Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I

Gil‐Martínez, Jon; Macías, Iratxe; Unione, Luca; Bernardo‐Seisdedos, Ganeko; Lopitz‐Otsoa, Fernando; Fernández‐Ramos, David; Laín, Ana; Sanz-Parra, Arantza; Mato, José M.; Millet, Óscar

doi:10.3390/ijms22041789

Cited by 4 publications

(2 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given that nitisinone has availability problems and liver transplantation carries risks of surgical complications, there is a need for new, effective, and less expensive treatments, especially for developing countries. Other therapeutic options are currently being explored for this disease, such as the use of molecular chaperones (35) and gene therapy (36).…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and Therapeutic Challenges of Hereditary Tyrosinemia Type 1 in Lebanon: A 12-Year Retrospective Review

et al. 2021

View full text Add to dashboard Cite

Background: Hereditary tyrosinemia type 1 is a rare genetic disorder leading to liver cirrhosis and hepatocellular carcinoma. Few decades ago, dietary measures and ultimately liver transplant constituted the only treatment modalities. Nowadays, early diagnosis and therapy with nitisinone can reverse the clinical picture. In developing countries, diagnostic and therapeutic challenges may affect the outcome of this disease. The choice of the treatment modality may depend on the economic status of each country. Few reports on the long-term outcome of hereditary tyrosinemia type 1 are available from developing and Arab countries.Methods: A retrospective study of charts of Lebanese patients diagnosed with tyrosinemia type 1 and followed, at the American University of Beirut, during a 12-year period was performed. Clinical presentation and liver biochemical profile at diagnosis were analyzed, along with therapeutic modalities and long-term outcome.Results: Twenty-two children were diagnosed and followed during the study period. Median age at diagnosis was 7 months (range: one day to 35 months). Most of the patients presented with hepatomegaly and jaundice. Four patients were referred for atypical presentations with developmental delay and seizures, secondary to undiagnosed hypoglycemia episodes. Around half of the patients presented with failure to thrive. Transaminitis, cholestasis and increased α-fetoprotein level were variably present at diagnosis (36% to 50%). All patients had elevated plasma tyrosine and urinary succinylacetone levels. Genetic testing was performed in 9%. Only one third could be treated with nitisinone. Liver transplant was electively performed in 9% of cases, to overcome the long-term cost of nitisinone. One third of the patients died between the age of 1 month and 11 years. Surviving patients are still candidates for liver transplant.Conclusion: Our experience reflects the challenges of diagnosis and treatment of hereditary tyrosinemia type 1 in a developing country. In the absence of specific neonatal screening, early diagnosis relies mostly on the clinical awareness of the physician. Long-term nitisinone use may be deterred by its high cost and liver transplantation carries risks of surgical complications. New, effective, and less expensive treatments are needed, especially for developing countries.

show abstract

Section: Discussionmentioning

confidence: 99%

Diagnostic and Therapeutic Challenges of Hereditary Tyrosinemia Type 1 in Lebanon: A 12-Year Retrospective Review

et al. 2021

View full text Add to dashboard Cite

show abstract

“…We recently demonstrated the medical plausibility of ciclopirox (CPX) for the treatment of CEP, acting as a pharmacological chaperone targeting uroporphyrinogen III synthase [3]. Pharmacological chaperones function by directly binding a folded or partially folded protein to stabilize it and allow completion of the folding process to yield a functional protein [11][12][13]. In turn, CPX is a topical treatment of cutaneous fungal infections and is believed to act as a fungicidal agent by chelating polyvalent metal cations such as Fe 3+ and Al 3+ , resulting in the inhibition of peroxide degradation [14].…”

Section: Introductionmentioning

confidence: 99%

Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic Porphyria

Bernardo‐Seisdedos¹,

Charco²,

SanJuan

et al. 2021

JPM

Self Cite

View full text Add to dashboard Cite

Congenital erythropoietic porphyria (CEP), also known as Günther’s disease, results from a deficient activity in the fourth enzyme, uroporphyrinogen III synthase (UROIIIS), of the heme pathway. Ciclopirox (CPX) is an off-label drug, topically prescribed as an antifungal. It has been recently shown that it also acts as a pharmacological chaperone in CEP, presenting a specific activity in deleterious mutations in UROIIIS. Despite CPX is active at subtoxic concentrations, acute gastrointestinal (GI) toxicity was found due to the precipitation in the stomach of the active compound and subsequent accumulation in the intestine. To increase its systemic availability, we carried out pharmacokinetic (PK) and pharmacodynamic (PD) studies using alternative formulations for CPX. Such strategy effectively suppressed GI toxicity in WT mice and in a mouse model of the CEP disease (UROIIISP248Q/P248Q). In terms of activity, phosphorylation of CPX yielded good results in CEP cellular models but showed limited activity when administered to the CEP mouse model. These results highlight the need of a proper formulation for pharmacological chaperones used in the treatment of rare diseases.

show abstract

The use of pharmacological chaperones in rare diseases caused by reduced protein stability

et al. 2022

Self Cite

View full text Add to dashboard Cite

Rare diseases are most often caused by inherited genetic disorders that, after translation, will result in a protein with altered function. Decreased protein stability is the most frequent mechanism associated with a congenital pathogenic missense mutation and it implies the destabilization of the folded conformation in favour of unfolded or misfolded states. In the cellular context and when experimental data is available, a mutant protein with altered thermodynamic stability often also results in impaired homeostasis, with the deleterious accumulation of protein aggregates, metabolites and/or metabolic by‐products. In the last decades, a significant effort has enabled the characterization of rare diseases associated to protein stability defects and triggered the development of innovative therapeutic intervention lines, say, the use of pharmacological chaperones to correct the intracellular impaired homeostasis. Here, we review the current knowledge on rare diseases caused by reduced protein stability, paying special attention to the thermodynamic aspects of the protein destabilization, also focusing on some examples where pharmacological chaperones are being tested.

show abstract

Therapeutic Targeting of Fumaryl Acetoacetate Hydrolase in Hereditary Tyrosinemia Type I

Cited by 4 publications

References 33 publications

Diagnostic and Therapeutic Challenges of Hereditary Tyrosinemia Type 1 in Lebanon: A 12-Year Retrospective Review

Diagnostic and Therapeutic Challenges of Hereditary Tyrosinemia Type 1 in Lebanon: A 12-Year Retrospective Review

Improving the Pharmacological Properties of Ciclopirox for Its Use in Congenital Erythropoietic Porphyria

The use of pharmacological chaperones in rare diseases caused by reduced protein stability

Contact Info

Product

Resources

About