Journal of Inherited Metabolic Disease最新文献

{"title":"Drosophila melanogaster models of MPS IIIC (Hgsnat-deficiency) highlight the role of glia in disease presentation","authors":"Laura Hewson,&nbsp;Amanda Choo,&nbsp;Dani L. Webber,&nbsp;Paul J. Trim,&nbsp;Marten F. Snel,&nbsp;Anthony O. Fedele,&nbsp;John J. Hopwood,&nbsp;Kim M. Hemsley,&nbsp;Louise V. O'Keefe","doi":"10.1002/jimd.12712","DOIUrl":"10.1002/jimd.12712","url":null,"abstract":"<p>Sanfilippo syndrome (Mucopolysaccharidosis type III or MPS III) is a recessively inherited neurodegenerative lysosomal storage disorder. Mutations in genes encoding enzymes in the heparan sulphate degradation pathway lead to the accumulation of partially degraded heparan sulphate, resulting ultimately in the development of neurological deficits. Mutations in the gene encoding the membrane protein heparan-α-glucosaminide <i>N</i>-acetyltransferase (<i>HGSNAT</i>; EC2.3.1.78) cause MPS IIIC (OMIM#252930), typified by impaired cognition, sleep–wake cycle changes, hyperactivity and early death, often before adulthood. The precise disease mechanism that causes symptom emergence remains unknown, posing a significant challenge in the development of effective therapeutics. As <i>HGSNAT</i> is conserved in <i>Drosophila melanogaster</i>, we now describe the creation and characterisation of the first <i>Drosophila</i> models of MPS IIIC. Flies with either an endogenous insertion mutation or RNAi-mediated knockdown of <i>hgsnat</i> were confirmed to have a reduced level of HGSNAT transcripts and age-dependent accumulation of heparan sulphate leading to engorgement of the endo/lysosomal compartment. This resulted in abnormalities at the pre-synapse, defective climbing and reduced overall activity. Altered circadian rhythms (shift in peak morning activity) were seen in <i>hgsnat</i> neuronal knockdown lines. Further, when <i>hgsnat</i> was knocked down in specific glial subsets (wrapping, cortical, astrocytes or subperineural glia), impaired climbing or reduced activity was noted, implying that <i>hgsnat</i> function in these specific glial subtypes contributes significantly to this behaviour and targeting treatments to these cell groups may be necessary to ameliorate or prevent symptom onset. These novel models of MPS IIIC provide critical research tools for delineating the key cellular pathways causal in the onset of neurodegeneration in this presently untreatable disorder.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12712","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139491500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mission possible: Gene therapy for inherited metabolic diseases","authors":"Julien Baruteau,&nbsp;Nandaki Keshavan,&nbsp;Charles P. Venditti","doi":"10.1002/jimd.12708","DOIUrl":"10.1002/jimd.12708","url":null,"abstract":"<p>Since the description of ‘inborn errors of metabolism’ as a novel field of medicine by Archibald Garrod in 1908,<span>¹</span> various breakthroughs in management and therapeutic milestones have been achieved: specific diets, newborn screening and enzyme replacement therapy to name a few (Figure 1). Genomic assays, including exome, genome and RNA sequencing, have led to the identification of a rapidly growing number of new inborn errors of metabolism and many new patients in recent years.</p><p>Gene therapy centred around gene addition and editing therapy has emerged in parallel with the technological progress in engineering nucleic acids, nucleases and viruses. Seminal early milestones have raised a huge hope for inherited metabolic diseases (IMDs) with little or no therapeutic benefit under standard of care.<span>^{2, 3}</span> Complex biotechnologies such as gene addition mediated by adeno-associated viral vectors (AAV) and integrating vectors that rely upon lentiviral and CRISPR-Cas9 mediated gene-editing platforms are now the basis of approved drug products for monogenic diseases.<span>^4-6</span> Application of gene therapy has been studied in many rare IMDs. Proof-of-concept data using varied technologies, nucleic acids, and delivery platforms to achieve gene replacement, integration and editing, especially in the liver and the central nervous system, have served to enable a wide range of exciting new therapies for genetic and metabolic disorders. Whilst first-in-man clinical trials expand, the challenges for this rapidly evolving field include the development of safer and more efficient vectors, more accessible technologies, and the development of new regulatory paradigms to expedite approvals. Today, a one-size-fits-all strategy remains elusive for most disorders given that even within a rare IEM patient population, phenotypic heterogeneity, variable disease progression and uncertainties surrounding the natural history can further complicate the risk–benefit balance for clinical trials.