Novel Gene-Correction-Based Therapeutic Modalities for Monogenic Liver Disorders

Ghasemzad, Mahsa; Hashemi, Mahdieh; Miri-Lavasani, Zohre; Bakhshandeh, Haleh; Gramignoli, Roberto; Alikhani, Hani Keshavarz; Najimi, Mustapha; Nikeghbalian, Saman; Vosough, Massoud

doi:10.3390/bioengineering9080392

Cited by 7 publications

(2 citation statements)

References 221 publications

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“…Liver transplant has shown promise in attenuating symptoms and helping normalize BCAA homeostasis and may be an option for some patients 32,33 . The benefits observed in some patients with liver transplant suggest that liver‐directed gene therapy also may hold promise as a treatment for MSUD 34,35 . Ultimately, an interventional therapy that alleviates the lifelong burden of dietary restrictions and concomitantly prevents or treats metabolic decompensation episodes would drastically improve patient morbidity and quality of life.…”

Section: Discussionmentioning

confidence: 99%

Oral enzyme therapy for maple syrup urine disease (MSUD) suppresses plasma leucine levels in intermediate MSUD mice and healthy nonhuman primates

Skvorak,

Liu,

Kruse

et al. 2023

J of Inher Metab Disea

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Maple syrup urine disease (MSUD) is an inborn error of branched‐chain amino acid metabolism affecting several thousand individuals worldwide. MSUD patients have elevated levels of plasma leucine and its metabolic product α‐ketoisocaproate (KIC), which can lead to severe neurotoxicity, coma, and death. Patients must maintain a strict diet of protein restriction and medical formula, and periods of noncompliance or illness can lead to acute metabolic decompensation or cumulative neurological impairment. Given the lack of therapeutic options for MSUD patients, we sought to develop an oral enzyme therapy that can degrade leucine within the gastrointestinal tract prior to its systemic absorption and thus enable patients to maintain acceptable plasma leucine levels while broadening their access to natural protein. We identified a highly active leucine decarboxylase enzyme from Planctomycetaceae bacterium and used directed evolution to engineer the enzyme for stability to gastric and intestinal conditions. Following high‐throughput screening of over 12 000 enzyme variants over 9 iterative rounds of evolution, we identified a lead variant, LDCv10, which retains activity following simulated gastric or intestinal conditions in vitro. In intermediate MSUD mice or healthy nonhuman primates given a whey protein meal, oral treatment with LDCv10 suppressed the spike in plasma leucine and KIC and reduced the leucine area under the curve in a dose‐dependent manner. Reduction in plasma leucine correlated with decreased brain leucine levels following oral LDCv10 treatment. Collectively, these data support further development of LDCv10 as a potential new therapy for MSUD patients.

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Section: Discussionmentioning

confidence: 99%

Oral enzyme therapy for maple syrup urine disease (MSUD) suppresses plasma leucine levels in intermediate MSUD mice and healthy nonhuman primates

Skvorak,

Liu,

Kruse

et al. 2023

J of Inher Metab Disea

View full text Add to dashboard Cite

show abstract

“…Strategies to block the inhibitory action of humoral and cell-mediated immunity towards these gene vectors are currently being investigated [84]. Further information is outside the scope of this review, and further discussion can be found in the following recent review [85].…”

Section: Gene Therapy For Metabolic Liver Diseasementioning

confidence: 99%

New Developments and Challenges in Liver Transplantation

Khalil,

Quaglia,

Gélat

et al. 2023

JCM

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Liver disease is increasing in incidence and is the third most common cause of premature death in the United Kingdom and fourth in the United States. Liver disease accounts for 2 million deaths globally each year. Three-quarters of patients with liver disease are diagnosed at a late stage, with liver transplantation as the only definitive treatment. Thomas E. Starzl performed the first human liver transplant 60 years ago. It has since become an established treatment for end-stage liver disease, both acute and chronic, including metabolic diseases and primary and, at present piloting, secondary liver cancer. Advances in surgical and anaesthetic techniques, refined indications and contra-indications to transplantation, improved donor selection, immunosuppression and prognostic scoring have allowed the outcomes of liver transplantation to improve year on year. However, there are many limitations to liver transplantation. This review describes the milestones that have occurred in the development of liver transplantation, the current limitations and the ongoing research aimed at overcoming these challenges.

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Development of analytics in newborn screening—from the Guthrie card to genetics

Janzen,

Sander

2023

Bundesgesundheitsbl

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ZusammenfassungSeit mehr als 5 Jahrzehnten wird allen Neugeborenen in Deutschland eine Vorsorgeuntersuchung zur Früherkennung angeborener behandelbarer Krankheiten angeboten. Seit Beginn sind so etwa 35 Mio. Kinder untersucht worden.Anfangs ging es nur um die Früherkennung der Phenylketonurie, die ohne frühzeitige Behandlung zu nicht mehr korrigierbarer geistiger Behinderung führt. Der bakteriologische Guthrie-Test erlaubte den Nachweis erhöhter Konzentrationen von Phenylalanin. Die heute eingesetzten Methoden sind das Ergebnis einer über Jahrzehnte verlaufenden Entwicklung. Hinzugekommen sind Tests zur Bestimmung von Enzymaktivitäten, Immunoassays zur Früherkennung wichtiger hormoneller Störungen wie der angeborenen Schilddrüsenunterfunktion sowie Hochdruck-Flüssigkeits-Chromatografie zur Identifizierung pathologischer Hämoglobine. Die sehr anspruchsvolle Tandem-Massenspektrometrie ermöglicht die gleichzeitige Erfassung von Aminosäuren und Derivaten organischer Säuren und Fettsäuren. Auch Steroide können damit identifiziert werden. Die Spezifität lässt sich durch Kombination mit chromatografischer Vortrennung noch erhöhen. In den letzten Jahren wurden die chemisch-analytischen Untersuchungen ergänzt durch gendiagnostische Verfahren, wie beispielsweise quantitative oder qualitative Polymerasekettenreaktion (PCR).Der Stand der Labortechnik ist keineswegs endgültig. Sowohl die klassische Analytik als auch besonders die genetischen Verfahren stehen vor einer weiteren rasanten Entwicklung. Während die Ausweitung des Screenings auch eine Folge der technischen Entwicklung ist, hängt die Einbeziehung weiterer angeborener Erkrankungen grundsätzlich von einer jeweiligen Therapie ab. Aber gerade hier werden gegenwärtig viele Neuerungen erprobt. Im Vordergrund des Interesses steht dabei die Gentherapie.

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Novel Gene-Correction-Based Therapeutic Modalities for Monogenic Liver Disorders

Cited by 7 publications

References 221 publications

Oral enzyme therapy for maple syrup urine disease (MSUD) suppresses plasma leucine levels in intermediate MSUD mice and healthy nonhuman primates

Oral enzyme therapy for maple syrup urine disease (MSUD) suppresses plasma leucine levels in intermediate MSUD mice and healthy nonhuman primates

New Developments and Challenges in Liver Transplantation

Development of analytics in newborn screening—from the Guthrie card to genetics

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