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Last update 08 May 2025

4HPPD

Last update 08 May 2025

Basic Info

Synonyms

4-HPPD, 4-hydroxyphenylpyruvate dioxygenase, 4-hydroxyphenylpyruvic acid oxidase

+ [7]

Introduction

Catalyzes the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid, one of the steps in tyrosine catabolism.

Drugs associated with 4HPPD

Nitisinone

Target

4HPPD

Mechanism

4HPPD inhibitors

Active Org.

Cycle Pharmaceuticals Ltd. [+7]

Originator Org.

Swedish Orphan Biovitrum AB

Active Indication

Alkaptonuria [+2]

Inactive Indication-

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

United States

First Approval Date18 Jan 2002

HPD siRNA

Target

4HPPD

Mechanism

4HPPD inhibitors

Active Org.

Alnylam Pharmaceuticals, Inc. [+1]

Originator Org.-

Active Indication

Tyrosinemia, Type I

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

HPD-targeted CRISPR/Cas9 gene therapy (Southern Medical University)

Target

4HPPD

Mechanism

4HPPD inhibitors

Active Org.

Southern Medical University

Originator Org.

Southern Medical University

Active Indication

Tyrosinemia, Type I

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with 4HPPD

NCT06227429

/ RecruitingNot Applicable

A Prospective, Non-interventional, Post-Marketing Study to Describe Outcome of Nitisinone Treatment in Hereditary Tyrosinemia Type 1 (HT-1) Patients in Routine Clinical Care in China

This is a prospective, non-interventional, non-comparative, multicenter study to collect data on HT-1 patients in China treated with Nitisinone in a routine clinical setting. No tests or examinations are mandated in the study.

Start Date01 Sep 2025

Sponsor / Collaborator

Swedish Orphan Biovitrum AB

CTRI/2024/03/063760

/ Not yet recruitingPhase 3IIT

Prospective, Randomised, Double blind, Parallel-group Study to Assess the Safety and efficacy of 2/5mg Once Daily Nitisinone among Indian Patients with Alkaptonuria – A randomised control trial. - Nil

Start Date25 Mar 2024

Sponsor / Collaborator

Indian Council of Medical Research

CTRI/2023/05/052626

/ Not yet recruitingNot ApplicableIIT

Pharmacokinetic and Dynamic Correlation for optimum therapy of NTBC for the Treatment of Indian Patients with Hereditary Tyrosinemia Type 1

Start Date15 May 2023

Sponsor / Collaborator-

100 Clinical Results associated with 4HPPD

100 Translational Medicine associated with 4HPPD

0 Patents (Medical) associated with 4HPPD

522

Literatures (Medical) associated with 4HPPD

01 May 2025·Journal of Magnetic Resonance Imaging

A Review of MRI Acoustic Noise Outputs and Hearing Protection Device Performance

Review

Author: Steckner, Michael

The acoustic noise outputs of MR equipment typically require a hearing protection device (HPD) to minimize the likelihood of patient hearing loss. Several different ways to quantify HPD performance have been developed and adopted over many years in different countries across the world (eg, NRR, SNR, SLC80). These HPD evaluations are done in controlled laboratory conditions, following different standardized methodologies, producing different performance ratings for the same HPD, and consequently of a variable relationship with achieved real‐world usage performance assessments. Conversely, the MR manufacturers follow one standard (NEMA MS‐4) which strives to produce a worst‐case peak and average acoustic noise output measurement. Measuring the acoustic output of MR equipment is a complex undertaking in the confined patient space, especially when considering the variability of what is in the patient imaging space. Given both the MR equipment acoustic output measurements and the HPD performance rating, it is theoretically possible to estimate the worst‐case patient exposure level, subject to the uncertainty of how successfully the protection was applied and population variability. An assessment, shown here, suggests that the worst‐case outputs from the loudest MR equipment requires the best passive HPD performance presently available in order to meet patient protection guidelines, but only when the HPD is properly deployed. However, when considering government agency derating recommendations that estimate protection achieved during practical application, the various metrics are not consistent in confirming that the best HPD provide sufficient protection. This paper reviews the challenges of determining and providing sufficient hearing protection. The correct deployment of HPD, and its verification, is thus a critical factor in ensuring adequate patient protection and the main concern of this review.Level of Evidence5Technical EfficacyStage 5

