PRE-CELL: Preparing for a future planned Phase 1 trial of genetically-modified stem
cells over-expressing BDNF in patients with Huntington’s disease
Wheelock V1, Tempkin T1, Duffy A1, Martin A1, Mooney L1, Scher L2, Farias S1, Swadell D1, DeCarli C1, Brunberg J3, Li C-S4, Liu Y4, Yarborough M5, Dayananthan A1, Stout J6, Hersch S7, Aylward E8, Fink KD9, Annett G9 and Nolta J9
1Department
of Neurology and HDSA Center of Excellence at UC Davis School of Medicine, Sacramento CA USA,2Department of Psychiatry, UC Davis School of Medicine, Sacramento CA USA, 3Department of Radiology, UC Davis School of Medicine, Sacramento CA USA, 4Department of Biostatistics, UC Davis School of
Medicine, Davis, CA USA, 5Bioethics Program, UC Davis School of Medicine, Sacramento CA USA, 6Department of Psychology, Monash University, Victoria, Australia, 7Department of Neurology, Massachusetts General Hospital/Harvard University, Boston MA USA, 8Department of Radiology, Seattle Children’s Hospital, Seattle
WA USA, 9UC Davis Institute for Regenerative Cures, UC Davis School of Medicine, Sacramento CA USA
Demographics
Figure 1, Enrollment
Background
Fig. 3. Rate of Change in Clinical Characteristics
Estimated
of Total
Functional
Capacity
Over Time
EstimatedTrajectory
Trajectory of UHDRS
Total Functional
Capacity
Score Over Time
Mesenchymal stem cells (MSCs) engineered to overexpress brain-derived
neurotrophic factor (BDNF) is a proposed therapeutic for neuroprotection
in Huntington’s disease (HD).1, 2 PRE-CELL is the lead-in observational
study for a future planned Phase I cellular therapy trial of MSC/BDNF in HD
(NCT01937923). The primary objective is to enroll a cohort of up to 40
subjects with early-stage Huntington’s disease (HD) to characterize the
rate of change in clinical, neuro-imaging, laboratory and biomarker
correlates of disease progression over a 12 – 24 month period.
Estimated
Trajectory
ofofUHDRS
Total
Motor
Score Over Time
Estimated
Trajectory
UHDRS Motor
Score
Over Time
69
61
53
12
UHDRS Motor Score
UHDRS Total Functional Capacity Score
14
10
Statistical analysis was performed using a linear mixed effects model was
used to analyze the repeated measures of the following selected clinical
outcome measures in the cohort.
Results
37
29
13
5
6
6
12
Baseline
18
6
Figure 2, Demographics
7
58.5%
41.5%
40
0
100.0%
0.0%
Parental Inheritance
n = 41
Mother (49%)
Father (51%)
Unknown* (10%)
16
21
4
* Responding “unknown” or "no" to both
6
2.5
Square Root of Total PBA Score
24
17
Square Root of Product of Severity and Frequency
Male
Female
2.0
1.5
1.0
CAG repeats
# subjects
CAG Repeats, Expanded Allele
mean = 43.7 (median = 42), SD = 3.9, range: 38 - 59
38
40
41
42
43
44
45
46
47
48
1
2
7
11
6
3
1
3
2
1
Burden of Pathology Score
mean = 373.7 (median = 363), SD = 86.7, range: 160 – 556.5
3
2
0
6
12
Baseline
6
Time (months)
12
18
Time (months)
Estimated
Trajectory
ofComposite
E-COGScore
Composite
Score
Estimated
Trajectory of
in E-COG Over
Time Over Time
Estimated Trajectory
of HD of
Quality
of Life Over
TimeTime
Estimated
Trajectory
HD-QOL
over
125
185
115
170
155
105
HD Quality of Life
# subjects
4
1
Baseline
Age range
# subjects
5
0.5
0.0
Demographics: Age & Education
Age: mean = 49.8 (median = 55) , SD = 12.5, range: 23 – 74
≤ 25
26-30 31-35 36-40 41-45 46-50 51-55 56-60 61-65 65-70 > 70
2
1
3
4
5
3
6
10
5
1
1
Education*: mean = 14.7 (median = 14), SD = 2.5, range: 11 - 20
Education in
years
11
12
13
14
15
16
17
18
19
20
1
11
3
7
0
10
1
5
0
2
18
Estimated Trajectory of Square Root of Product of
Frequency
and
Severity
PBA-s
Total
Score
Over
Time
Estimated Trajectory of
Square
Root of Total of
Problem
Behavior
Assessment
(PBA) Score
Over
Time
Estimated Trajectory of Square Root of Product of Frequency
and
Severity
Apathy
Over
Time
Estimated
Trajectory
of Squareof
RootPBA-s
of Product of
Severity andSubscore
Frequency in PBA-s
Apathy Over
Time
3.0
Demographics: Gender, Ethnicity, Race
n = 41*
Hispanic
4
10.0%
"White"
Non-Hispanic
36
90.0%
All other
12
Time (months)
Time (months)
Composite Score
Subjects were recruited from July 2013 – June 2015 with the following
inclusion criteria: adult men and women with clinically diagnosed HD,
CAGn > 37, TFC 9 – 13, without dementia or unstable psychiatric
symptoms, and with a care partner willing to enroll in the study and to
report on their status. Exclusion criteria included pre-manifest or
prodromal HD, minors, advanced HD clinical, stage, history of substance
abuse, unstable psychiatric status, dementia, unstable general health,
coagulopathy, history of previous stem cell or cytokine treatment, and
contraindication
to
MRI.
