gsd type i clinical and research update · 2019. 1. 22. · gsdia canine gt vector stability aav 8...
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David A. Weinstein, M.D, M.M.Sc.
Director, Glycogen Storage Disease Program
Professor, University of Florida College of Medicine
GSD Type I Clinical and Research Update
Glycogen Storage Disease in 1998
• Many children in the United States were getting liver transplants
• Little clinical research was occurring
• 16 years without a major advancement
There was little hope
for families
Progress since 1998
• Clinically approved blood and saliva tests have been created to diagnose GSD
• Evidence that all complications in GSD can be prevented
• New therapies have been introduced
• Gene therapy has successfully been performed in the animal models
Prevention of Complications
There is increasing evidence that complications can be prevented or completely avoided in GSD through maintenance of outstanding metabolic control.
Complications can be Avoided
• Hepatic adenomas (Ia/Ib)
• Osteoporosis (Ia, Ib, III)
• Anemia (Ia, Ib)
• Splenic Complications (Ib)
• Myopathy (GSD III)
• Cardiomyopathy (III)
• Cirrhosis (IX)
• Growth (0, Ia, Ib, III, IX)
Mean triglycerides
> 5.6 mmol/L
p = 0.008
mean triglycerides < 5.6 mmol/L
Wang DQ et al, J Pediatr, 2011
Regression of Adenomas with Improved Metabolic Control
• Regression of adenomas in 13 patients
• 9 patients with MRI confirmation
• 6/9 with complete regression
• Regression occurred when triglycerides fell below 300
• Total: 8 years follow-up
• Average of 4.8 years to complete regression
There is one medical condition that we are seeing more frequently in our adults with
GSD Ia and GSD Ib……
Pregnancy
46 healthy children have been born to mothers with GSD in our
program including a mother with GSD Ia who has 7 children
and a mother with GSD Ib who has 6 children
Why Do We Need New Treatments
• No children and less than 10% of adults can sleep through the night without awakening
• Over sleeping can result in severe hypoglycemia, seizures, and even death
• Complications common when suboptimal compliance
Glycogen Storage Disease Type I
Glucose Gluc -6- Phos
Pyruvate Lactate
Uric Acid
Acetyl CoA
Krebs
Cycle
GSD I
Lipids
GLYCOGEN
Entrance for Sugars Exit
Dairy Sugar Fruit
Must get the defective gene to the liver
Key = gene that is defective (G-6-Pase)
Virus: Transporter to the liver
Entrance for Sugars Exit
+/+ -/- Liver Kidney
+/+
-/-
The GSD-Ia mice manifest growth retardation, hypoglycemia,
hyperlipidemia, hyperuricemia, hepatomegaly, nephromegaly, as
well as hepatic and renal glycogen deposition
Slide courtesy of Dr. Janice Chou
Glucose Cholesterol Triglyceride Uric Acid
mg/d
l
Weeks Weeks Weeks Weeks
AAV1-G6Pase infusion normalizes plasma glucose, cholesterol, triglyceride, and uric
acid profiles
Zingone A, et al., J Biol Chem, 2000
The GSD dogs
• Naturally occurring in maltese
• Fatal disease in dogs, and all
dogs die within hours of birth
• Prior to study, no dog had
survived more than 4 weeks
even with medical treatment
Supported by AGSD from 1999 – 2005 and given to the UF team by the teams at NC State and Duke
The Gene Therapy Team
University of Florida College of MedicineThomas Conlon, Ph.D.Youngmok Lee,, Ph.D.Cathryn Mah, Ph.DBarry J. Byrne, M.D., Ph.D.Laurie BrownCatherine Correia
NIHJanice Chou
University of Florida College of Veterinary MedicineJohn Verstegen, DVMKarine Onclin-Verstegen, DVMAndrew Specht, DVMAndre ShihGurmeet Dhaliwal, DVMLayla Mirian
University of Florida Animal Care ServicesMaggie StruckHarvey RamirezJuan Jordan
Acknowledgments: The Dog Caregivers
Abdul-Hamid, Cherissa
Adorno, Melissa
Aguilar, Mike
Alfonso,Danaimys
Appel, Venus
Arana, Scarlett
Ashley Young
Aviles, Kristine
Bellville, Michelle L
Brecht,Christopher A
Brown, Megan F
BUEHLER,RACHEL ANNE
Burgess, Jessie
Busch, Megan L
BYARS,ASHLEY A
Canada, Megan
Carmona, Christopher
CARROLL,CASSANDRA M
Carter, Benjamin
Caruana, Claire H
Cintron, Maite
CLARKE,TANNELLE O
COLLINS,JESSE F
cora jones
Cortez, Ricardo
CROOK,KATHERINE I
Daly,Alexander C
Daniel,Erika
Davis,Michelle E
DEGROAT,ABBE REBECCA
DIAZ,SANTIAGO E
Dingman, Patty
Drogan, Diana
Dunbar,Misha Lydia
Erin Brearley
FEINGOLD,ANDREA M
FONSECA,MARIANA
Forness,Stefanie M
FUENTES,SOFIA A
Gabriel Davila