01 Apr 2025·JHEP Reports

CRISPR/Cas9 gene therapy increases the risk of tumorigenesis in the mouse model of hereditary tyrosinemia type I

Article

Author: Wheeler, David A ; Chen, Tong ; Borowiak, Malgorzata ; Kim, Hyunjae R ; Legras, Xavier ; Pankowicz, Francis P ; Bissig-Choisat, Beatrice ; Hurley, Ayrea E ; Barzi, Mercedes ; Furey, Nika ; Elsea, Sara H ; Yang, Diane ; Sumazin, Pavel ; Bissig, Karl-Dimiter

Background & AimsThe therapeutic potential of CRISPR gene editing has been demonstrated in various animal models; however, little is known about its long-term consequences. This study seeks to bridge this gap by investigating the lasting consequences of CRISPR gene therapy in an animal model of hereditary tyrosinemia type I (HT-I). We compared the standard of care-nitisinone, a small molecule inhibitor of hydroxyphenylpyruvate dioxygenase (HPD)-with the deletion of the Hpd gene by CRISPR gene therapy. Both treatments block flux through tyrosine catabolism and thereby prevent the accumulation of toxic catabolites in HT-I.MethodsWe assessed the efficacy and safety of CRISPR gene editing in fumarylacetoacetate hydrolase-deficient (Fah-/-) mice, the mouse model of HT-I, 12 months post treatment with either nitisinone or CRISPR deletion of Hpd. We deleted the Hpd gene using an adenovirus containing Cas9 and an adeno-associated virus containing two sgRNA against the Hpd gene. Primary endpoints were survival, urine biochemistry, liver (immuno)histochemistry, and genetic analyses.ResultsCRISPR deletion and pharmacological inhibition of HPD both demonstrate efficient metabolic correction and rescue of lethality. Surprisingly, we detected a markedly increased incidence of hepatocellular cancer in the CRISPR gene therapy group (71%, 12/17 mice) compared with four control groups (nitisinone [19%, four of 21 mice], sgRNA only [6%, one of 16 mice], Cas9 only [11%, two of 19 mice], and hydrodynamic tail vein injection of both CRISPR constructs [24%, four of 17 mice]). All analyzed tumors in the CRISPR gene therapy group were deleted for Hpd but showed on-and-off target vector integrations.ConclusionsCRISPR gene therapy increases the risk of hepatocellular cancer in the mouse model of HT-I. Because HT-I is characterized by inherent cancer susceptibility, this severe adverse event exposes the potential limitations of CRISPR gene therapy in cancer-prone disorders.Impact and implicationsNot much is known about the long-term consequences of somatic gene editing. Our study investigates CRISPR gene therapy in tyrosinemia type I using viral vectors. Although the CRISPR-based therapy effectively treated the metabolic condition, it was associated with a higher incidence of liver cancer than the current standard of care. These findings highlight the potential risks of using CRISPR gene therapy in conditions predisposed to cancer development.

26 Mar 2025·Zeitschrift für Naturforschung C

Redefining a new frontier in alkaptonuria therapy with AI-driven drug candidate design via in- silico innovation

Article

Author: Khan, Ayaz Ali ; Aziz, Tariq ; Ali, Imran ; Naveed, Muhammad ; Albekairi, Thamer H. ; Fatima, Mahnoor ; Zafar, Ali ; Javed, Khushbakht

