GSD Type I Clinical and Research Update · 2019. 1. 22. · GSDIa Canine GT Vector Stability AAV 8 / AAV 1 Tissues Copies after 3 years ug/gDNA Copies after 5 years ug/gDNA Liver

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!