</p><p>This themed issue of <i>Journal of Inherited Metabolic Disease</i> reviews state-of-the-art of gene therapy technologies applied to various inborn metabolic diseases. It provides updates on clinical successes, limitations and future directions whilst considering specificities for liver and fetal applications. The special issue starts with two reviews concerning liver-directed gene therapy. Baruteau et al. present an overview of the progress, challenges and perspectives for the main liver IMDs from a clinical perspective.<span>⁷</span> Chuecos and Lagor introduce AAV, which represent currently the leading liver-targeting gene therapy technology, with a particular focus on AAV physiology, AAV transduction including sex differences and an updated review of AAV clinical trials for liver IMDs and their contribution to the field of gene therapy.<span>⁸</span> Pontoizeau et al. provide an additional pro","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12708","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139466798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene therapy for neurotransmitter-related disorders","authors":"Wing Sum Chu,&nbsp;Joanne Ng,&nbsp;Simon N. Waddington,&nbsp;Manju A. Kurian","doi":"10.1002/jimd.12697","DOIUrl":"10.1002/jimd.12697","url":null,"abstract":"<p>Inborn errors of neurotransmitter (NT) metabolism are a group of rare, heterogenous diseases with predominant neurological features, such as movement disorders, autonomic dysfunction, and developmental delay. Clinical overlap with other disorders has led to delayed diagnosis and treatment, and some conditions are refractory to oral pharmacotherapies. Gene therapies have been developed and translated to clinics for paediatric inborn errors of metabolism, with 38 interventional clinical trials ongoing to date. Furthermore, efforts in restoring dopamine synthesis and neurotransmission through viral gene therapy have been developed for Parkinson's disease. Along with the recent European Medicines Agency (EMA) and Medicines and Healthcare Products Regulatory Agency (MHRA) approval of an AAV2 gene supplementation therapy for AADC deficiency, promising efficacy and safety profiles can be achieved in this group of diseases. In this review, we present preclinical and clinical advances to address NT-related diseases, and summarise potential challenges that require careful considerations for NT gene therapy studies.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12697","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139466797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glyoxylate reductase: Definitive identification in human liver mitochondria, its importance for the compartment-specific detoxification of glyoxylate","authors":"Sander F. Garrelfs,&nbsp;Serhii Chornyi,&nbsp;Heleen te Brinke,&nbsp;Jos Ruiter,&nbsp;Jaap Groothoff,&nbsp;Ronald J. A. Wanders","doi":"10.1002/jimd.12711","DOIUrl":"10.1002/jimd.12711","url":null,"abstract":"<p>Glyoxylate is a key metabolite generated from various precursor substrates in different subcellular compartments including mitochondria, peroxisomes, and the cytosol. The fact that glyoxylate is a good substrate for the ubiquitously expressed enzyme lactate dehydrogenase (LDH) requires the presence of efficient glyoxylate detoxification systems to avoid the formation of oxalate. Furthermore, this detoxification needs to be compartment-specific since LDH is actively present in multiple subcellular compartments including peroxisomes, mitochondria, and the cytosol. Whereas the identity of these protection systems has been established for both peroxisomes and the cytosol as concluded from the deficiency of alanine glyoxylate aminotransferase (AGT) in primary hyperoxaluria type 1 (PH1) and glyoxylate reductase (GR) in PH2, the glyoxylate protection system in mitochondria has remained less well defined. In this manuscript, we show that the enzyme glyoxylate reductase has a bimodal distribution in human embryonic kidney (HEK293), hepatocellular carcinoma (HepG2), and cervical carcinoma (HeLa) cells and more importantly, in human liver, and is actively present in both the mitochondrial and cytosolic compartments. We conclude that the metabolism of glyoxylate in humans requires the complicated interaction between different subcellular compartments within the cell and discuss the implications for the different primary hyperoxalurias.