How To Treat The Sando Syndrome

Transcription

1 Consultation on Drugs for Rare Diseases Rare Disease Day Symposium Hannover Medical School (MHH), Solidarity Rare but Strong Together Roland Seifert, MHH

2 @ Dear Sir, I am writing hoping that there might be an expert at the Center for Rare Diseases of the Hannover Medical School who can help us. Last year, my wife (45 years old) was diagnosed the SANDO syndrome. It took several years until this diagnosis was found. In the last months the disease has got worse, and seeing the disease proceed, we feel so helpless. Could you help us, please? Sometimes, in Europe there is more innovative research and better treatment than here in the US. Thank you!

3 What is the SANDO syndrome?

4 What is the SANDO syndrome? Symptoms Cause of the disease: Mutations in the mitochondrial DNA (POLG1- or PEO1 (Twinkle) gene) Possible treatment?

5 What is the SANDO syndrome? Pubmed research The SANDO syndrome among other mitochondrial diseases belongs to the POLG-related diseases.

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7 What is the SANDO syndrome? Mitochondrial diseases (examples) Defects in mitochondrial DNA Complex 1 of the oxidative phosphorylation chain: LHON (Leber s hereditary opticus neuropathy) trna: MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) Defects in nuclear genes Frataxin: FA (Friedreich s ataxia) POLG: AHS (Alpers-Huttenlocher syndrome) MEMSA (myoclonic epilepsy myopathy sensory ataxia) SANDO (sensory ataxia neuropathy dysarthria and ophtalmoplegia)

8 POLG = mitochondrial DNA polymerase γ mitochondrion mtdna ADP ATP POLG

9 Mitochondrion function: Physiology and Pathophysiology K1 K2 Q10 K3 K4 K5 POLG mitochondrion ATP cell metabolism

10 Mitochondrion function: Physiology and Pathophysiology K1 K2 Q10 K3 K4 K5 ROS mutations POLG mitochondrion ATP cell metabolism clinical symptoms neuronal degeneration impaired neurotransmitter release

11 Therapeutic trial with coenzyme Q10 (idebenone) in mitochondrial diseases coenzyme Q (Q10) K1 K2 Q10 K3 K4 K5 ROS mutations POLG mitochondrion ATP cell metabolism clinical symptoms neuronal degeneration impaired neurotransmitter release

12 What are possible treatments for POLG-related diseases? Pubmed research 28 publications for example

13 Symptomatic therapy with antiepileptic drugs (e.g. lamotrigine) Magnesium with status epilepticus Caution with valproic acid because of its mitochondrial toxicity!

14 Possible treatment of the SANDO syndrome Coenzyme Q (because the pathophysiological symptoms of SANDO are similar to other POLG-related diseases) Symptomatic treatment of epilepsy Symptomatic treatment of polyneuropathy Problems Off-label use No clinical trials so far Early therapy start required Does health insurance cover therapy costs?

15 Present medication list of the SANDO patient Drug Mechanism of action Evaluation Coenzyme Q10 Improves the function of the No proven value in clinical oxidative phosphorylation chain, trials; but not harmful radical scavenger Amitriptyline Non-selective monoamine Symptomatic improvement reuptake inhibitor of the polyneuropathy, overdose might cause seizures and anticholinergic syndrome Escitaloprame Selective serotonin No synergistic effect with reuptake inhibitor amitriptyline in polyneuropathy, mechanism of action similar to that of amitriptyline; overdose might cause serotoin syndrome and seizures Advice: Discontinue drug!

16 Present medication list of the SANDO patient Drug Mechanism of action Evaluation Coenzyme Q10 Amitriptyline Escitaloprame Advice: Dicontinue drug Lamotrigine Antiepileptic drug, Antiepileptic effect, pleiotropic mechanisms neuroprotective effect, of action no mitochondrial toxicity Clobazam Benzodiazepine, Antiepileptic effect, no antiepileptic drug mitochondrial toxicity, but dependence and addiction, withdrawal syptoms, not recommended for long-term use Advice: Dicontinue drug If necessary, the dose of lamotrigine may be increased

17 Advised medication for the SANDO patient Use as few drugs as possible Find a compromise between symptom relief and undesired drug effects No perfect therapy, no evidence-based therapy

18 Therapeutic strategies currently in the pipeline Endurance training Gene therapy: Introduction of intact POLG into mitochondria Antioxidants and radical scavengers: Vitamine E, carnitine, unsaturated omega-3 fatty acids, vitamines B, C, K ( cocktail ) Stimulation of the mitochondrial biogenesis: e. g. via β 2 adrenoceptor and nuclear receptor PGC1α: bezafibrate Reduction of mitochondrial permeability: cyclosporin A, sangliferin Improvement of Ca 2+ homeostasis: Blocking of mitochondrial Ca 2+ channels Inhibition of mitochondrial fragmentation Currently over 40 double-blind randomized trials on drugs for mitochondrial diseases

19 Targeted therapy of mitochondrial diseases Disease Drug Mechanism MNGIE CoQ defiziency MELAS MELAS MERFF Thymidine phosphorylase Coenzyme Q10 Dichloracetate L-arginine NO-release CGP37157 (mitochondr. calcium channel blocker) Gene therapy by means of bone marrow transplantation Specific substrate of one component of the mitochondrial electron transport Inhibition of pyruvate dehydrogenase, lactate acidosis ; trial was stopped because of reversible polyneuropathy in all participants Fewer strokes due to enhanced NO-dependent vasodilatation Enhanced mitochondrial Ca 2+ homeostasis

20 Mitochondrial diseases as a model for common diseases Alzheimer s K1 K2 Q10 K3 K4 K5 POLG Parkinson s Diabetes POLG mutation Mitochondrium Heart attack ROS ATP cell metabolism clinical symptoms cell destruction

21 Conclusions Orphanet and Pubmed are important and complementary - but not perfect - data bases Expert knowledge on pathophysiological mechanisms required Often no clinical trials exist; only off-label use possible In-depth pharmacological knowledge required for assessing the risk of undesired drug effects Drugs for rare diseases have a broader range of application than primarily assumed Close relationship to research entities required Research on orphan drugs is worthwhile for everyone!