Changing the Future for People with Down syndrome - By Roger Reeves, Ph.D.
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Transcript of Changing the Future for People with Down syndrome - By Roger Reeves, Ph.D.
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Roger H. Reeves, Ph.D.Dept. of PhysiologyMcKusick-Nathans Institute for Genetic MedicineJohns Hopkins University School of [email protected]
Changing the future for people with Down syndrome
A discussion for general audiences of recent research advances that have led to an historic clinical trial to improve cognition in Down syndrome,
and which hold the promise of further advances. Adapted from a presentation at the Linda Crnic Institute for Down Syndrome, Denver CO
(2011)
This work was supported by NICHD and NCI under PHS award HD38384. NHLBI supports identification of genetic modifiers of Congenital Heart Disease in Down syndrome under award HL83330. The Down Syndrome Research and Treatment Foundation (DSRTF) and Research Down Syndrome (RDS) support assessment of the ameliorative effects of SAG on trisomic brain development. The Anna and John Sie Foundation supported establishment of the testing network for the DS Cognitive test battery. Dr. Reeves is a consultant for Hoffman-LaRoche Inc. and Elan Pharmaceuticals and on the SABs of DSRTF, RDS and the Linda Crnic Foundation. Nov. 2011
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www.dsrtf.org
400,000 Americans have Down syndrome (DS). 6000 children are born with DS every year in the US alone.
It is the most complex genetic condition that is compatible with survival past term.
Because the root cause – over-representation of ~500 genes – is so complex and the effects of the extra chromosome are present
in all cells from conception onward, animal models are an essential tool in efforts to study and ameliorate effects of trisomy
21.
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DS affects every cell, tissue and organ in the body from
conception onward.Trisomy 21 has many effects, and
key among them is a cognitive deficit.
A small increase in cognitive ability could greatly expand the
opportunities of tens of thousands of people with DS.
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• Mouse models with three copies of the same genes present in Down syndrome develop features like people with DS.
• These models make it possible to identify
the basis for cognitive deficits, and to test drugs that diminish these deficits.
• Clinical safety trials in people with DS using some of these drugs started in
2011. (Watch http://clinicaltrials.gov/)
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What do we know for sure about Down Syndrome?
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What do we know for sure about Down Syndrome?
1. It occurs due to Trisomy 21.
2. Every individual has a different subset of features that are more common in people with trisomy 21 than in the “typical” (euploid) population
3. It is among the most complex genetic conditions compatible with human survival beyond term.
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Comparativemapping
Genes on human Chr 21 are found on Chr
16, 17 and 10 in mouse
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Ts65Dn mouse (karyotype by Gail Stetten, Sarah South)
Muriel Davisson
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Can a mouse have Down syndrome?
A.Short stature*Flat facies *Flat nasal bridge *Protruding tongue *Mental retardation, “DS type” * Small cerebellum * Highly arched palate (*)
{
Yes! Trisomic mice develop a number of the same features as do trisomic people.
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4. Mental retardation, “DS type”
Ts65Dn mice are significantly deficient in functions that require the hippocampus,
like the Morris water maze test.
Reeves, R.H., N.G. Irving, T. Moran, A. Wohn, C. Kitt, S. Sisodia, C. Schmidt, R.T. Bronson and M.T. Davisson. 1995. A mouse model for Down Syndrome exhibits learning and behavior deficits. Nature Genetics 11:177-184.
This brain regions is affected in DS, too.
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The Down syndrome brain: functional outcomes
• Hippocampal function is robustly affected in mouse DS
models (Ts65Dn, Ts1Cje) Reeves et al., Nat. Gen. 1995; Escorihuela, Neuro Lett. 1995; Holtzman et al., PNAS 1996
•
Hippocampal deficits especially affect declarative learning and memory, affecting speech, language and short-term memory.
• J Neurosci 2004
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The Down syndrome brain: functional outcomes
Hippocampal deficits include excessive inhibitory input in electrophysiological studies.
