Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
2000-11-17
2003-06-24
Priebe, Scott D. (Department: 1635)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C435S320100, C435S455000, C514S04400A
Reexamination Certificate
active
06582692
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to recombinant adeno-associated virus (AAV) expression vectors and virions, as well as methods of using the same. More specifically, the present invention relates to recombinant AAV vectors and virions comprising genes encoding proteins deficient or lacking in lysosomal storage diseases, and methods of delivering recombinant AAV virions to a mammalian subject to treat lysosomal storage diseases.
BACKGROUND OF THE INVENTION
Lysosomal storage diseases develop when cells are missing one or more of the many lysosomal enzymes essential for breaking down natural macromolecules. Typically, the undegraded molecules accumulate in the lysosomes to form storage vesicles, which eventually distort cellular structure and compromise function. The result is a chronic and progressive condition that causes a variety of physiological problems often leading to organ failure and premature death. Approximately 40 lysosomal storage diseases have been characterized, each of which involves deficiency in one or more specific enzymes.
A. The Mucopolysaccharidoses (MPS)
The Mucopolysaccharidoses (MPS) include seven subtypes. Each subtype is caused by a defect in an enzyme necessary for the sequential breakdown of glycosaminoglycans. The MPS diseases share many clinical features, although each type may vary in severity. Patients generally suffer from organomegaly, dysostosis multiplex, impaired hearing and vision, cardiovascular abnormalities and joint immobility. MPS I (Hurler's Disease) is caused by a deficiency in &agr;-L-iduronidase necessary to breakdown the glycosaminoglycans, dermatan sulfate and heparin sulfate. MPS II (Hunter's Syndrome) is due to the deficiency of iduronidase-2-sulfatase causing the accumulation of partially degraded heparan and dermatan sulfates. MPS III (Sanfilippo Syndrome) has four subtypes categorized by various deficiencies in sulpaminidase and N-acetylglucosamine 6-sulfatase. MPS IV (Morquoi Syndrome) is due to a deficiency of N-acetylgalactosamine-6-sulphate sulphatase. MPS V (Scheie Syndrome) has a deficiency in a-L-iduronidase that is qualitatively different from MPS I. MPS VI (Maroteaux-Lamy Syndrome) is due to deficiency of N-acetylgalactosamine-4-sulfatase. Finally, MPS VII (Sly Syndrome) is due to a deficiency in the lysosomal enzyme &bgr;-glucuronidase (GUS) which aids in the breakdown of glycosaminoglycans (GAGs) (Sly et al. (1973)
J Pediatr
82: 249-257).
Sly Syndrome is characterized by mental retardation, abnormal bone development, distorted features, and organ malfunctions leading eventually to organ failure (Neufeld et al. (1995) “The mucopolysaccharidoses.” In: Scriver C R, Beaudet A L, Sly W S, Valle D (eds),
The Metabolic and Molecular Bases of Inherited Disease
. McGraw-Hill: New York, pp. 2465-2494). Although Sly syndrome is rare, a great deal is known about GUS and because there are animal models of this disease, Sly syndrome has become a paradigm for the study of lysosomal storage diseases in general and for gene therapy in particular.
Both dog (Haskins et al. (1984)
Pediatr Res
18: 980-984) and mouse (Birkenmeier et al. (1989)
J Clin Invest
83: 1258-1266) models of MPS VII have been studied. In these models, animals homozygous for mutations eliminating GUS activity display symptoms analogous to those in humans with Sly syndrome. In mice, the mutation is a spontaneous, single base pair deletion that results in a frameshift and a subsequent stop codon in the sequence coding for the GUS protein (Sands et al. (1993)
Proc Natl Acad Sci USA
90: 6567-6571). Without GUS activity, GAGs cannot be completely catabolized and therefore accumulate in the lysosomes to form storage granules or vacuoles in almost all tissues. This in turn results in animals that have distorted facial features, defects in skeletal development, dwarfism, reduced learning. capacity, and early death at approximately 5 months of age (Birkenmeier et al. (1989)
J Clin Invest
83: 1258-1266; Bastedo et al. (1994)
J Clin Invest
94: 1180-1186). Another useful mutation in mice is the “nearly null” GUS mutation, which was developed by V Chapman at Roswell Park Cancer Institute. These mice have only 1-3% of normal GUS activity yet do not display any overt MPS phenotypes. This implies that if a therapy provided even a minimal amount of GUS activity, the progression of MPS pathology would be halted or reversed.
