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SUMMARY:Mutation-free cells prevent transmission of mtDNA disease and enab
 le new treatment options  - Professor Bert Smeets | Maastricht University
DTSTART:20191120T150000Z
DTEND:20191120T160000Z
UID:TALK124939@talks.cam.ac.uk
CONTACT:Hannah Burns
DESCRIPTION:Mitochondrial diseases are among the most common inborn errors
  of metabolism\, in at least 15% caused by mitochondrial DNA (mtDNA) mutat
 ions. Considering the clinical severity and lack of treatment\, preventing
  transmission to offspring is often requested. Preimplantation Genetic Dia
 gnosis or embryo selection is currently the best reproductive option for m
 ost cases of maternally transmitted heteroplasmic mtDNA point mutations. A
 nalysis of PGD embryos demonstrated a role for genetic drift in combinatio
 n with the mitochondrial bottleneck\, but also revealed selection mechanis
 ms. To get further insight in bottleneck and selection mechanisms\, we exp
 lored zebrafish as a model.  We characterized the mtDNA copy number in ge
 rmline and non-germline cells in zebrafish throughout development and dete
 rmined the occurrence of de novo mtDNA mutations\, which in humans are res
 ponsible for 25% of the mtDNA cases. By knocking-down Tfam we were able to
  manipulate the mtDNA copy number during zebrafish development. The next s
 tep will be the introduction of mtDNA mutations. Due to the high rate of d
 e novo cases\, preventing the transmission is not sufficient to eliminate 
 mtDNA disease and it remains essential to develop new therapeutic approach
 es to treat patients. Currently\, we are establishing a treatment based on
  autologous mtDNA mutation-free muscle stem cell\, called mesoangioblasts\
 , which can be administered through the blood to treat myopathy in patient
 s with mtDNA disease. We have approval for starting a phase I/II clinical 
 trial early next year in 5 patients with the m.3243A>G mutation\, who by n
 ature produce mutation-free mesoangioblasts. To improve the therapeutic po
 tential of these stem cells\, we will stimulate mitochondrial biogenesis a
 nd load them with nanoparticles\, containing antigenomic compounds\, that 
 prohibit replication of the mutated mtDNA in existing muscle fibres.
LOCATION:Sackler Lecture Theatre (Level 7) The Keith Peters Building\, Cam
 bridge Biomedical Campus
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