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Definitions

• the present invention relates generally to the introduction of genetic material into the joints and cells comprising the joint structures for the purpose of somatic gene therapy. Further, it relates to methods for introducing novel genetic material into cells within the joint and achieving expression of gene products with therapeutic potential.
• An additional object of the present invention is the coupling of genetic materials to non-genetic materials termed vehicles which enhance the uptake, stability, and expression of genetic material into cells of the joint.
• Figure A is a schematic of one proposed mechanism for targeting DNA to different cells such as chondrocytes and synovial cells as a complex with a vehicle that is capable of receptor mediated uptake, membrane fusion, or enhanced pinocytosis.
• Stable expression may presently be achieved by the use of viral vectors or the transplantation of cells which are stably transformed with viral or DNA vectors.
• An alternative embodiment of the present invention includes a method of treating arthritis in humans comprising the step of injecting an inflamed joint of a human with a pharmacological dose of a DNA vector in a vehicle, wherein the nucleic acid cassette in the vector encodes a sequence for a steroid receptor.
• This can be the normal receptor or it can be a genetically modified receptor.
• a useful nucleic acid cassette encodes antisense RNA to prostaglandin synthase.
• Another embodiment of the present invention is a transformed synovial cell comprised of nucleic acid incorporated into a synovial cell by gene transfer.
• the nucleic acid can be any of the genetic materials described above.
• Synovial cells are capable of expressing either protein, polypeptide or antisense RNA.
• Another embodiment of the present invention is a method of gene therapy in animals or humans comprising the step of introducing a pharmacological dose of DNA vector in a vehicle into a fluid space of the animal or human.
• the flow and removal of the fluid through a membrane causes the fluid to be filtered and the cells of the membrane then uptake the filtered DNA.
• An example of this is in the kidney and in the central nervous system, including the spinal column and brain.
• tissue, fluid space and extracellular spaces may be used.
• Example 1 Introduction of a Marker Gene into Cells of the Joint
• a vector comprising the cytomegalovirus immediate early promotor, 5' untranslated sequences and an intron from SV40, 3' untranslated sequences from SV40 including the polyadenylation signal and a nucleic acid cassette containing the E. coli beta- galactosidase gene was combined with a vehicle containing 20% sucrose at pH 7.4. This solution was injected into the knee joint of rabbits using a transpatellar injection.
• an identical vector containing the E. coli chloramphenicol acetyltransferase gene in place of the beta-galactosidase gene was injected into joints on the opposite leg using identical methods.
• cytokines such as
• IL-1 and I -6 which stimulate the local inflammatory response.
• the inflammatory reaction may be modified by local secretion of soluble fragments of the receptors for these ligands.
• the complex between the ligand and the soluble receptor prevents the ligand from binding to the receptor which is normally resident on the surface of cells, thus preventing the stimulation of the inflammatory effect.
• Therapy consists of the construction of a vector containing the soluble form of receptors for appropriate cytokines (for example II-1 or IL-6) together with promotors capable of inducing high level expression in structures of the joint and a vehicle which enables efficient uptake of this vector.
• This DNA is injected into affected joints where the secretion of an inhibitor for I -1 such as a soluble IL-1 receptor or natural IL-1 inhibitor modifies the local inflammatory response and resulting arthritis.
• This method is useful in treating episodes of arthritis which characterize many "autoimmune” or “collagen vascular” diseases. This method can also prevent disabling injury of large joints by inflammatory arthritis.
• Steroid response by gene transfer of steroid receptors into cells of the joint
• Current therapy for severe arthritis involves the administration of pharmacological agents including steroids to depress the inflammatory response.
• Steroids can be administered systemically or locally by direct injection into the joint space.
• Steroids normally function by binding to receptors within the cytoplasm of cells. Formation of the steroid-receptor complex changes the structure of the receptor so that it becomes capable of binding to specific sequences within the genome of the cell and altering the expression of specific genes. Genetic modifications of the steroid receptor can be made which enable this receptor to bind naturally occurring steroids with higher affinity, bind pharmacological forms of steroid at higher affinity, or bind to synthetic steroids. Other modifications can be made to create steroid receptor which is "constitutively active" meaning that it is capable of binding to DNA and regulating gene expression in the absence of steroid altogether.
• One approach to treating arthritis is to introduce a vector in which the nucleic acid cassette expresses a genetically modified steroid receptor into cells of the joint.
• steroid receptors which have a higher affinity for natural steroids can be introduced into the joint. These receptors exert an increased anti-inflammatory effect when stimulated by physiological concentrations of steroids or lower doses of pharmacologically administered steroids.
• constitution of a steroid receptor which binds a novel steroid enables the use of drugs which would affect only cells taking up this receptor. These strategies obtain a therapeutic effect from steroids on arthritis without the profound systemic complications associated with these drugs.
• Example 4 Inhibition of prostaglandin synthase Drugs which inhibit the enzyme prostaglandin synthase are important agents in the treatment of arthritis. This is due, in part, to the important role of certain prostaglandin in stimulating the local immune response. Salicylates are widely used drugs but can be administered in limited doses which are often inadequate for severe forms of arthritis.
