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CFERV 2019 Poduri

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A range of approaches to clinical trials for targeted therapy in rare diseases will be discussed, highlighting the need for natural history data to determine which outcomes are important and feasible to measure in a trial setting. Dr. Poduri will review what is needed for a robust, blinded trial as well as N of 1 treatment experiences relevant to the GRIN community. Specific examples of successful N of 1 cases will be discussed for both pharmacological and genetic approaches. Questions around
dosing, gain- and loss-of-function properties of variants, and resource requirements will be considered.

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CFERV 2019 Poduri

  1. 1. Annapurna Poduri, MD, MPH Epilepsy Genetics Program, Boston Children’s Hospital Department of Neurology, Harvard Medical School CFERV Conference | September 13, 2019 Clinical Trials for Rare Genetic Disorders © Annapurna Poduri, MD, MPH
  2. 2. Outline • Translational framework for epilepsy genetics • Considerations for rare genetic ‘epilepsies’ • N of 1 ‘trials’ © Annapurna Poduri, MD, MPH
  3. 3. Outline • Translational framework for epilepsy genetics • Considerations for rare genetic ‘epilepsies’ • N of 1 ‘trials’ © Annapurna Poduri, MD, MPH
  4. 4. Epilepsy Genetics: A Translational Approach © Annapurna Poduri, MD, MPH
  5. 5. Outline • Translational framework for epilepsy genetics • Considerations for rare genetic ‘epilepsies’ • N of 1 ‘trials’ © Annapurna Poduri, MD, MPH
  6. 6. What outcomes should be targeted? • Seizure • Epilepsy—more than one unprovoked seizure* • Epilepsy syndrome – characteristic features – other features: developmental delay/intellectual disability, autism, hypotonia, movement disorders © Annapurna Poduri, MD, MPH
  7. 7. What outcomes should be targeted? • Seizure • Epilepsy—more than one unprovoked seizure* • Epilepsy syndrome – characteristic features – other features: developmental delay/intellectual disability, autism, hypotonia, movement disorders © Annapurna Poduri, MD, MPH
  8. 8. Epilepsy Genetics: A Translational Approach ? © Annapurna Poduri, MD, MPH
  9. 9. What do we seek in epilepsy treatments? • Efficacy—do they work? – For what core features? • Tolerability – Target specific dysfunction, avoid unneeded side effects • Benefit/risk balance • When are clinical trials appropriate? © Annapurna Poduri, MD, MPH
  10. 10. Outline • Translational framework for epilepsy genetics • Considerations for rare genetic epilepsies • N of 1 ‘trials’ © Annapurna Poduri, MD, MPH
  11. 11. Rationale for pursuing targeted n of 1 therapy: a ‘simple’ case Diagnostic certainty: -2 sibs, compound heterozygous CAD -MRI progression -blood smear: anisopoikilocytosis Risks of not pursuing treatment: -ongoing seizures/risk of status epilepticus -developmental regression Risks of treatment with uridine: theoretical © Annapurna Poduri, MD, MPH
  12. 12. A year later… © Annapurna Poduri, MD, MPH
  13. 13. And 2 years later… © Annapurna Poduri, MD, MPH
  14. 14. And this past Tuesday © Annapurna Poduri, MD, MPH
  15. 15. 10 months from mutation identification to first dosing 4 months from lead to first dosing Slide courtesy Tim Yu, BCH Targeted n of 1 therapy: a complex case with Batten disease © Annapurna Poduri, MD, MPH
  16. 16. CLN7: 6 7 8 13••••••1 Trapped CLN7: 6 7 8 13••••••1 SVAi6 stop* Native E6-E7 Mutant E6-i6 Blood RNA → RNA-seq → Splice junction analyses → RT-PCR confirmation SVA ? Slide courtesy Tim Yu, BCH Targeted n of 1 therapy: a complex case with Batten disease © Annapurna Poduri, MD, MPH