Using the mouse model for MPS VII, several experimental therapies have been tried. These include enzyme replacement (Vogler et al. (1993)
Pediatr Res
34: 837-840; O'Connor et al. (1998)
J Clin Invest
101: 1394-1400), a variety of cell transplantation approaches (Bastedo et al. (1994)
J Clin Invest
94: 1180-1186; Sands et al. (1993)
Lab Invest
68: 676-686; Poorthuis et al. (1994)
Pediatr Res
36: 187-193; Moullier et al. (1993)
Nat Genet
4: 154-159; Naffakh et al. (1994)
J Exp Clin Hematol
36: S11-S16; Wolfe et al. (1995)
Gene Therapy
2: 70-78; Taylor et al. (1997)
Nature Med
3: 771-774), and direct administration of adenoviral vectors (Li et al. (1995)
Proc Natl Acad Sci USA
92: 7700-7704; Ohashi et al. (1997)
Proc Natl Acad Sci USA
94: 1287-1292). All of these treatments provided measurable improvement, but none was entirely satisfactory.
Major problems that need to be overcome are the transient nature of enzyme replacement and adenoviral vector therapies, the invasiveness and potential complications of transplantation therapies, and the difficulty in restoring therapeutic GUS activity throughout the organism. The brain in particular has resisted most forms of therapy (Taylor et al. (1997)
Nature Med
3: 771-774; Sly et al. (1997)
Nature Med
3: 719-720).
B. Gaucher Disease
Gaucher Disease occurs in approximately 20,000 Americans. Many cases of mild disease are undiagnosed and the actual occurrence of the gene defect in the general population may be as high as 1 in 640.
There are three major types of Gaucher Disease, called Type 1, Type 2 and Type 3. Type 1, an adult-onset form, is the most common form and is non-neuropathic. The disease has a variable spectrum of severity. Clinical manifestations result from macrophages engorged with glucocerebroside which clog and enlarge the liver and spleen and displace normal bone marrow. This results in hepatosplenomegaly, bone pain and fractures, mild anemia and leukopenia, and bleeding due to displacement of platelet precursors in the bone marrow. Pulmonary infiltration by engorged macrophages can cause respiratory failure. Type 2 disease occurs in infants and is characterized by an acute neuropathic phenotype. This subtype has an extensive pathology, including the symptoms of Type 1, as well as oculomotor abnormalities, extreme retroflexion of the neck, limb rigidity, and seizures. Most infants with this form of Gaucher Disease die within the first 2 years of life. Type 3 disease is a juvenile onset form of the disease that presents with mild neurologic involvement in the first decade of life, progressing gradually toward severe neurologic impairment. The severity of Type 3 disease is intermediate to the other subtypes. In addition to the symptoms of Type 1, Type 3 pathology includes massive visceral involvement. CNS manifestations begin with disorders of eye movement, with progression to neurological symptoms equivalent to the severity of Type 2 disease.
A variety of mutations in the glucocerebrosidase (GC) gene cause Gaucher Disease. These gene defects include missense, frameshift and splicing mutations, deletions, gene conversions, and gene fusions with a pseudogene located 16 kb downstream of the GC gene. The most common mutation in Type 1 disease is an A to G transition at nucleotide position 1226 of the GC gene, causing an amino acid substitution which results in the non-neuropathic form of the disease. Neuropathic disease is associated with a T to C transition at nucleotide position 1448 of the GC gene.
Current treatment of Gaucher Disease includes hydration, analgesics and narcotics for pain during bone crises, in addition to the use of Vi
Podsakoff Gregory
Watson Gordon
Avigen, Inc.
Cooley & Godward LLP
Priebe Scott D.
Robins Roberta L.
Whiteman Brian
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