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Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

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Page 1: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.
Page 2: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

Advances in Mitochondrial Disease

Darius J. Adams, M.D.

Genetics and Metabolism

Page 3: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

Diagnostics and Therapeutics

Page 4: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.
Page 5: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

Mitochondrial Function

• 1200-1500 genes involved in mitochondrial function

• Combination of:– Nuclear DNA– Mitochondrial DNA

• 37 genes

Reference: http://www.kathleensworld.com/mitochon.html

Page 6: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

Diagnostics

• Critical to potential future therapies• Nuclear Gene discovery

– Autosomal recessive mitochondrial genes– Autosomal dominant mitochondrial genes– X-linked

Page 7: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

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

Page 8: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

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

Page 9: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

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

Page 10: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.
Page 11: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

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

Page 12: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

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

Page 13: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

Gene Therapy

Page 14: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

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

Page 15: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

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

Page 16: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

Lysosome

Page 17: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

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

Page 18: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

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

Page 19: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

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

Page 20: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

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

Page 21: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

Model of Gene Correction

Page 22: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

Plasmids

Page 23: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

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

Page 24: Advances in Mitochondrial Disease Darius J. Adams, M.D. Genetics and Metabolism.

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


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