Gene Therapy

Gene Therapy is a highly targeted therapeutic approach designed to insert modified genes into cells in order to produce a potentially therapeutic protein or reduce production of a potentially toxic target. In a neurodegenerative disease like ALS there are multiple cell types potentially involved in disease including motor neurons, glial cells in the central nervous system, skeletal muscle, and peripheral immune cells. In order to reduce potential toxicity it is often necessary to target the gene therapy construct to specific tissues or even specific cell types within a given tissue. A variety of tools are used to deliver genes including retroviruses, adenoviruses, adeno-associate viruses along with non-viral methods that delivery DNA and RNA in special solutions to help them enter the cell.

The current state of the art for gene therapy studies in ALS is hampered by the ability to effectively insert functional genes into cells in the central nervous system and maintain and maximize long-term function of the gene after injection. This is often a problem because the immune system can mount a response to the virus or the product of the inserted gene. For example, the injection of adenoviral based gene therapies in animals or humans typically results in a rapid immune response within 24 hours after viral injection. The clearance of viral particles results in rapidly lost production, or expression, by the therapeutic gene seven to fourteen days after viral injection. In addition another type of virus used for gene therapies, adeno-associated viruses (AAV), do not efficiently enter the central nervous system when delivered intravenously or intramuscularly.

ALS TDI has several gene therapy based collaborations to improve the expression of adenoviral vectors, and assess the expression levels and tissue specificity of specially engineered AAV's and rabies pseudotyped lenti viruses (EIAV) after intravenous or intramuscular injection ALS TDI has developed a novel strategy to maintain the expression of the adenoviral based vectors for as long as 200 days after injection with extensive expression in the central nervous system from intramuscular injection (Figure 1). A significant hurdle with adenoviral based gene therapy vectors is that these viruses elicit a significant immune response after injection. The immune response may make it difficult to observe a therapeutic benefit in preclinical disease models, especially in models where the activation of the immune system is already a component of disease pathology. As can be seen in Figure 2 there is a dose dependent activation of the immune system after intramuscular injection of adenoviral vectors in the SOD1G93A model.