36e45d0fea9df245806eddb110291884 pmc_34208592.pdf a56bd12946cc75547fd1334193d00441a786eef2 pmc_34208592.pdf 2714f2ec44b2208ac412feaa3311b4ab7a5b21d1eae82146a7e72eb37ce759a9 pmc_34208592.pdf Title: Therapy Prospects for Mitochondrial DNA Maintenance Disorders Subject: Mitochondrial DNA depletion and multiple deletions syndromes (MDDS) constitute a group of mitochondrial diseases defined by dysfunctional mitochondrial DNA (mtDNA) replication and maintenance. As is the case for many other mitochondrial diseases, the options for the treatment of these disorders are rather limited today. Some aggressive treatments such as liver transplantation or allogeneic stem cell transplantation are among the few available options for patients with some forms of MDDS. However, in recent years, significant advances in our knowledge of the biochemical pathomechanisms accounting for dysfunctional mtDNA replication have been achieved, which has opened new prospects for the treatment of these often fatal diseases. Current strategies under investigation to treat MDDS range from small molecule substrate enhancement approaches to more complex treatments, such as lentiviral or adenoassociated vector-mediated gene therapy. Some of these experimental therapies have already reached the clinical phase with very promising results, however, they are hampered by the fact that these are all rare disorders and so the patient recruitment potential for clinical trials is very limited. Keywords: mitochondria; mtDNA; replication; depletion; multiple deletions; therapy; nucleoside; gene therapy Author: Javier Ramón, Ferran Vila-Julià, David Molina-Granada, Miguel Molina-Berenguer, Maria Jesús Melià, Elena García-Arumí, Javier Torres-Torronteras, Yolanda Cámara and Ramon Martí Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Thu Jun 17 08:02:16 2021 CEST ModDate: Thu Jun 17 08:09:08 2021 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 35 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 996260 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- CCDETI+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 VMPQTK+VnURWPalladioL Type 1 Custom yes yes no 15 0 PKRZPL+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 WODMHT+URWPalladioL-Bold Type 1 Custom yes yes no 24 0 SAZNBQ+URWPalladioL-Roma Type 1 Custom yes yes no 28 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 36 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 39 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 61 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 65 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 69 0 VLBWDI+URWPalladioL-BoldItal Type 1 Custom yes yes no 87 0 PYTLFY+EURB10 Type 1 Builtin yes yes no 97 0 JRWONR+CMSY10 Type 1 Builtin yes yes no 104 0 GOCQIR+EURM10 Type 1 Builtin yes yes no 115 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 123 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 127 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 131 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 135 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-10-02 03:11:58 CEST RepresentationInformation: pmc_34208592.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 12:14:23 CEST Size: 996260 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 894 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Mitochondria and Mitochondrial Diseases Destination: section.1 Item: Title: Mitochondrial DNA Depletion and Multiple Deletions Syndromes (MDDS) Destination: section.2 Children: Item: Title: Genes Encoding Proteins of the mtDNA Replication Machinery Destination: subsection.2.1 Item: Title: Genes Involved in dNTP Metabolism Destination: subsection.2.2 Children: Item: Title: dNTP Anabolism Destination: subsubsection.2.2.1 Item: Title: dNTP Catabolism Destination: subsubsection.2.2.2 Item: Title: Nucleoside/Nucleotide Transporters Destination: subsubsection.2.2.3 Item: Title: Genes Involved in Mitochondrial Dynamics Destination: subsection.2.3 Item: Title: Genes Involved in mtDNA Maintenance through Unknown Mechanisms Destination: subsection.2.4 Item: Title: Non-Targeted Therapies for Mitochondrial DNA Maintenance Disorders Destination: section.3 Children: Item: Title: Symptomatic Treatments and Other Non-Targeted Treatments Applied to MDDS Patients Destination: subsection.3.1 Item: Title: Non-Targeted Experimental Approaches Destination: subsection.3.2 Item: Title: Targeted Therapies for MDDS Destination: section.4 Children: Item: Title: Direct Scavenging of Toxic Metabolites Destination: subsection.4.1 Item: Title: Enzyme Replacement Destination: subsection.4.2 Item: Title: Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT) Destination: subsection.4.3 Item: Title: Liver Transplantation Destination: subsection.4.4 Item: Title: Administration of Deoxyribonucleosides (dNs) Destination: subsection.4.5 Item: Title: Gene Therapy Destination: subsection.4.6 Item: Title: Improving Mitochondrial Shape and Other Approaches Destination: subsection.4.7 Item: Title: Prospects and Specific Barriers Destination: section.5 Item: Title: Conclusions Destination: section.6 Item: Title: References Destination: section.6 Info: Title: Therapy Prospects for Mitochondrial DNA Maintenance Disorders Author: Javier Ramón, Ferran Vila-Julià, David Molina-Granada, Miguel Molina-Berenguer, Maria Jesús Melià, Elena García-Arumí, Javier Torres-Torronteras, Yolanda Cámara and Ramon Martí Subject: Mitochondrial DNA depletion and multiple deletions syndromes (MDDS) constitute a group of mitochondrial diseases defined by dysfunctional mitochondrial DNA (mtDNA) replication and maintenance. As is the case for many other mitochondrial diseases, the options for the treatment of these disorders are rather limited today. Some aggressive treatments such as liver transplantation or allogeneic stem cell transplantation are among the few available options for patients with some forms of MDDS. However, in recent years, significant advances in our knowledge of the biochemical pathomechanisms accounting for dysfunctional mtDNA replication have been achieved, which has opened new prospects for the treatment of these often fatal diseases. Current strategies under investigation to treat MDDS range from small molecule substrate enhancement approaches to more complex treatments, such as lentiviral or adenoassociated vector-mediated gene therapy. Some of these experimental therapies have already reached the clinical phase with very promising results, however, they are hampered by the fact that these are all rare disorders and so the patient recruitment potential for clinical trials is very limited. 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