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12711","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139417337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Folate receptor α deficiency – Myelin-sensitive MRI as a reliable biomarker to monitor the efficacy and long-term outcome of a new therapeutic approach","authors":"Steffi Dreha-Kulaczewski,&nbsp;Prativa Sahoo,&nbsp;Matthias Preusse,&nbsp;Irini Gkalimani,&nbsp;Peter Dechent,&nbsp;Gunther Helms,&nbsp;Sabine Hofer,&nbsp;Robert Steinfeld,&nbsp;Jutta Gärtner","doi":"10.1002/jimd.12713","DOIUrl":"10.1002/jimd.12713","url":null,"abstract":"<p>Cerebral folate transport deficiency, caused by a genetic defect in folate receptor α, is a devastating neurometabolic disorder that, if untreated, leads to epileptic encephalopathy, psychomotor decline and hypomyelination. Currently, there are limited data on effective dosage and duration of treatment, though early diagnosis and therapy with folinic acid appears critical. The aim of this long-term study was to identify new therapeutic approaches and novel biomarkers for assessing efficacy, focusing on myelin-sensitive MRI. Clinical, biochemical, structural and quantitative MRI parameters of seven patients with genetically confirmed folate receptor α deficiency were acquired over 13 years. Multimodal MRI approaches comprised MR-spectroscopy (MRS), magnetization transfer (MTI) and diffusion tensor imaging (DTI) sequences. Patients started oral treatment immediately following diagnosis or in an interval of up to 2.5 years. Escalation to intravenous and intrathecal administration was performed in the absence of effects. Five patients improved, one with a presymptomatic start of therapy remained symptom-free, and one with inconsistent treatment deteriorated. While CSF 5-methyltetrahydrofolate and MRS parameters normalized immediately after therapy initiation, myelin-sensitive MTI and DTI measures correlated with gradual clinical improvement and ongoing myelination under therapy. Early initiation of treatment at sufficient doses, considering early intrathecal applications, is critical for favorable outcome. The majority of patients showed clinical improvements that correlated best with MTI parameters, allowing individualized monitoring of myelination recovery. Presymptomatic therapy seems to ensure normal development and warrants newborn screening. Furthermore, the quantitative parameters of myelin-sensitive MRI for therapy assessments can now be used for hypomyelination disorders in general.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12713","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139417336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tetrahydrobiopterin (BH4) treatment stabilizes tyrosine hydroxylase: Rescue of tyrosine hydroxylase deficiency phenotypes in human neurons and in a knock-in mouse model","authors":"Kunwar Jung-KC,&nbsp;Alba Tristán-Noguero,&nbsp;Altanchimeg Altankhuyag,&nbsp;David Piñol Belenguer,&nbsp;Karina S. Prestegård,&nbsp;Irene Fernandez-Carasa,&nbsp;Arianna Colini Baldeschi,&nbsp;Maria Sigatulina Bondarenko,&nbsp;Angeles García-Cazorla,&nbsp;Antonella Consiglio,&nbsp;Aurora Martinez","doi":"10.1002/jimd.12702","DOIUrl":"10.1002/jimd.12702","url":null,"abstract":"<p>Proteostatic regulation of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis, is crucial for maintaining proper brain neurotransmitter homeostasis. Variants of the <i>TH</i> gene are associated with tyrosine hydroxylase deficiency (THD), a rare disorder with a wide phenotypic spectrum and variable response to treatment, which affects protein stability and may lead to accelerated degradation, loss of TH function and catecholamine deficiency. In this study, we investigated the effects of the TH cofactor tetrahydrobiopterin (BH₄) on the stability of TH in isolated protein and in DAn- differentiated from iPSCs from a human healthy subject, as well as from THD patients with the R233H variant in homozygosity (THDA) and R328W and T399M variants in heterozygosity (THDB). We report an increase in TH and dopamine levels, and an increase in the number of TH+ cells in control and THDA cells. To translate this in vitro effect, we treated with BH₄ a knock-in THD mouse model with <i>Th</i> variant corresponding to R233H in patients. Importantly, treatment with BH₄ significantly improved motor function in these mice, as demonstrated by increased latency on the rotarod test and improved horizontal activity (catalepsy). In conclusion, our study demonstrates the stabilizing effects of BH₄ on TH protein levels and function in THD neurons and mice, rescuing disease phenotypes and improving motor outcomes. These findings highlight the therapeutic potential of BH₄ as a treatment option for THDA patients with specific variants and provide insights into the modulation of TH stability and its implications for THD management.