J Neurosci 2004
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Fernandez et al., Nat Neurosci., published online Feb 25 2007
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Proposed Mechanism for Decreased Synaptic Plasticity in Ts65Dn, Fernandez et al. 2007
Ts65Dn mice show:
Reduced spatial memory and its physiological correlate, LTP
Greater Inhibition in the Hippocampus via GABAA neurons in Ts65Dn mice (Kleschevnikov et al., 2004)
Ts65Dn shows an increase in inhibitory (GABA-ergic) inputs relative to excitatory inputs to (Hanson et al., J Phys 2007)
Approach: Restore this balance with drugs that reduce GABAA receptor activity and measure tests of hippocampal function
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Experimental Protocol: Assessing the Cognitive Effects of Pentylenetetrazole in Ts65Dn Mice
Day 1 and 2: Home Cage Feeding
Day 3 and 4: Milk Intake in
Feeding Tubes
Day 5 thru 21: Drug
Administration in Feeding Tubes
Time
Test
Day 14
Test
Day 21Fernandez et al., Nat Neurosci., published online Feb 25 2007
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Pentylenetetrazole Treated Ts65Dn Mice Exhibit Improved Object Recognition Memory
Milk PTZ0
10
20
30
40 WTTs65Dn
*
Dis
crim
inat
ion
inde
x
Fernandez et al., Nat Neurosci., 2007
Short term evaluation at the end of 2 wks. of treatment
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fEP
SP
(%)
Time (min)
0 10 20 30 40 50 60
100
110
120
130
140
150
160
170 Dentate LTP
Pentylenetetrazole Causes a Lasting Improvement in Circuit Functionality (2-3 months)
2 weeks of treatment, test 2-3 months later
wt
Ts65 + PTZ
Ts65Dnctrl.
Fernandez et al., Nat Neurosci., 2007
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Arizona Cognitive Test Battery
Lynn NadelJamie Edgin
Stephanie Sherman
Tracie Rosser Stuart Tinker
Cheryl Maslen
Len AbbedutoRene Pierpoint
Roger ReevesIser DeLeonMelissa AllmanGeorge CaponeValerie DeLeon
A battery of tests focused specifically on brain regions that are highly affected in Down syndrome
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Targeted Brain Regions
• Cerebellum– Tested core function(s): motor responsiveness, reaction
times
• Prefrontal cortex– Tested core function(s): Holding of information in active or
working memory to guide action selection; executive function
• Hippocampus– Tested core function(s): Storage of episodic information in
long-term memory
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Selection of Tests
• Performance not at floor or ceiling• Mostly nonverbal:
– Avoids potential confound of well-known verbal STM and language deficits (e.g. syntax, articulation) in DS
– Analogues or variants exist or can be developed for animal models of DS
• Global measures of cognitive function & measures sensitive to regions of structural and functional abnormalities in DS
• Validated (e.g., neuroimaging or lesion data)
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Edgin et al., J. Neurodevelop. Disord. 2:149–164
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Research Design
(U. Wisconsin, Oregon Health Science Univ., Children’s Nat’l. Medical Center)
J Neurodevel Disord (2010) 2:149-164
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A novel alternative approach to therapy for Down syndrome
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Laura BaxterJuan TroncosoRandall RoperNidhi SaranDonna KlinedinstPhil BeachyAnn LawlerHeidi St. JohnHernan Lorenzi Ishita DasYan Xiang
Baxter, L.L. et al. 2000. Human Mol. Genet. 9:195-202.Roper, R.J. et al., 2006. Proc. Natl. Acad. Sci. 103(5):1452-6.
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Euploid Down syndrome
Cerebellar volume is reduced in DS and in Ts65Dn mice
From Kesslak et al., Neurology, 1994, 44: 1039-1045.
Ts65Dn
Baxter, L.L. et al. 2000. Human Mol. Genet. 9:195-202.
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Cerebellar volume and cell density are reduced in Ts65Dn mice
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Reduced granule cell density in the Ts65Dn cerebellum correctly predicted the same phenotype in DS
Baxter, L.L. et al. 2000. Human Mol. Genet. 9:195-202.
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When in development do the trisomic and euploid
cerebellums begin to diverge?