Georgiou,Alexis A
GOMEZ,VERONICA M
GUND,MICHAEL A
Halse, Stacey
HAMANG,LISA CATHERINE
Helmich,Brantley A
Hirst,Ashley
HOLLISTER, KELLY JEAN
Hreha,Allison D
Hunley, Sharon
Irvine, Brooke
JAMES,STUART HILL
Jennifer Bier
Jonovich,Laura E
Jordan, Juan
Joustra, Molly
KAPLAN,AMY J
Keenan, Dawn
Keener,Jonathon E
KELLEY,SARAH SUZANNE
KUNIHIRO,EMILY MARIKO
LAO,SHIN-PING C
Lauren Edwards
Leonel Londono
Leung,Yuet-Ming R
Levitt,Janna
Liz Tringas
Longobardi,Venessa L
Martinez, Claudia
McGill, Erin
Mcintyre,Robin L
Medina, Javier
Melendez, Veronica
Molero, Kathleen
Moyer, Melissa
NELSON,MEGHAN C
O'Connor, Jessica Swan
Porter, Marcus D
Porvasnik, Stacy
Raddatz,Kristine M
RAMIREZ,CATALINA M
Rhiannon Lewis
Rieder,Christopher H
RIEDER,MARY ELLEN
Rodriguez, Effie
Romina Hennig
ROY, ELIZABETH M
Sarabando,Catarina P
SCHNOKE,ALLISON T
SEIBERT,RACHEL
Shook,Brittany Grace
Singleton, Sabrina
Starks, Linwood A
Stephanie Starling
Stevens, John M
Stone, Jenny
Struck, Maggie
TAN,JESSICA M
Tatgenhorst,Carrie A
Thomas,Amanda L
THOMAS,MELANIE VICTOR
TISDELLE,SANDRA M
Travis Cossette
Tringas, Liz
Unger, Lauren
VanRysdam, Megan
VANSICKLE,ALLISON E
Vaughn, Tiffani
VENCIL,JACOB R
Wang, Sophia
Warren,Ashley L
White, Stephanie
WISDOM,GENEVIEVE A
Woltman,Rachel A
WRENCH,ALGEVIS P
Zahn-Saucier,Maya
Gene Therapy in the canine model:The team
Gene Therapy in Dogs with GSD
• Undetectable glucose at birth
• Confirmed by mutation analysis on DOL #1
Gene therapy was performed on our dogs with GSD type Ia for the first time on September 11, 2007
• Vector: AAV-8
• Dose: 5 x 1013 vector genomes/kg
• Method: IV injection into the jugular vein
Minutes Post-Feeding
20 40 60 80 100 120 140 160 180
Blo
od
Glu
co
se
(m
g/d
L)
0
40
80
120
160
200
240
280
rAAV2/8-CBA-G6Pase
Carrier Control
GSDIa
Fasting Blood Glucose 2 wks post-injection of
rAAV2/8
Blood Lactate Levels 180 minutes post-feed2 wk post administration of rAAV2/8-CBA-mG6Pase
G6Pase +/- GSDIa* AAV8-G6Pase
0
1
2
3
4
5
6
* GSDIa value after 60 min
Untreated GSDIa affected dog
•18 days old
Treated GSDIa affected dog
•17 days old
•16 days post AAV8 treatment
1 2 4 9 12
0
1
2
3
4
5
6
Blo
od
Lacta
te (
mm
ol/L
)
Hours of Fasting
Blood Lactate Levels 7 wks Post-Injection of rAAV2/1
GSDIa rAAV2/8+rAAV2/1 Carrier Control
Blood Glucose Levels
Hours Post Feeding
0 1 2 3 4 5 6 7 8 9 10 11 12 13
Blo
od
Glu
co
se
(m
g/d
L)
0
40
80
120
GSDIa
rAAV2/8 + rAAV2/1
Carrier Control
•
Fasting Study 7 weeks after AAV-1 infusion
All glucose support was stopped at 6 months of age
• No problems clinically while weaning off therapy
• On the day after all support was stopped, dog went 22 hours without food yet remained clinically well
Dulce Following Gene Therapy
Liver biopsy 6 months after the 2nd gene therapy dose
demonstrated 7% activity
H & E Staining
GSD Ia Dogs at 2 months of age
AAV-8 at Birth Medically Treated
Impact of Gene Therapy at 2 months
GSD Ia Canine Colony Overview
• 11 GSD Ia dogs
• 8 have undergone gene therapy– 5 treated at birth
• 3 received AAV 8 (1-5 x 1013 vg/Kg) followed by AAV 1 (1 x 1013 vg/Kg)
• 2 received AAV 1 first
– 3 received delayed treatment• 1 dog at 2 months and 2 dogs at 6 months
• All received AAV 8 (2 x 1013 vg/Kg) as primary treatment
GSD Type Ia Dogs After Gene Therapy
GSDIa Canine GT Vector Stability
AAV 8 / AAV 1
TissuesCopies after 3 years
ug/gDNACopies after 5 years
ug/gDNA
Liver 3355 3058
Ovary 773 18
Kidney 29724 447
Pancreas 19 118
Spleen 4305 70
Jejunum 7 370
Quad 108 ---
Lymph Node 635 0
Diaphragm 40 146
Heart 542 140
Lung 18 5
• November 2012:
Glybera first gene therapy treatment approved as a medication for lipoprotein lipase deficiency
(European Commission)
Gene Therapy for GSD Ib
• [376] Correction of Metabolic Abnormalities in Murine Glycogen Storage Disease Type Ib by Gene Therapy
Young Mok Lee, Joonhyun Kwon, David A. Weinstein, Janice Y. Chou. Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; Glycogen Storage Disease Program, Division of Pediatric Endocrinology, Department of Pediatrics, University of Florida, Gainesville, FL
GSD-Ib gene therapy
GSD-Ib gene therapy
(9)
0
20
40
60
80
100
120
4 8 12 16 20 24 28 32 36 40 44
Su
rviv
al
rate
%
Age (weeks)
Survival rate (%) of AAV-hG6PT infused mice
Thank you for inviting me!
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