Neonatal gene therapy of glycogen storage disease type Ia using a feline immunodeficiency virus-based vector.
Glycogen storage disease type Ia (GSD-Ia), also known as von Gierke disease, is caused by a deficiency of glucose-6-phosphatase-alpha (G6Pase), a key enzyme in glucose homeostasis. From birth, affected individuals cannot maintain normal blood glucose levels and suffer from a variety of metabolic disorders, leading to life-threatening complications. Gene therapy has been proposed as a possible option for treatment of this illness. Vectors have been constructed from feline immunodeficiency virus (FIV), a nonprimate lentivirus, because the wild-type virus does not cause disease in humans. Previously, we have shown that these vectors are capable of integrating stably into hepatocyte cell lines and adult murine livers and lead to long-term transgene expression. In the current work, we have assessed the ability to attenuate disease symptoms in a murine model of GSD-Ia. Single administration of FIV vectors containing the human G6Pase gene to G6Pase-alpha(-/-) mice did not change the biochemical and pathological phenotype. However, a double neonatal administration protocol led to normalized blood glucose levels, significantly extended survival, improved body weight, and decreased accumulation of liver glycogen associated with the disease. This approach shows a promising paradigm for treating GSD-Ia patients early in life thereby avoiding long-term consequences.
Grinshpun
Albert
A
Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Condiotti
Reba
R
Waddington
Simon N
SN
Peer
Michael
M
Zeig
Eli
E
Peretz
Sima
S
Simerzin
Alina
A
Chou
Janice
J
Pann
Chi-Jiunn
CJ
Giladi
Hilla
H
Galun
Eithan
E
D000818:Animals; D000831:Animals, Newborn; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000502:physiology*; D005953:Glycogen Storage Disease Type I / Q000378:metabolism* / Q000628:therapy*; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000235:genetics*; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009929:Organ Size / Q000235:genetics / Q000502:physiology; D016133:Polymerase Chain Reaction
D002784:Cholesterol; D005952:Glucose-6-Phosphatase