Alzheimer's Disease
Ceregene is conducting human clinical trials of CERE-110 (AAV-nerve growth factor) with the goal of preventing further dehumanizing loss of memory and cognition that occurs with Alzheimer’s Disease (AD), while also restoring lost function. Alzheimer’s Disease is a common, insidiously progressive form of dementia that robs its victims of their minds. There are more than five million Americans living with AD, with comparable numbers in Europe and the Pacific Rim. There is no effective means of reducing the rate at which the disease progresses. In the early stages of the disease, the symptoms are primarily limited to loss of memory and other cognitive deficits. This early stage is also characterized by loss of function and death of cholinergic neurons, as well as other pathologies in the brain. The loss of these cholinergic neurons was long-ago linked to the early cognitive deficits in AD. Nerve growth factor (NGF) is known to rejuvenate, restore function and protect these same cholinergic neurons from degeneration. Thus, CERE-110 (AAV-NGF) provides the opportunity to treat the earliest stages of AD, potentially improving the major cognitive symptoms and loss of memory, like no other treatment.
Treatment of Alzheimer’s Disease
A great deal of effort has been expended by researchers all over the world to design drugs to treat the functional deficits that accompany Alzheimer’s Disease (AD) and related disorders. The most successful approach to date has been to improve the biochemistry of the AD brain, by increasing acetylcholine levels with drugs that block its normal breakdown. This is intended to enhance impaired cortical cholinergic function in the AD brain. Acetylcholinesterase inhibitors are the best example of these drugs, but they provide only modest elevation in brain acetylcholine levels and similarly modest symptomatic benefits, for it is impossible to selectively increase cholinergic function in only those neurons. Thus, significant side effects occur when the dose is raised to try and substantially enhance levels in the neurons that are malfunctioning. Moreover, in no case are these drugs able to improve the vitality or viability of the degenerating cholinergic neurons and thus, they have little genuine impact on disease progression or further neurodegeneration. Removal of these drugs results in the rapid re-emergence of significant cognitive impairment. While these treatments by no means normalize patient function, they are currently the best treatment that medicine can provide.
Nerve growth factor (NGF) is a neurotrophic factor known to be a potent survival factor for acetylcholine-containing neurons that degenerate in AD. The ability of NGF to prevent or reduce cholinergic cell loss in animal models of neurodegenerative diseases has led to attempts to deliver NGF to human patients in clinical trials. In these clinical trials (not conducted by Ceregene) NGF was continuously delivered into the brain or the surrounding cerebrospinal fluid of AD patients. However, these methods of delivery did not allow sufficiently high doses of neurotrophic factors to be achieved in the target regions of the brain to efficiently improve neuronal function or modify disease progression. Additionally, they led to troubling side-effects because of the delivery of NGF to non-targeted cells.
Ceregene's Alzheimer’s Disease Treatment Approach
We are actively pursuing a new way to treat AD with NGF that avoids problems inherent in prior approaches. Using our gene delivery technology, the gene for NGF is delivered directly into the acetylcholine-cell rich regions of the brain that degenerate early in the disease and whose degeneration has been linked to the cognitive deficits. The gene that encodes NGF can be delivered with a single procedure and thereafter resides in the cholinergic neurons to produce NGF for the lifetime of these cells in the affected tissue. This approach offers the possibility of improving memory, cognition and attention, while also delaying disease progression by restoring neuronal function and slowing, or even reversing, the degenerative condition of cholinergic neurons.
Based on animal studies, production of NGF or closely related neurotrophic factors in affected regions of the brains of patients with AD should preserve and restore cholinergic neuronal function and thereby improve cognition and slow its further decline. Only the affected neuronal populations are treated and therefore unwanted side effects attributable to treatment of other neuronal populations should be avoided. Because of these invaluable advantages, the gene transfer being employed in our clinical trials for Alzheimer’s disease may provide the best approach for effective disease-modifying treatment. We have completed an initial Phase 1 clinical trial in AD from which we helped establish the safety of delivering CERE-110 to AD patients. We have now initiated a multi-center, controlled Phase 2 clinical trial in collaboration with the Alzheimer's Disease Cooperative Study (ADCS). For more information on participation see www.clinicaltrials.gov.
By using the same gene delivery technology to deliver the genes for other neurotrophic factors known to support other types of neurons, we have created potential treatments for a range of other diseases, including Parkinson’s Disease, amyotrophic lateral sclerosis (ALS), Huntington’s Disease and several ocular diseases that cause blindness.