AbstractA rare metabolic condition called alkaptonuria (AKU) is caused by a decrease in homogentisate 1,2 dioxygenase (HGO) activity due to a mutation in homogentisate dioxygenase (HGD) gene. Homogentisic acid is a byproduct of the catabolism of tyrosine and phenylalanine that darkens the urine and accumulates in connective tissues which causes an agonizing arthritis. Employing the use of deep learning artificial intelligence (AI) drug design, this study aims to alleviate the current toxicity of the AKU drugs currently in use, particularly nitisinone, by utilizing the natural flavanol kaempferol molecule as a 4-hydroxyphenylpyruvate dioxygenase inhibitor. Kaempferol was employed to generate three effective de novo drug candidates targeting the enzyme 4-hydroxyphenylpyruvate dioxygenase using an AI drug design tool. We present novel AIK formulations in the present study. The AIK’s (Artificial Intelligence Kaempferol) examination of drug-likeliness among the three led to its choice as a possible target. The toxicity assessment research of AIK demonstrates that it is not only safer to use than other treatments, but also more efficient. The docking of the AIGT with 4-hydroxyphenylpyruvate dioxygenase, which revealed a binding affinity of around −9.099 kcal/mol, highlights the AIK’s potential as a therapeutic candidate. An innovative approach to deal with challenging circumstances is thus presented in this study by new formulations kaempferol that have been meticulously designed by AI. The results of the in vitro tests must be confirmed in vivo, even though AI-designed AIK is effective and sufficiently safe as computed.

News (Medical) associated with 4HPPD

18 Jan 2024

·www.outsourcing-pharma.com

Inceptua and Cycle partnership brings hope to patients at the end of the treatment road

The partnership, announced today (January 18) will make NITYR (nitisinone) tablets available for eligible patients in the UK with Hereditary Tyrosinemia Type 1 (HT-1) and Alkaptonuria (AKU). A Free Goods Programme is a compliant way for medicines that are not approved in their country of intended use to be made available for patients who either have no alternative treatment option or have exhausted all other treatment options available in their country of residence. Stuart Bell, senior vice president, Inceptua early access said: “Inceptua is proud to partner with Cycle in this Free Goods Programme to allow access to NITYR to a broader number of countries and patients. Cycle’s ethos around medicine provision aligns very closely to those of Inceptua’s, and we look forward to supporting patients with no other treatment options for these devastating diseases.” Rare genetic condition Ht-1 is a very rare genetic condition. It prevents the body from breaking down a substance called tyrosine found in food. This leads to the build-up of toxic levels of substances in the blood. If left untreated, TYR1 can damage the liver, kidneys, and the nervous system. The NHS describes AKU, or black urine disease, as a very rare inherited disorder that prevents the body fully breaking down two protein building blocks (amino acids) called tyrosine and phenylalanine. It results in a build-up of a chemical called homogentisic acid in the body. This can turn urine and parts of the body a dark color and lead to a range of health problems over time. googletag.cmd.push(function () { googletag.display('text-ad1'); }); Cycle has an existing Free Goods Program with patients with HT-1 in India, Bangladesh, Pakistan, and Sudan. Inceptua will support Cycle through the expansion of the Free Goods Programme to include further countries where NITYR is not commercially available, or where the local healthcare system is unable to afford this medication. Countries in scope of the NITYR Free Goods Programme include Argentina, Bangladesh, Brazil, Chile, Colombia, Dominican Republic, Jordan, Mexico, Nigeria, Pakistan, Peru, Tunisia, and Turkey. Cycle says it is committed to supporting patients on the Free Goods Programme for the duration of their lifetime. Proud and humbled James Harrison, CEO of Cycle Pharmaceuticals said: “Right from the beginning of Cycle’s story in 2012, we made a commitment to provide a Free Goods Programme for rare disease patients that cannot otherwise access our medicines.  The whole Cycle team is extremely proud and humbled to be able to expand the NITYR Free Goods Programme. It really matters.” In its research, the companies found that HT-1 affects about 1 in 100,000 individuals worldwide, whilst AKU affects 1 in 250,000 to 1 million people worldwide. NITYR (nitisinone) tablets are a competitive inhibitor of 4-hydroxyphenyl-pyruvate dioxygenase indicated for the treatment of adult and pediatric patients with HT-1 in combination with dietary restriction of tyrosine and phenylalanine. NITYR has been approved for use by the FDA, Health Canada, EMA, MHRA and TGA.

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4HPPD

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