Gene therapy by delivery of transgenes encoding therapeutic neurotrophic factors into the brain offers great promise for treating neurodegenerative conditions such as Alzheimer's Disease, Parkinson's Disease and Huntington's Disease. The protocols by which these therapies are provided are highly exacting, requiring that the therapeutic composition dosage (e.g., viral titer) be consistently provided at precise locations in the brain, to ensure that a predictable amount of neurotrophic factor be delivered only to targeted cells.
For example, U.S. Pat. No. 6,451,306 provides a method for treating Alzheimer's Disease which requires donor cells containing a neurotrophic factor-encoding transgene to be grafted at pre-determined sites in the forebrain located no more than 5 mm apart and no more than 500 μm from a targeted cell. The dosage of donor cells provided at each site preferably falls within a range of 2 to 20 μl per ml of composition. Similarly, U.S. Pat. Nos. 6,683,058 and 6,851,431 provide methods to treat defects, disease or damaged cholinergic and dopaminergic neuron populations, respectively, by delivering transgenes at sites within 500 μm of a targeted neuron and no more than 10 mm apart. Such parameters leave the practicing neurosurgeon relatively little room for error in dosing or placement of each graft or transgene injection.
Yet the conventional drug delivery devices available for use in gene therapy of the brain do not necessarily provide the consistent precision the therapeutic protocols require. For example, it has been reported that polynucleotides can become inactivated when introduced through a conventional needle cannula; e.g., made of a metal such as stainless steel (see, e.g., U.S. Pat. No. 7,060,056). The '056 patent inventors opined that the metal interacted with polynucleotides in a way that compromised their pharmaceutical activity by inactivation, rather than binding (see, e.g., '056 patent, Example 10). However, the inventors have discovered that many commonly used viral recombinant expression vectors are not inactivated by contact with metals and the like, most likely due to their proteinaceous coating (e.g., the capsid proteins of a virus). Instead, such material retains its activity, but is lost during delivery to binding within the lumen of conventional metal needles. The extent of loss varies from passage to passage, which limits the clinician's ability to accurately predict how much viral vector will actually be delivered out of any given injection or infusion.
The margin for dosing error in gene therapy of the brain can be increased if the instruments utilized to deliver a neurotrophic factor-encoding transgene (e.g., as part of a viral vector) cannot be consistently and accurately targeted to cell populations that may be only microns apart. If a target cell is missed, the extent to which expressed neurotrophic factor secreted by another cell will diffuse to a targeted cell is limited. Therefore, improvements in therapeutic efficacy can be obtained by enhancing the accurate placement of transgene-containing donor cell grafts or viral vectors into the brain.