Nerve growth factor gene therapy delivered safely in Alzheimer’s patients

SAN DIEGO – Delivery of a gene therapy viral vector designed to express only the gene for human growth factor to the nucleus basalis of Meynert in patients with mild to moderate Alzheimer’s disease appears to be safe and feasible, results from a first-in-human trial demonstrated.

"There are significant deficiencies with the therapies that exist for treating the memory and cognitive impairments of Alzheimer’s disease," Raymond T. Bartus, Ph.D., said at the Clinical Trials Conference on Alzheimer’s Disease.

Currently available cholinesterase inhibitors "are nonselective and suffer from serious dose-limiting side effects," said Dr. Bartus, president of San Diego–based RTBioconsultants. "Their mechanism of action for cholinergic enhancement is suboptimal, and they do not repair neurons, protect against death, or truly restore lost neuronal function. While they work to some extent, they are modest in their level of efficacy and do not improve symptoms in all patients. Moreover, they do nothing to affect the disease progression."

Nerve growth factor neurotrophic therapy, he continued, "should overcome all of these deficiencies and therefore provide a more effective therapy, applying a variation of the cholinergic approach that has shown proof of concept." Decades of research in animal models suggest that nerve growth factor "has remarkable antiapoptotic (i.e., antideath) and reparative properties for certain neurons in the degenerative brain," Dr. Bartus said. "There are at least two major obstacles to apply this technology to Alzheimer’s disease. The first is, Alzheimer’s is an extremely complicated disease, so determining where to target the treatment is especially important. Targeting the cholinergic neurons is compelling because their degeneration is known to contribute significantly to the memory loss."

The second key challenge, he said, is the need for constant exposure to cholinergic neurons that comprise the nucleus basalis of Meynert (NBM) while avoiding exposure to untargeted neuronal populations. This has proven very difficult in past efforts extending back 20 years. In the past decade, gene therapy combined with stereotactic surgery has emerged as a practical enabling technology to accomplish this. On this basis, Dr. Bartus and his associates at Ceregene (where he served as chief scientific officer for more than 10 years) developed a viral gene therapy vector bioengineered to express only the gene for human nerve growth factor (AAV2-NGF, or CERE-110).

"You can think of it as an off-the-shelf biopharmaceutical that when injected into the human brain will induce the target neurons to produce or express and secrete only nerve growth factor and therefore provide support to NBM cholinergic neurons," he explained. "Preclinical studies have demonstrated an orderly dose-response relationship with NGF restricted to targeted basal forebrain cholinergic neurons, and no side effects or toxicity, even after testing very high doses in animals. That was quite surprising and certainly welcome."

Dr. Bartus presented phase I clinical data from 10 patients aged 50-79 years with mild to moderate Alzheimer’s disease who received one of three ascending doses of AAV2-NGF via bilateral stereotactic injection into the nucleus basalis of Meynert: dose A (1.2 x 10¹⁰ viral genomes), dose B (5.8 x 10¹⁰ viral genomes; five times more than dose A), and dose C (1.2 x 10¹¹ viral genomes; two times more than dose B). Patients were followed at 24 months for safety and feasibility and preliminary efficacy as measured by 18-fluorodeoxyglucose PET scans at baseline, 6, 12, and 24 months; autopsy tissue; and validated neuropsychological tests that included the Alzheimer’s Disease Assessment Scale–Cognitive (ADAS-Cog). Computer graphic software was used to provide a 3-D model of the nucleus basalis of Meynert in an effort to "determine where to distribute CERE-110 in the NBM and how much should be given to achieve optimal NGF exposure."

Dr. Bartus reported that AAV2-NGF was safe and well tolerated through 24 months. Adverse events and serious adverse events "were uneventful," he said. "What you see is a profile that reflects either incidental or unrelated events, or those related to a surgical procedure (e.g., temporary headache)."

PET imaging showed no evidence of accelerated decline, and brain autopsy tissue from three patients who died of unrelated causes confirmed long-term, therapeutically active, gene-mediated NGF expression accurately targeted to the nucleus basalis of Meynert.

The researchers observed some deterioration over time based on the ADAS-Cog and other neuropsychological measures. "There is no clinical evidence that cognitive decline is accelerated, but we can’t speak to whether or not we actually improved rate of decline," Dr. Bartus said.

These findings formed the basis of a phase II trial currently underway that is funded by the National Institutes of Health under the auspices of the Alzheimer’s Disease Collaborative Study. Outcomes from that 24-month trial are expected in 2015.

The phase 1 study was funded by Ceregene, which was acquired in October 2013 by Sangamo BioSciences.

Dr. Bartus disclosed that he is a consultant for Sangamo BioSciences.

