advances in mitochondrial disease darius j. adams, m.d. genetics and metabolism
TRANSCRIPT
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Advances in Mitochondrial Disease
Darius J. Adams, M.D.
Genetics and Metabolism
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Diagnostics and Therapeutics
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Mitochondrial Function
• 1200-1500 genes involved in mitochondrial function
• Combination of:– Nuclear DNA– Mitochondrial DNA
• 37 genes
Reference: http://www.kathleensworld.com/mitochon.html
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Diagnostics
• Critical to potential future therapies• Nuclear Gene discovery
– Autosomal recessive mitochondrial genes– Autosomal dominant mitochondrial genes– X-linked
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Next Generation Genomic Sequencing
• Can analyze the coding regions 20,000 genes with one blood test
• The targeted panels are based on clinical findings– Mito panels now with over 1,200 genes
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Goals of Treatment
• Slow or arrest progression of symptoms– Increase mitochondrial ATP production– Support electron transfer– Inhibit free radicals– Stabilize OXPHOS complexes– Avoid drugs capable of affecting the
respiratory complexes
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Current Cofactor Treatment of Mitochondrial Disorders
• L-Carnitine• Coenzyme Q10/Ubiqinone/CytoQ• L-Arginine• Alpha Lipoic Acid• Dietary manipulation (low carbohydrate diet)• Creatine (high energy phosphate bond)• Vit. C up to 4g/day• Vit. E 10 U/Kg/day• Vit. B1 (PDH), B2(CI&II), Nicotinamide/Niacin• Vit. B6, B12 and Biotin• Vit. K Menadione and Phylloquinone• Exercise
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Experimental Cofactor Treatment of Mitochondrial
disorders• Idebenone 90 mg/day similar to CoQ10
(experimental)• Succinate 6 g/day in MELAS and Complex I
deficiency• Uridine (support general enzyme function)• Dichloroacetate (found to be harmful)• Organ transplantation• Physical therapy
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Medications That Impact Mitochondria
• AZT (Inhibitor to gamma polymerase)• Fialuridine antiviral agent for Treatment of
Hepatitis B• Valproate, aspirin due to (effect on FAO or
CoA sequestration)• Nucleoside analogues: didanosine,
zalcitabine• Lamivudine and famciclovir are permitted• Gentamicin and Tetracyclines
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Gene Therapy
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Gene Therapy Challenges and Successes
• Targeting gene insertion– Successfully inserting plasmids
• Immune reactions– Use of Adeno-associated viral (AAV)
vectors minimizes immune response• Differential tissue targeting
– AAV vectors can target specific tissues like brain and liver
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Gene Therapy
• Success demonstrated in individuals with severe combined immunodeficiency (SCID)
• Exploring direct injection vs. IV infusion of gene therapy
• Advances in DNA diagnostics for mitochondrial disease allowing of possible gene correction
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Lysosome
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Active Trials in Gene Therapy
• University of North Carolina, Dr. Steven Gray and Thomas Jefferson, Dr. David Wenger– Using AAV9 to transfer corrective gene for
Krabbe disease (lysosomal storage disorder)
– Discovered that may need a combination of a bone marrow transplant, intrathecal gene therapy and blood gene therapy
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Going Forward
• Now that we are able to obtain more precise diagnostics, targeting specific mutations associated with mitochondrial disorders can be explored
• Start to prepare for human phase I trials
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Personalized Treatment
• It is likely, given the variety of mutations, gene therapy treatment will need to be customized to the individual
• Will need specific replacement gene and to be placed in the transport vector
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Model Vector Cassette
• Rep 68/78 mRNA needed to integrate into chromosome 19 region that is devoid of active genes for permanent correction
ITR RBE sequence
Transgene - ssDNA
Rep 68/78 mRNA
Promoter
PolyA
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Model of Gene Correction
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Plasmids
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How Do We Get There?
• Likely will need proof of concept to be done at Academic Medical Centers
• BioTech will likely be needed for clinical trial work as this will require vast resources to prove safety and efficacy
• However, making advances on multiple fronts
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Conclusion
• Advancing our diagnostic abilities will allow for the implementation of targeted therapies
• Nutritional and cofactor interventions continue to be refined
• Genetic therapeutics are now much closer with advances in vector technology