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12702","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139403143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression and function of the urea cycle in widely-used hepatic cellular models.","authors":"Georgios Makris, Lara Veit, Véronique Rüfenacht, Sven Klassa, Nadia Zürcher, Shirou Matsumoto, Martin Poms, Johannes Häberle","doi":"10.1002/jimd.12701","DOIUrl":"https://doi.org/10.1002/jimd.12701","url":null,"abstract":"<p><p>The group of rare metabolic defects termed urea cycle disorders (UCDs) occur within the ammonia elimination pathway and lead to significant neurocognitive sequelae for patients surviving decompensation episodes. Besides orthotopic liver transplantation, curative options are lacking for UCDs, with dietary management being the gold clinical standard. Novel therapeutic approaches are essential for UCDs; however, such effort presupposes preclinical testing in cellular models that effectively capture disease manifestation. Several cellular and animal models exist and aim to recapitulate the broad phenotypic spectrum of UCDs; however, the majority of those lack extensive molecular and biochemical characterization. The development of cellular models is emerging since animal models are extremely time and cost consuming, and subject to ethical considerations, including the 3R principle that endorses animal welfare over unchecked preclinical testing. The aim of this study was to compare the extent of expression and functionality of the urea cycle in two commercial hepatoma-derived cell lines, induced pluripotent stem cell hepatocytes (iPSC-Heps), primary human hepatocytes (PHHs) and human liver cell preparations. Using immunoblotting, immunocytochemistry, and stable isotope tracing of the urea cycle metabolites, we identified that the hepatoma-derived, 2-week differentiated HepaRG cells are urea cycle proficient and behave as cellular alternatives to PHHs. Furthermore, HepaRG cells were superior to iPSC-Heps, which are known to exhibit batch-to-batch variabilities in terms of hepatic maturity and enzyme expression. Finally, HepG2 cells lack the urea cycle enzymes ornithine transcarbamylase and arginase 1, the transporter ORNT1, which limits their suitability as model for the study of UCDs.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139403142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repurposing empagliflozin in individuals with glycogen storage disease Ib: A value-based healthcare approach and systematic benefit-risk assessment","authors":"Terry G. J. Derks,&nbsp;Annieke Venema,&nbsp;Clara Köller,&nbsp;Eline Bos,&nbsp;Ruben J. Overduin,&nbsp;Nina N. Stolwijk,&nbsp;Peter Hofbauer,&nbsp;Mathieu S. Bolhuis,&nbsp;Fred van Eenennaam,&nbsp;Henk Groen,&nbsp;Carla E. M. Hollak,&nbsp;Saskia B. Wortmann","doi":"10.1002/jimd.12714","DOIUrl":"10.1002/jimd.12714","url":null,"abstract":"<p>Off-label repurposing of empagliflozin allows pathomechanism-based treatment of neutropenia/neutrophil-dysfunction in glycogen storage disease type Ib (GSDIb). From a value-based healthcare (VBHC) perspective, we here retrospectively studied patient-reported, clinical and pharmacoeconomic outcomes in 11 GSDIb individuals before and under empagliflozin at two centers (the Netherlands [NL], Austria [AT]), including a budget impact analysis, sensitivity-analysis, and systematic benefit–risk assessment. Under empagliflozin, all GSDIb individuals reported improved quality-of-life-scores. Neutrophil dysfunction related symptoms allowed either granulocyte colony-stimulating factor cessation or tapering. Calculated cost savings per patient per year ranged between € 6482–14 190 (NL) and € 1281–41 231 (AT). The budget impact analysis estimated annual total cost savings ranging between € 75 062–225 716 (NL) and € 37 697–231 790 (AT), based on conservative assumptions. The systematic benefit-risk assessment was favorable. From a VBHC perspective, empagliflozin treatment in GSDIb improved personal and clinical outcomes while saving costs, thereby creating value at multiple pillars. We emphasize the importance to reimburse empagliflozin for GSDIb individuals, further supported by the favorable systematic benefit-risk assessment. These observations in similar directions in two countries/health care systems strongly suggest that our findings can be extrapolated to other geographical areas and health care systems.