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Ts65Dn cerebellum is overtly normal at P0, but significantly smaller by P6
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0.18
0.20
1P0 P6 P14 P24
EuploidTs65Dn
**
P28 P35
*
*
Eu. N=10Ts. N=10
Eu. N=10Ts. N=10
Eu. N=10Ts. N=10
Eu. N=10Ts. N=10
Eu. N=7Ts. N=5
Eu. N=5Ts. N=7
Normalized
cerebellar area
EGL is the same size at P0
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Euploid (n=6): 951,995 16,970 1.8%
Ts65Dn (n=6): 931,976 13,354 1.4%
T-test: p = 0.40 p = 0.05
Euploid (n=5): 7,381,391 135,359 1.8%
Ts65Dn (n=5): 5,269,919 98,781 1.8%
T-test: p = 0.001 p = 0.04
P0
P6
gc precursors Mitotic cells Mitotic index
Stereology demonstrates an early mitotic deficit in trisomic mice
Roper, R.J. et al., 2006. Proc. Natl. Acad. Sci. 103(5):1452-6.
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Is the growth deficit in trisomic mice related to the role of SHH in gcp
proliferation?
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-20
-10
0
10
20
30
40
50
60
70
Shh-Np (nM)
CP
M (
x 10
3)
Eu
Ts
0 2 5 7.5 10
Isolated granule cell precursors from Ts65Dn mice do not respond to Sonic hedgehog to the same degree as
euploid gcp
Roper, R.J. et al., 2006. Proc. Natl. Acad. Sci. 103(5):1452-6.
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Can the Ts65Dn/DS granule cell deficit be “cured”?
Frank-Kamenetsky et al., J Biol. 2002 Nov 6;1(2):10.
SAG is a small molecule (potential drug) that has the same effects as the SHH growth factor
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A single dose of SAG on the day of birth restores Ts65Dn cerebellar structure at P6, ~ 1/3 of the way though cerebellar
development. Because the number of dividing cells is also normal after SAG treatment, the cerebellum may be “cured” in
adult Ts65Dn mice.
Randall J. Roper, Laura L. Baxter, Nidhi G. Saran, Donna K. Klinedinst, Philip A. Beachy & Roger H. Reeves. 2006. Defective cerebellar response to mitogenic Hedgehog signalling in Down syndrome mice. Proc. Natl. Acad. Sci. 103: 1452-1456.
0
1,000,000
2,000,000
3,000,000
4,000,000
5,000,000
6,000,000
7,000,000
8,000,000
9,000,000
10,000,000
Ts u
ntre
ated
Ts S
AG
Eu un
treat
ed
Eu ve
hicle
Eu SAG
a. Granule cell precursors b. Mitotic granule cell precursors
0
20,000
40,000
60,000
80,000
100,000
120,000
140,000
160,000
180,000
200,000
Ts u
ntre
ated
Ts S
AG
Eu un
treat
ed
Eu ve
hicle
Eu SAG
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Does the SAG effect last beyond early development?
What aspects of the Ts65Dn phenotype are affected?
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Basic research has changed the game for people with Down syndrome.
A number of the key findings that made this possible were supported by private Foundations,
including the Down Syndrome Research and Treatment Foundation, the John and Anna Sie Foundation and Research Down Syndrome.*
*Dr. Reeves is a member of the Science Advisory Boards of the Linda Crnic Institute, which is affiliated with the Sie Foundation, and of DSRTF and RDS. He is a grantee of DSRTF and RDS, non-profit foundations dedicated to
amelioration of cognitive deficits in DS.
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Conclusions
1. Trisomy for orthologs of Hsa21 genes in mice has related effects on developmental pathways and functions
2. Trisomy affects the function of the hippocampus in similar ways in mice and people. Down-regulation of GABA-A interneurons hold promise as therapeutic targets – A Clinical trial to test this has started.
3. The Arizona Cognitive Test Battery provides a focused instrument for assessing possible improvements and represents a substantial part of the current Clinical Trial evaluation.
4. Additional approaches in the pipeline may eliminate some congenital problems of Down syndrome altogether
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http://www.roche-trials.com/
The first clinical trial by a major pharmaceutical company to test a drug that may improve learning and memory in Down syndrome started in the fall of 2011.
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Cerebellum project:Laura BaxterRandall RoperNidhi SaranJuan TroncosoIshita Das
and Phil Beachy, Stanford University
Current lab members:Donna Klinedinst Huiqing LiMeifang XiaoSarah McGuireDuane CurrierSarah EdieRenita PolkJennifer PoitrasTara HowardBen Devenney
Craniofacial Joan T. Richtsmeier
Reeves lab
Jamie Edgin Lynn Nadel Stephanie Sherman George Capone Julie Hoover-Fong Iser DeLeon Len Abbeduto Cheryl Maslen Valerie DeLeon
Cognition