Assessments
were
performed
at
screening/baseline and then every 6 months, including vital signs, clinical
and neurological examinations, concomitant medication review, UHDRS
motor examination, Total Functional Capacity, Functional Examination and
Independence scores, cognitive assessment using the CAB-HD battery,
Columbia Suicide Rating Score, Problem Behaviors Assessment-short
form, HD Quality of Life, Neuropsychiatric Inventory-Caregiver, E-COG
assessment, modified Rankin Scale, serum and CSF biomarkers, structural
MRI and safety laboratories. Interim telephone visits are scheduled every 3
months.
45
21
8
Baseline
Methods
Fig. 4. Rate of change in Cognitive Measures
95
85
75
65
140
125
110
95
80
49
2
54
1
59
1
55
65
45
50
35
Baseline
35
6
12
Time (months)
18
Baseline
6
12
18
Time (months)
Fig. 6. Structural Imaging Analysis
Figure 5
Forty-two subjects have been screened and 32 enrolled, (Figure 1).
Demographics are presented in Figure 2. Interim analysis of study
measures for the 32 subjects meeting enrollment criteria was performed in
month 23 of the study, with 26/32 subjects completing 6 months of followup, 18 completing 12 months, and 7 completing 18 months.
The estimated change rates for selected clinical measures include: Total
Functional Capacity score, -0.7884 per year, (p-value < 0.0001);
Independence Score, -6.2546 per year, (p-value < 0.0001); Total Motor
Score, 9.1038 per year, (p-value < 0.0001); change rate in square root of
total Problem Behaviors Assessment score, 0.12942 per year, (n.s.; p-value
= 0.6521). Additional significant changes were seen in the HD-QOL, 17.089
per year, (p-value = 0.0078), E-COG total score, 6.6312 per year, (p-value =
0.0035), square root of PBA-s Apathy sub-score, 0.7518 per year, (p-value
< 0.0001). (See Figure 3).
Baseline and longitudinal cognitive assessment scores for the cohort are
consistent with those of cohorts identified as early-diagnosis in previous
studies (Track-HD and CAB-Beta, not shown). Rate of change in selected
cognitive measures are presented in Figure 4. Preliminary biomarker
analysis revealed significant variability in serum BDNF levels. CSF BDNF
analysis is still underway. Detection of mutant Huntingtin (mHtt) protein
levels in serum and CSF by the Hersch lab revealed a strong linear
relationship between serum mHtt and CSF mHtt (correlation of 0.87774, pvalue <0.0001), (Figure 5). Cross sectional and longitudinal analysis of
imaging data for the cohort shows significant reduction in striatal,
putaminal region, and white matter volume and increase in CSF volume
detected 6 months (Figure 6), with a significant correlation in rate of
change seen with CAP scores.
Conclusions
The PRE-CELL study has successfully enrolled a cohort of subjects with early-stage HD and has characterized the
rate of change in clinical, imaging and biomarker measures. The rate of change in TFC, independence score,
functional check lists, PBA-s apathy subscore and CAB-HD battery are similar to findings seen in TRACK-HD and
CAB-HD studies, while the rate of change in the UHDRS total motor score is greater than that seen in TRACK-HD.
Additionally, we have shown that the rate of change in the HD-QOL, E-COG, and the modified Rankin score are also
statistically significant. We have detected novel findings in HD serum and CSF biomarkers, and the cross sectional
and longitudinal rates of change in structural imaging are robust at 6 months and correlate with CAP scores. This
data will be used as a baseline for comparison in subjects who may enroll in the future planned Phase 1 trial once
regulatory approval has been obtained and may be generalizable to other studies in early-stage HD.
Acknowledgements
The investigators wish to thank PRE-CELL subjects and care partners for their extraordinary contributions to this study.
Support for this project was provided by California Institute for Regenerative Medicine (CIRM)
grant no. DR2-05415 (Wheelock/Nolta)