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12714","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139377811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liver-directed gene therapy for inherited metabolic diseases","authors":"Julien Baruteau,&nbsp;Nicola Brunetti-Pierri,&nbsp;Paul Gissen","doi":"10.1002/jimd.12709","DOIUrl":"10.1002/jimd.12709","url":null,"abstract":"<p>Gene therapy clinical trials are rapidly expanding for inherited metabolic liver diseases whilst two gene therapy products have now been approved for liver based monogenic disorders. Liver-directed gene therapy has recently become an option for treatment of haemophilias and is likely to become one of the favoured therapeutic strategies for inherited metabolic liver diseases in the near future. In this review, we present the different gene therapy vectors and strategies for liver-targeting, including gene editing. We highlight the current development of viral and nonviral gene therapy for a number of inherited metabolic liver diseases including urea cycle defects, organic acidaemias, Crigler–Najjar disease, Wilson disease, glycogen storage disease Type Ia, phenylketonuria and maple syrup urine disease. We describe the main limitations and open questions for further gene therapy development: immunogenicity, inflammatory response, genotoxicity, gene therapy administration in a fibrotic liver. The follow-up of a constantly growing number of gene therapy treated patients allows better understanding of its benefits and limitations and provides strategies to design safer and more efficacious treatments. Undoubtedly, liver-targeting gene therapy offers a promising avenue for innovative therapies with an unprecedented potential to address the unmet needs of patients suffering from inherited metabolic diseases.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12709","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene therapy for mitochondrial disorders","authors":"Nandaki Keshavan,&nbsp;Michal Minczuk,&nbsp;Carlo Viscomi,&nbsp;Shamima Rahman","doi":"10.1002/jimd.12699","DOIUrl":"10.1002/jimd.12699","url":null,"abstract":"<p>In this review, we detail the current state of application of gene therapy to primary mitochondrial disorders (PMDs). Recombinant adeno-associated virus-based (rAAV) gene replacement approaches for nuclear gene disorders have been undertaken successfully in more than ten preclinical mouse models of PMDs which has been made possible by the development of novel rAAV technologies that achieve more efficient organ targeting. So far, however, the greatest progress has been made for Leber Hereditary Optic Neuropathy, for which phase 3 clinical trials of lenadogene nolparvovec demonstrated efficacy and good tolerability. Other methods of treating mitochondrial DNA (mtDNA) disorders have also had traction, including refinements to nucleases that degrade mtDNA molecules with pathogenic variants, including transcription activator-like effector nucleases, zinc-finger nucleases, and meganucleases (mitoARCUS). rAAV-based approaches have been used successfully to deliver these nucleases <i>in vivo</i> in mice. Exciting developments in CRISPR-Cas9 gene editing technology have achieved <i>in vivo</i> gene editing in mouse models of PMDs due to nuclear gene defects and new CRISPR-free gene editing approaches have shown great potential for therapeutic application in mtDNA disorders. We conclude the review by discussing the challenges of translating gene therapy in patients both from the point of view of achieving adequate organ transduction as well as clinical trial design.</p>","PeriodicalId":16281,"journal":{"name":"Journal of Inherited Metabolic Disease","volume":null,"pages":null},"PeriodicalIF":4.2,"publicationDate":"2024-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/jimd.12699","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}