  17. 17. Normal CLN7 splicing: 6 7 8 13••••••1 After transposon insertion: SVA6•••1 i6 stop* 6 7 8 1 3 • • • • • • 1 * S V A i 6 Restoration of normal splicing Mila Fibroblasts Antisense oligos A patient-specific screen: Slide courtesy Tim Yu, BCH Targeted n of 1 therapy: a complex case with Batten disease © Annapurna Poduri, MD, MPH
  18. 18. Seizure frequency & intensity Christelle Achkar, BCH © Annapurna Poduri, MD, MPH
  19. 19. 10 months from mutation identification to first dosing 4 months from lead to first dosing Slide courtesy Tim Yu, BCH Targeted n of 1 therapy: a complex case with Batten disease © Annapurna Poduri, MD, MPH
  20. 20. NIH Undiagnosed Disease Program Pierson et al., Annals of Clinical Translational Neurology, 2014 GRIN2A and memantine © Annapurna Poduri, MD, MPH
  21. 21. NIH Undiagnosed Disease Program Pierson et al., Annals of Clinical Translational Neurology, 2014 GRIN2A and memantine © Annapurna Poduri, MD, MPH
  22. 22. Jurriaan Peters, Heather Olson, BCH New patient with Glu2NA S644G • Epileptic spasms • Now ‘standard’ evaluation with gene panel • Standard treatments not effective © Annapurna Poduri, MD, MPH
  23. 23. GRIN2A and memantine LBD M3 LBD ATD M4 M2 * b GluN1/GluN2A Tetramer S644 Transmembrane Domains Ligand Binding Domain Amino Terminal Domain COOH GluN2A Out In Agonist a Human GluN2A (630) MVSVWAFFAVIFLASYTANLAAFMIQEEFVDQ GRIN2A ATD S1 S2 CTDM1 M2 M3 M4 * * Steve Traynelis (Emory) © Annapurna Poduri, MD, MPH
  24. 24. 100 80 60 40 20 0 S644G WT 2A Glutamate, mM MaximalResponse,% 0.1 1 10 1000.01 a Figure-2. Functional evaluation of GluN1/GluN2A receptors and GluN1/GluN2A-S644G receptors by two-electrode voltage clamp recording from Xenopus laevis oocytes. (a) The composite glutamate (in the presence of 100 mM glycine) and (b) glycine (in the presence of 100 mM glutamate) concentration-response curves show an increased agonist potency (17-fold for glutamate, 11-fold for glycine) in the mutant receptors compared to the wild-type (WT) receptors. The data were expressed as Mean ± SEM (n).* p < 0.05, compared to WT, unpaired t-test. Table-1. Summary of pharmacological data for S644G WT 2A 2A-S644G Glu EC50, mM (n) 3.4 ± 0.40 (6) 0.20 ± 0.0.3 (6)* Gly, EC50, mM (n) 1.0 ± 0.09 (5) 0.09 ± 0.02 (10)* Glycine, mM S644G WT 2A100 80 60 40 20 0 MaximalResponse,% b 0.1 1 100.010.001 Steve Traynelis (Emory) © Annapurna Poduri, MD, MPH
  25. 25. New patient with Glu2NA S644G • 2015 discussion—N of 1 vs. await a trial • Interim guidelines • Progress report © Annapurna Poduri, MD, MPH
  26. 26. What have we learned? Multi-center trial vs. N of 1 trial Needs infrastructure +/- infrastructure Slower Faster Standardized outcomes Customized outcomes Randomization possible Non-generalizable Needed if high risk Better for low risk? © Annapurna Poduri, MD, MPH
  27. 27. Goal: achieving precision treatment © Annapurna Poduri, MD, MPH
  28. 28. What have we learned? • Precision diagnosis • Risk/benefit discussion – Disease course/need for treatment – Meaningful outcomes and how to measure them – Pre-clinical data re: specific mechanisms, drugs © Annapurna Poduri, MD, MPH
  29. 29. Thank you • Patients and families • Tim Yu, Heather Olson, Jurr Peters, BCH • Steve Traynelis, Emory • Wayne Frankel, Columbia • Tim Benke, Kristen Park, Colorado • Eric Marsh, Ingo Helbig, CHOP • International epilepsy genetics community of collaborators BCH Epilepsy Genetics Program/Poduri Lab epilepsygenetics@childrens.harvard.edu © Annapurna Poduri, MD, MPH

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