[email protected]

SAN DIEGO – Delivery of a gene therapy viral vector designed to express only the gene for human growth factor to the nucleus basalis of Meynert in patients with mild to moderate Alzheimer’s disease appears to be safe and feasible, results from a first-in-human trial demonstrated.

"There are significant deficiencies with the therapies that exist for treating the memory and cognitive impairments of Alzheimer’s disease," Raymond T. Bartus, Ph.D., said at the Clinical Trials Conference on Alzheimer’s Disease.

Currently available cholinesterase inhibitors "are nonselective and suffer from serious dose-limiting side effects," said Dr. Bartus, president of San Diego–based RTBioconsultants. "Their mechanism of action for cholinergic enhancement is suboptimal, and they do not repair neurons, protect against death, or truly restore lost neuronal function. While they work to some extent, they are modest in their level of efficacy and do not improve symptoms in all patients. Moreover, they do nothing to affect the disease progression."

Nerve growth factor neurotrophic therapy, he continued, "should overcome all of these deficiencies and therefore provide a more effective therapy, applying a variation of the cholinergic approach that has shown proof of concept." Decades of research in animal models suggest that nerve growth factor "has remarkable antiapoptotic (i.e., antideath) and reparative properties for certain neurons in the degenerative brain," Dr. Bartus said. "There are at least two major obstacles to apply this technology to Alzheimer’s disease. The first is, Alzheimer’s is an extremely complicated disease, so determining where to target the treatment is especially important. Targeting the cholinergic neurons is compelling because their degeneration is known to contribute significantly to the memory loss."

The second key challenge, he said, is the need for constant exposure to cholinergic neurons that comprise the nucleus basalis of Meynert (NBM) while avoiding exposure to untargeted neuronal populations. This has proven very difficult in past efforts extending back 20 years. In the past decade, gene therapy combined with stereotactic surgery has emerged as a practical enabling technology to accomplish this. On this basis, Dr. Bartus and his associates at Ceregene (where he served as chief scientific officer for more than 10 years) developed a viral gene therapy vector bioengineered to express only the gene for human nerve growth factor (AAV2-NGF, or CERE-110).

"You can think of it as an off-the-shelf biopharmaceutical that when injected into the human brain will induce the target neurons to produce or express and secrete only nerve growth factor and therefore provide support to NBM cholinergic neurons," he explained. "Preclinical studies have demonstrated an orderly dose-response relationship with NGF restricted to targeted basal forebrain cholinergic neurons, and no side effects or toxicity, even after testing very high doses in animals. That was quite surprising and certainly welcome."

Dr. Bartus presented phase I clinical data from 10 patients aged 50-79 years with mild to moderate Alzheimer’s disease who received one of three ascending doses of AAV2-NGF via bilateral stereotactic injection into the nucleus basalis of Meynert: dose A (1.2 x 10¹⁰ viral genomes), dose B (5.8 x 10¹⁰ viral genomes; five times more than dose A), and dose C (1.2 x 10¹¹ viral genomes; two times more than dose B). Patients were followed at 24 months for safety and feasibility and preliminary efficacy as measured by 18-fluorodeoxyglucose PET scans at baseline, 6, 12, and 24 months; autopsy tissue; and validated neuropsychological tests that included the Alzheimer’s Disease Assessment Scale–Cognitive (ADAS-Cog). Computer graphic software was used to provide a 3-D model of the nucleus basalis of Meynert in an effort to "determine where to distribute CERE-110 in the NBM and how much should be given to achieve optimal NGF exposure."

Dr. Bartus reported that AAV2-NGF was safe and well tolerated through 24 months. Adverse events and serious adverse events "were uneventful," he said. "What you see is a profile that reflects either incidental or unrelated events, or those related to a surgical procedure (e.g., temporary headache)."

PET imaging showed no evidence of accelerated decline, and brain autopsy tissue from three patients who died of unrelated causes confirmed long-term, therapeutically active, gene-mediated NGF expression accurately targeted to the nucleus basalis of Meynert.

The researchers observed some deterioration over time based on the ADAS-Cog and other neuropsychological measures. "There is no clinical evidence that cognitive decline is accelerated, but we can’t speak to whether or not we actually improved rate of decline," Dr. Bartus said.

These findings formed the basis of a phase II trial currently underway that is funded by the National Institutes of Health under the auspices of the Alzheimer’s Disease Collaborative Study. Outcomes from that 24-month trial are expected in 2015.

The phase 1 study was funded by Ceregene, which was acquired in October 2013 by Sangamo BioSciences.

Dr. Bartus disclosed that he is a consultant for Sangamo BioSciences.

