Methods for therapy of neurodegenerative disease of the brain

Details Methods for therapy of neurodegenerative disease of the brain Methods for therapy of neurodegenerative disease of the brain

1998-04-15

2002-09-17

Priebe, Scott D. (Department: 1632)

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

Genetically modified micro-organism, cell, or virus

C424S093200, C514S04400A, C435S320100, C435S455000

Reexamination Certificate

active

06451306

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to methods for treatment of neurodegenerative disease and methods for delivery of neurotrophic factors into the mammalian brain.
HISTORY OF THE RELATED ART
Neurotrophic factors play a physiological role in the development and regulation of neurons in mammals. In adults, basal forebrain cholinergic neurons, motor neurons and sensory neurons of the CNS retain responsiveness to neurotrophic factors and can regenerate after loss or damage in their presence. For this reason, neurotrophins are considered to have great promise as drugs for the treatment of neurodegenerative conditions such as Alzheimer's Disease (AD), Parkinson's Disease (PD), amyotrophic lateral sclerosis (ALS), peripheral sensory neuropathies and spinal cord injuries.
Clinical trials for the use of neurotrophins in the treatment of AD, ALS and sensory neuropathies are underway. However, the search for a protocol for delivery of neurotrophins to target tissues with minimal side effects (e. g., from diffusion to non-targeted cells or immune reaction to the delivery vehicle) and sufficient penetration of the CNS (e. g., bypassing the blood-brain barrier and achieving chronic delivery of neurotrophin to target cells) has not yet revealed a clear path for clinical administration of neurotrophins. In particular, effective delivery methods and dosing parameters have not yet been identified, although several methods have been proposed. Therefore, although the prospects for therapy of neurodegenerative disease of the brain and CNS are believed to be bright, a successful clinical protocol remains elusive.
SUMMARY OF THE INVENTION
The invention provides a protocol for delivery of recombinant nerve growth factors into the mammalian brain. The invention is particularly useful in treating neurodegenerative conditions in large primates, in whom nerve growth factors delivered according to the invention stimulate growth of neurons and recovery of function.
More specifically, the invention consists of methods for intraparencymal delivery of recombinant nerve growth factors to defective, diseased or damaged cells in the mammalian brain. In one aspect, the invention provides a specific protocol for use in grafting donor cells genetically modified to produce nerve growth factors into grafting sites within the cholinergic basal forebrain. Grafting sites are selected for proximity to previously identified defective, diseased or damaged brain cells. To intensify exposure of such cells to the delivered growth factors, each graft is situated no more than about 550 &mgr;m from a targeted cell and no more than about 5 mm from another graft. Depending on the size of the region to be treated, the number of grafting sites will vary upwards of 10 sites, with between 5 and 10 sites serving to deliver a therapeutically significant dosage of nerve growth factors to targeted cells.
For most clinical applications, donor cells will be delivered as part of a pharmaceutically acceptable composition. Each composition contains a concentration of donor cells of at least 1×10
5
cells/&mgr;l. Each graft is comprised of between 2 and 20 &mgr;l of a donor cell composition. The composition is delivered to each grafting site in the target tissue through a surgical incision over a period of about 5-10 minutes (depending on the total volume of cell suspension to be delivered). The rate of delivery of the cells may therefore vary from about 0.2 &mgr;l cell suspension/minute to about 4 &mgr;l cell suspension/minute.
Particularly useful nerve growth factors for use in the invention are the neurotrophins. Of the neurotrophins, particularly useful compounds are &bgr;-NGF (beta nerve growth factor) and NT3 (neurotrophin 3). The brain is an immune-protected environment; however, use of species-matched nerve growth factor encoding transgenes will reduce the risk of an unforseen adverse immune reaction to the transgene product.
This targeted, regionally specific protocol for neurotrophin delivery avoids limitations imposed by diffusion of substances across the blood-brain barrier and through central nervous system (CNS) parenchyma, while avoiding adverse effects of neurotrophic factors delivered intact in a non-directed manner to the CNS.
DETAILED DESCRIPTION OF THE INVENTION
I. Target Tissue and Dosing Parameters for Use in Practicing the Invention
The invention identifies two parameters required for successful regeneration of neurons in the brain with neurotrophic factors; especially, the neurons whose loss is associated with neurodegenerative conditions with impairment of cognition such as Alzheimer's Diesease (AD).
The first parameter defined by the invention is the target tissue. A region of the brain is selected for its retained responsiveness to neurotrophins. In humans, CNS neurons which retain responsiveness to neurotrophins into adulthood include the cholinergic basal forebrain neurons, the entorhinal corical neurons, the thalamic neurons, the locus ceruleus neurons, the spinal sensory neurons and the spinal motor neurons. For treatment of neurodegenerative conditions with impairment of cognition such as AD, the preferred target tissue is the Ch4 region of the basal forebrain.
Magnocellular neurons Ch1-Ch4 of the primate basal forebrain provide cholinergic innervation to the cerebral cortex, thalamus and basolateral nucleus of amygdala. In subjects with neurodegenerative diseases such as AD, neurons in the Ch4 region (nucleus basalis of Meynert) which have nerve growth factor (NGF) receptors undergo marked atrophy as compared to normal controls (see, e. g., Kobayashi, et al.,
Mol. Chem. Neuropathol.,
15:193-206 (1991); Higgins and Mufson,
Exp. Neurol.,
106:222-236 (1989); Mufson, et aL,
Exp. Neurol,
105:221-232 (1989) and, Mufson and Kordower,
Prog. Clin. Biol. Res.,
317:401-414 (1989)). In normal subjects, NGF prevents sympathetic and sensory neuronal death during development and prevents cholinergic neuronal degeneration in adult rats and primates (Tuszynski, et al.,
Gene Therapy,
3:305-314 (1996)). The resulting loss of functioning neurons in this region of the basal forebrain is believed to be causatively linked to the cognitive decline experienced by subjects suffering from neurodegenerative conditions such as AD (Tuszynski, et al., supra and, Lehericy, et al.,
J Comp. Neurol.,
330:15-31 (1993)).
For therapy of neurodegenerative disease in humans, an appropriate region of the basal forebrain is treated with a neurotrophic factor. Within the targeted region, a neurotrophic factor is preferably delivered into 5 to 10 separate sites, depending on the condition treated. For example, in human AD, basal forebrain neuronal loss occurs over an intraparenchymal area of approximately 1 cm in diameter. To treat affected neurons over such a large region, affixation of grafts at upwards of 10 separate sites is desirable. However, in treating localized injuries to the basal forebrain, the affected areas of the brain will likely be smaller such that selection of fewer grafting sites (e. g., 5 or fewer) will be sufficient for restoration of a clinically significant number of cholinergic neurons.
Importantly, specific grafting sites are selected so as to cluster in an area of neuronal loss. Such areas may be identified clinically using a number of known techniques, including magnetic resonance imaging (MRI) and biopsy. In humans, non-invasive, in vivo imaging methods such as MRI will be preferred. Once areas of neuronal loss are identified, grafting sites are selected for stereotaxic distribution so each graft is placed at a distance of no more than about 550 &mgr;m from an injured neuron and at a distance of 5 mm or less from another graft.
The second parameter defined by the invention is the dosage of neurotrophic factor to be delivered into the target tissue. In this regard, “dosage” refers to both concentration of neurotrophic factor encoding cells/graft and rate of delivery of the cells into the target tissue. total number of grafts made. As described in greater detail elsewhere below, grafts

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