Neonatal Gene Therapy of Glycogen Storage Disease Type Ia Using a Feline Immunodeficiency Virus–based Vector

Abstract

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.

A Lentiviral Vector-Based, Herpes Simplex Virus 1 (HSV-1) Glycoprotein B Vaccine Affords Cross-Protection against HSV-1 and HSV-2 Genital Infections

“…FIV is a lentivirus in domestic cats and similar to HIV-1 in many respects, including genomic organization, but is unable to infect humans (20). Vectors derived from FIV have been successfully used to transduce primary cells from feline and nonfeline species (24,52), including humans (60), and proved safe in vitro and in vivo (4,8,52).…”

Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics

“…189 Other vectors that have been evaluated in the G6pase(−/−) mouse model have included helper-dependent adenovirus vector encoding canine G6Pase 183 and a feline immunodeficiency virus vector encoding murine G6Pase. 190 Although both vectors prolonged survival and prevented hypoglycemia in the majority of treated mice, each remains limited by significant concerns related to potential toxicity, and more preclinical experiments will be needed to further evaluate the potential of these systems for clinical translation. Furthermore, complications of GSD Ib were incompletely reversed in experiments with an AAV vector encoding G6PT, and longer-term surviving mice developed hepatocellular carcinoma related to inadequate correction.…”

Treatment of newborn G6pc mice with bone marrow-derived myelomonocytes induces liver repair

“…Previous works on GSD1a therapy in this experimental mouse model have shown that viral vectors can deliver the G6pc gene into the G6pc À/À mouse, restore kidney and/or liver functions and improve the survival of mice to various degrees [8,9,11,15,31,32]. In particular, combined treatment with adeno virus and adeno-associated virus or treatment with recombinant adeno-associated virus-1 [9,11] was particularly effective in extending the life span of mice, demonstrating the efficiency of viral transfer in correcting the genetic defect of the G6pc À/À mice.…”

“…Newborn gene transfer with viral vectors has been reported to be an effective therapy both in the liver and in the nervous system [8][9][10][11][12][13][14][15]. We have previously shown that newborns are particularly susceptible to lentiviral-mediated, liver targeted, gene delivery [16].…”