[email protected]

SAN DIEGO – Delivery of a gene therapy viral vector designed to express only the gene for human growth factor to the nucleus basalis of Meynert in patients with mild to moderate Alzheimer’s disease appears to be safe and feasible, results from a first-in-human trial demonstrated.

"There are significant deficiencies with the therapies that exist for treating the memory and cognitive impairments of Alzheimer’s disease," Raymond T. Bartus, Ph.D., said at the Clinical Trials Conference on Alzheimer’s Disease.

Currently available cholinesterase inhibitors "are nonselective and suffer from serious dose-limiting side effects," said Dr. Bartus, president of San Diego–based RTBioconsultants. "Their mechanism of action for cholinergic enhancement is suboptimal, and they do not repair neurons, protect against death, or truly restore lost neuronal function. While they work to some extent, they are modest in their level of efficacy and do not improve symptoms in all patients. Moreover, they do nothing to affect the disease progression."

Nerve growth factor neurotrophic therapy, he continued, "should overcome all of these deficiencies and therefore provide a more effective therapy, applying a variation of the cholinergic approach that has shown proof of concept." Decades of research in animal models suggest that nerve growth factor "has remarkable antiapoptotic (i.e., antideath) and reparative properties for certain neurons in the degenerative brain," Dr. Bartus said. "There are at least two major obstacles to apply this technology to Alzheimer’s disease. The first is, Alzheimer’s is an extremely complicated disease, so determining where to target the treatment is especially important. Targeting the cholinergic neurons is compelling because their degeneration is known to contribute significantly to the memory loss."

The second key challenge, he said, is the need for constant exposure to cholinergic neurons that comprise the nucleus basalis of Meynert (NBM) while avoiding exposure to untargeted neuronal populations. This has proven very difficult in past efforts extending back 20 years. In the past decade, gene therapy combined with stereotactic surgery has emerged as a practical enabling technology to accomplish this. On this basis, Dr. Bartus and his associates at Ceregene (where he served as chief scientific officer for more than 10 years) developed a viral gene therapy vector bioengineered to express only the gene for human nerve growth factor (AAV2-NGF, or CERE-110).

"You can think of it as an off-the-shelf biopharmaceutical that when injected into the human brain will induce the target neurons to produce or express and secrete only nerve growth factor and therefore provide support to NBM cholinergic neurons," he explained. "Preclinical studies have demonstrated an orderly dose-response relationship with NGF restricted to targeted basal forebrain cholinergic neurons, and no side effects or toxicity, even after testing very high doses in animals. That was quite surprising and certainly welcome."

Dr. Bartus presented phase I clinical data from 10 patients aged 50-79 years with mild to moderate Alzheimer’s disease who received one of three ascending doses of AAV2-NGF via bilateral stereotactic injection into the nucleus basalis of Meynert: dose A (1.2 x 10¹⁰ viral genomes), dose B (5.8 x 10¹⁰ viral genomes; five times more than dose A), and dose C (1.2 x 10¹¹ viral genomes; two times more than dose B). Patients were followed at 24 months for safety and feasibility and preliminary efficacy as measured by 18-fluorodeoxyglucose PET scans at baseline, 6, 12, and 24 months; autopsy tissue; and validated neuropsychological tests that included the Alzheimer’s Disease Assessment Scale–Cognitive (ADAS-Cog). Computer graphic software was used to provide a 3-D model of the nucleus basalis of Meynert in an effort to "determine where to distribute CERE-110 in the NBM and how much should be given to achieve optimal NGF exposure."

Dr. Bartus reported that AAV2-NGF was safe and well tolerated through 24 months. Adverse events and serious adverse events "were uneventful," he said. "What you see is a profile that reflects either incidental or unrelated events, or those related to a surgical procedure (e.g., temporary headache)."

PET imaging showed no evidence of accelerated decline, and brain autopsy tissue from three patients who died of unrelated causes confirmed long-term, therapeutically active, gene-mediated NGF expression accurately targeted to the nucleus basalis of Meynert.

The researchers observed some deterioration over time based on the ADAS-Cog and other neuropsychological measures. "There is no clinical evidence that cognitive decline is accelerated, but we can’t speak to whether or not we actually improved rate of decline," Dr. Bartus said.

These findings formed the basis of a phase II trial currently underway that is funded by the National Institutes of Health under the auspices of the Alzheimer’s Disease Collaborative Study. Outcomes from that 24-month trial are expected in 2015.

The phase 1 study was funded by Ceregene, which was acquired in October 2013 by Sangamo BioSciences.

Dr. Bartus disclosed that he is a consultant for Sangamo BioSciences.

[email protected]