Weitere ähnliche Inhalte Ähnlich wie CFERV 2019 Poduri (20) Mehr von JillianHastingsWard (11) Kürzlich hochgeladen (20) CFERV 2019 Poduri1. 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
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. 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
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
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
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. 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. 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
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. NIH Undiagnosed Disease Program
Pierson et al., Annals of Clinical Translational Neurology, 2014
GRIN2A and memantine
© Annapurna Poduri, MD, MPH
21. NIH Undiagnosed Disease Program
Pierson et al., Annals of Clinical Translational Neurology, 2014
GRIN2A and memantine
© Annapurna Poduri, MD, MPH
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. 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. 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. New patient with Glu2NA S644G
• 2015 discussion—N of 1 vs. await a trial
• Interim guidelines
• Progress report
© Annapurna Poduri, MD, MPH
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
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. 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