• Gene transfer is used to inhibit the action of prostaglandin synthase specifically in affected joints by the expression of an antisense RNA for prostaglandin synthase.
• the complex formed between the antisense RNA and mRNA for prostaglandin synthase interferes with the proper processing and translation of this mRNA and lowers the levels of this enzyme in treated cells.
• genes encoding enzymes which alter prostaglandin metabolism can be transferred into the joint. These have an important anti-inflammatory effect by altering the chemical composition or concentration of inflammatory prostaglandin.
• Example 5 Generating an animal model of inflammatory arthritis
• Inflammatory arthritis is thought to result from an autoimmune attack on cells comprising essential structures of the joint.
• tissue transplantation Haistocompatibility antigens
• Animal models of inflammatory arthritis can be generated by gene transfer of vectors capable of expressing heterogenic (not self) or xenogeneic (other species) transplantation antigens within the joint, thus mimicking the effect of dysregulation of tissue transplantation antigens. This induces an autoimmune attack not only on the transplantation antigens themselves, but on other antigens within the joint which are presented to the immune system in an abnormal manner.
• interferon in tissues is thought to induce dysregulation of class I antigens and potentiate a inflammatory reaction.
• This can be modeled in animals by introduction of vectors expressing interferon into cells of the joint.
• Example 6 Gene transfer to enhance repair or regeneration of joints
• the regenerative capacity of the joint is limited by the fact that chondrocytes are nofeecapable of remodelling and repairing cartilaginous tissues suck ⁇ ias tendons and cartilage.
• collagen which is producetkincresponse to injury is of a different type — lacking the tensile-strength of normal collagen.
• the injury collagen is not remodeled effectively by available collagenase.
• Gene transfer using promoters specific to chondrocytes is used to express different collagens or collagenase for the purpose of improving the restoration of function in the joints and prevent scar formation.
• Gene transfer into fibroblasts or muscle cells in the environment of the joint is used to locally secrete growth factors such as IGF-1.
• the growth factors maintain muscle mass and proliferation and enhance the strength of the damaged joint.
• Gene transfer for these purposes is affected by direct introduction of DNA into the joint space where it comes into contact with chondrocytes and synovial cells, further, the genes infiltrate into the environment of the joint where they are taken up by fibroblasts, myoblasts, and other constituents of periarticular tissue.
• Example 7 Treatment of gouty arthritis by gene transfer Gout is caused by the accumulation of uric acid in joints. This remains a common and painful disorder in the aging population despite medical management. Gene transfer into the joints is used to express products (for example enzymes) capable of degrading uric acid to non-toxic products. These products include urease or urate oxidase which are capable of metabolizing uric acid or urate binding globulins which render this compound more soluble and thus prevent crystalline formation within the joint.
• products for example enzymes
• Example 8 Persistent expression using episomal vectors
• transient expression of recombinant genes induces the desired biological response.
• more persistent expression of recombinant genes is desirable. This is achieved by adding elements which enable extrachromosomal (episomal) replication of DNA to the structure of the vector.
• Vectors capable of episomal replication are maintained as extrachromosomal material and can replicate. These sequences will not be eliminated by simple degradation but will continue to be copied.
• Episomal vectors provide prolonged or persistent expression, though not necessarily stable or permanent, expression of recombinant genes in the joint. Persistent as opposed to stable expression is desirable to enable adjustments in the pharmacological dose of the recombinant gene product as the disease evolves over time.
• Example 9 Gene delivery using the gene gun
• the repair and regeneration of tissues comprising the joint following injury or surgery is enhanced by directly delivering recombinant genes to specific sites at the time of surgery. This is done in conjunction with surgical reconstructions or arthroscopy using the "gene gun" (Yang, N.S. et al.; In vivo and in vitro gene transfer to mammalian somatic cells by particle bombardment; Proc. Natl. Acad. Sci. USA 87:9568-72 (1990)) to deliver particles coated with DNA to specific regions of the joint.
• the use of the gene gun and particle bound DNA enables constitution of gene expression at highly specific locations.
• Example 10 Vehicles for gene delivery into cells of the joint
• DNA is taken up by synovial cells during the process of these cells continually resorbing and remodeling the synovial fluid by secretion and pinocytosis.
• Gene delivery is enhanced by packaging DNA into lipophilic particles (for example lipofectin) which binds nonspecifically to hydrophobic membranes resulting in a fusion of the particle with the membrane and release of the DNA into the cytoplasm.
• lipophilic particles for example lipofectin
• complexes of DNA and proteins which bind to receptors on the surface of cells in the joint enhances uptake and expression.
• particulate DNA complexed with CaPO ⁇ or polycations can be efficient substrates for phagocytosis by monocytes or other inflammatory cells.
• Inflammatory cells invading the joint are ablated using vectors which contain the diphtheria toxin gene under the control of a promotor which is expressed only in leukocytes. These vectors are delivered to the joint as particles and are selectively taken up by phagocytotic cells. The uptake and expression of this vector results in expression of diphtheria toxin which is lethal to that specific cell.
• a vector which expressed herpes thymidine kinase gene under the control of a specific promoter could be introduced into cells, and these cells are then ablated by administration of acytovin.

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