and exhibit high level of tyrosine in blood, but otherwise appear to be largely asymptomatic (52,53).…”

Section: Pathway Reprogramingmentioning

confidence: 99%

All-in-One Adeno-associated Virus Delivery and Genome Editing by Neisseria meningitidis Cas9 in vivo

Ibraheim¹,

Song²,

Mir³

et al. 2018

Preprint

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Clustered, regularly interspaced, short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) have recently opened a new avenue for gene therapy. Cas9 nuclease guided by a single-guide RNA (sgRNA) has been extensively used for genome editing. Currently, three Cas9 orthologs have been adapted for in vivo genome engineering applications: SpyCas9, SauCas9 and CjeCas9. However, additional in vivo editing platforms are needed, in part to enable a greater range of sequences to be accessed via viral vectors. Here, we present an additional in vivo editing platform using Neisseria meningitidis Cas9 (NmeCas9). NmeCas9 is compact, edits with high accuracy, and possesses a distinct PAM, making it an excellent candidate for safe gene therapy applications. Here we demonstrate that NmeCas9 can be used to target the Pcsk9 and Hpd genes in mice. Using tail vein hydrodynamic-based delivery of NmeCas9 plasmid to target the Hpd gene, we successfully reprogrammed the tyrosine degradation pathway in Hereditary Tyrosinemia Type I mice. More importantly, we delivered NmeCas9 with its single-guide RNA in a single recombinant adeno-associated vector (rAAV) to target Pcsk9, resulting in lower cholesterol levels in mice. This all-in-one vector yielded >35% gene modification after two weeks of vector administration, with minimal off-target cleavage in vivo. Our findings indicate that NmeCas9 can facilitate future efforts to correct disease-causing mutations by expanding the targeting scope of RNA-guided nucleases.3 SignificanceWe and others have shown that NmeCas9 is an efficient Cas9 nuclease with a high degree of specificity in cultured human cells. NmeCas9 has a unique PAM that expands the targeting range of Cas9-based genome editing. Since NmeCas9 is more compact than SpyCas9, its delivery with its guide-RNA in a single recombinant adeno-associated virus becomes a viable option. Furthermore, NmeCas9 has an unusually low off-target profile. These characteristics make NmeCas9 an ideal candidate for in vivo genome editing, including therapeutic gene knockouts, as we demonstrate in the mouse liver. We anticipate that successful in vivo delivery of this accurate and effective Cas9 can advance therapeutic editing in humans.

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“…However, it was not clear if the nephrological complications were associated with tyrosinemia type III. 4 In a 2001 review, which included 13 patients, the most common long-term complication was intellectual impairment (75% patients). Five patients were diagnosed by newborn screening, three of whom started a low-tyrosine and -phenylalanine diet after diagnosis; among them, two had no symptoms and presented normal development at 13 months and five years and five months, respectively, while the third had a delayed psychomotor development but demonstrated an average developmental quotient at the age of four (Griffiths Mental Development Scale).…”

Section: Discussionmentioning

confidence: 99%

Tyrosinemia Type Iii: A Case Report of Siblings and Literature Review

Barroso

Correia

Bandeira

et al. 2020

Rev. paul. pediatr.

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ABSTRACT Objective: Tyrosinemia type III (HT III) is the rarest form of tyrosinemia, and the full clinical spectrum of this disorder is still unknown. The neurological involvement varies, including intellectual impairment and attention deficit disorder with hyperactivity (ADHD). We report the case of two siblings diagnosed with HT III at different ages. Case description: The index case was diagnosed by newborn screening for endocrine and metabolic disorders, starting a low-protein diet immediately, with a consistent decrease in tyrosine levels. By the age of three, the child displayed a hyperactive behavior, starting treatment for ADHD two years later. At seven years of age, he shows a slight improvement in terms of behavior and attention span and has a cognitive performance slightly lower than his peers, despite maintaining acceptable tyrosine levels. His sister, who had a history of ADHD since age five, was diagnosed with HT III after family screening at the age of eight. Despite initiating a dietetic treatment, her behavior did not improve, and she has a mild intellectual impairment. Comments: This is the first case report describing siblings with HT III who underwent nutritional treatment with a low-protein diet in different phases of life, with a better neurological and behavioral evaluation in the patient who started treatment earlier.

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Tyrosinemia type III in an asymptomatic girl

Cited by 16 publications

References 14 publications

All-in-one adeno-associated virus delivery and genome editing by Neisseria meningitidis Cas9 in vivo

All-in-one adeno-associated virus delivery and genome editing by Neisseria meningitidis Cas9 in vivo

All-in-One Adeno-associated Virus Delivery and Genome Editing by Neisseria meningitidis Cas9 in vivo

Tyrosinemia Type Iii: A Case Report of Siblings and Literature Review

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