Transcript Scientific Achievements - Lysosomal Disease Network

Lysosomal Disease Network
Scientific Achievements
Chester B Whitley, PhD, MD
James Cloyd, PharmD
Brenda Diethelm-Okita, MPA
Rare Diseases Clinical Research Network (RDCRN) is coordinated by Office of Rare Diseases Research, NCATS.
Funding and programmatic support is provided by ORDR in collaboration with participating NIH Institutes.
Lysosomal Disease Network
Publications to-date
53
Peer-reviewed
NCBI-compliant public access
2010-2016
Rare Diseases Clinical Research Network (RDCRN) is coordinated by Office of Rare Diseases Research, NCATS.
Funding and programmatic support is provided by ORDR in collaboration with participating NIH Institutes.
LDN: Publications
LDN: Fellows
At this week’s CCRRD Meeting
• Li “Leo”Ou, PhD
• Reena Kartha, PhD
• Michael “Mike” Flanagan, PhD
• Zoheb Kazi, MD
• Mari Mori, MD
• Melani Solomon, MD
• Kwangchea “KC” Yoon, PharmD
• Joseph “Joe” Schneider, MS, PhD
Lysosomal Disease Network
LDN 6703:
Longitudinal Studies of Brain Structure and
Function in MPS Disorders
Elsa G Shapiro PhD
Chester B Whitley PhD MD
Lysosomal Disease Network
LDN 6705:
Longitudinal Study of Bone and Endocrine
Disease in Children with MPS I, II and VI: A
Multicenter Study of the Lysosomal
Disease Network
Lynda E Polgreen, MD
Lysosomal Disease Network
Lysosomal Disease Network
LDN 6709:
Longitudinal Follow-up of Individuals with
Infantile Pompe Disease
Priya Kishnani, MD
Lysosomal Disease Network
• Durable and sustained immune tolerance to ERT in Pompe disease with
entrenched immune responses. Zoheb B. Kazi, Sean N. Prater, Joyce A.
Kobori, David Viskochil, Carrie Bailey, Renuka Gera, David W. Stockton,
Paul McIntosh, Amy S. Rosenberg, and Priya S. Kishnani. JCI Insight. 2016;
1(11):e86821. doi:10.1172/jci.insight.86821.
• Clinical laboratory experience of blood CRIM testing in infantile Pompe
disease. Deeksha S. Bali, Jennifer L. Goldstein, Catherine Rehder, Zoheb B.
Kazi, Kathryn L. Berrier, Jian Dai, Priya S. Kishnani. Molecular Genetics and
Metabolism Reports 5 (2015) 76–79.
• Immune tolerance strategies in siblings with infantile Pompe disease —
Advantages for a preemptive approach to high-sustained antibody titers.
Elizabeth O. Stenger, Zoheb Kazi, Emily Lisi, Michael J. Gambello, Priya
Kishnani. Molecular Genetics and Metabolism Reports 4 (2015) 30–34.
• The first successful induction of
long-term immune tolerance in
the setting of an entrenched
immune response to a lifesaving
therapeutic protein
• The reduction in rhGAA IgG
antibody titers with bortezomibbased immune tolerance
induction (ITI) protocol provides
evidence that HSAT are mediated
by long-lived plasma cells, and by
targeting such, significant
reductions in antibody titers and
immune tolerance are feasible
JCI Insight. 2016; 1(11):e86821. doi:10.1172/jci.insight.86821.
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Development of a rapid method for determining CRIM status in patients with IPD is
important so that appropriate treatment can be initiated as soon as possible.
Our results indicate that the results of CRIM status determined by Western blot analysis
of PBMC may not always be clear or concordant with that by analysis of skin fibroblast
and CRIM status predicted from GAA gene mutations.
While a blood-based assay to determine CRIM status has the advantage of rapid results
for faster initiation of treatment, further method development is needed to ensure the
accuracy of the results.
Molecular Genetics and Metabolism Reports 5 (2015) 76–79.
Fig. 1. Bortezomib-based ITI in Patient 1 with HSAT Fig. 2. Prophylactic ITI in Patient 2 in ERT-naïve setting
• These two siblings expand upon the use of a bortezomib-based regimen for
HSAT and support the use of preemptive ITI for high-risk CRIM-positive IPD
• Early ERT does not necessarily prevent the development of HSAT
• In patients at high-risk for developing HSAT, including CRIM-negative patients
and affected siblings of CRIM-positive patients with HSAT, short course ITI with
rituximab, IVIG and methotrexate can prevent the development of HSAT and
improve clinical outcomes.
Molecular Genetics and Metabolism Reports 4 (2015) 30–34.
Statement of Impact
This study has provided clinical treatment outcomes
and natural history of cross reactive immunological
material (CRIM)-positive and CRIM-negative Pompe
disease patients on enzyme replacement therapy (ERT)
with and without immune suppression regimens.
By assessing long-term outcomes, efficacy and
safety of various immune-tolerizing induction (ITI)
protocols, our results have guided management and
influenced treatment standards for patients with infantile
Pompe disease, changing the course of the disease as we
know it—the importance underscored by the advent of
newborn screening for Pompe disease.
Lysosomal Disease Network
LDN 6716:
Genotype-Phenotype Correlations of Late
Infantile Neuronal Ceroid Lipofuscinosis
Doug Ballon, MD
Lysosomal Disease Network
LDN 6716: Biomarkers for Disease Severity and Therapeutic Response in LINCL
1) Whole brain MRI biomarkers of disease severity (Am J Neuroradiol. 2013;34:884-89)
ADC
%CSF
MRS
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>> Developed non-invasive MRI Disease Severity Score (MRIDSS) in subjects with CLN2 disease.
2) Brain region specific MRI biomarkers of CLN2 severity (Am J Neuroradiol. 2016;37:1160-69)
Healthy
Control Subject
6.1 years
Vs.
>> Cortical thickness degeneration in CLN2 (blue) vs. controls (red) vs. age.
CLN2 Subject
5.9 years
CLN2
Score 1.5
Lysosomal Disease Network
LDN 6722:
Role of Oxidative Stress and Inflammation
in Type 1 Gaucher Disease (GD1): Potential
Use of Antioxidant/Anti-inflammatory
Medications
James Cloyd, PharmD
Lysosomal Disease Network
Lysosomal Disease Network
Gaucher disease and related disorders cause oxidative stress and/or
inflammation
N-acetyl cysteine (NAC) works as an antioxidant/anti-inflammatory
Pilot study in a small number of people shows that IV NAC can improve
oxidative stress
Larger study with oral NAC to determine if it can improve oxidative stress
and/or inflammation
If yes, a large, clinical trial comparing NAC versus placebo to determine if
NAC as co-therapy can improve GD1 symptoms
Lysosomal Disease Network
Evidence of oxidative stress and
inflammation in Gaucher Disease supports
use of an antioxidant (NAC) to reduce
symptoms