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#2 - A novel therapy for neurodegenerative diseases for example Alzheimer’s disease
Long Title: Treatment of neurodegenerative diseases with cyclin dependent kinase 5 (Cdk5) inhibitory peptide TFP5
NIH Reference No.: E-144-2010
Executive Summary
General Description
An estimated 5.2 million Americans have Alzheimer’s disease (AD) in 2014. This includes approximately 11% of Americans over the age of 65. Currently, there is no treatment available today that slows or stops the decay of neurons in the brain that cause AD symptoms1. In addition, there are an estimated 0.5-1.5 million Americans living with Parkinson’s disease (PD) and currently no treatment exists that slows the progression of PD. PD is currently the 14th leading cause of death in the United States2. Finally, it is estimated that 20,000-30,000 Americans are living with Amyotrophic Lateral Sclerosis (ALS), and currently there is no known treatment for the disease and the average patient lives 3-5 years after symptoms develop3. Cyclin dependent kinase 5 (Cdk 5) has been implicated in all three diseases.
This invention discloses methods for treating neurodegenerative diseases by administering cyclin dependent kinase 5 (Cdk5) inhibitory peptides. Abnormally hyperactive Cdk5 has been shown to be associated with a variety of neurodegenerative disorders. Disclosed in this invention are isolated peptide fragments, pharmaceutical compositions and methods for use of such for treating subjects with a neurodegenerative disease, such as AD, PD, and ALS.
Scientific Progress
The invention describes use of novel cyclin dependent kinase 5 (Cdk5) inhibitory peptides to treat a range of neurodegenerative diseases including AD, PD, and ALS without any apparent phototoxicity. An inhibitory fragment, TFP5, disclosed in this invention, has been shown to ameliorate symptoms of AD in disease animal models without any evidence of toxicity. TPF5 is derived from a natural product, P5, but has been modified to cross the BBB. In particular, TFP5 treatment of rat cortical neurons reduced hyperactivation of Cdk5 upon neuronal stress and insults. Following intraperitoneal (ip) injection, TFP5 was capable of crossing the BBB and localizing within the brain where it was found to rescue memory deficits and pathology in a double transgenic mouse (APP/PS1) AD model.
Future Direction
Strengths
Weaknesses
Patent Status
US Patent Grant No. US 8597660 B2
Relevant Publications
B, K.B., et al., J Alzheimers Dis. 2014;39(4):899-909. [PMID: 24326517]
Shukla, V., et al., FASEB J. 2013 Jan;27(1):174-86. [PMID:23038754]
Inventor Bio
Harish Pant, PhD.
Dr. Pant received his M.A. and Ph.D. degrees in Physics from Agra University, Agra, India. His postdoctoral studies were conducted on the mechanisms of electron and ion transport in model membrane systems at the Department of Biophysics at Michigan State University. He joined the Laboratory of Neurobiology in the NIMH as a senior staff fellow in 1974 with Dr. Ichiji Tasaki where he studied the function of the axonal cytoskeleton in the squid giant axon. In 1979 he moved to the NIAAA extending his studies on the neuronal cytoskeleton and the effects of alcohol on its regulation. Dr. Pant moved to the NINDS, Laboratory of Neurochemistry in 1987 where he is presently chief of the section on Cytoskeleton Regulation. His laboratory is studying the mechanisms of topographic regulation of neuronal cytoskeleton proteins by post-translational modification, including the role of kinase cascades in normal brain and during neurodegeneration.
References
1. http://www.alz.org/downloads/facts_figures_2014.pdf
2. http://www.parkinsonsaction.org/news/cdc-lists-parkinsons-14th-leading-cause-death-america
3. http://wwwn.cdc.gov/als/whatisals.aspx
NIH Reference No.: E-144-2010
Executive Summary
- Invention Type: Therapeutic
- Patent Status: US Patent Grant No. US 8597660 B2
- LINK: http://www.ott.nih.gov/technology/E-144-20100
- NIH Reference Number: E-144-2010
- NIH Institute or Center: National Institute of Neurological Disorders and Stroke (NINDS)
- Disease Focus: Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS)
- Basis of Invention: Small inhibitory peptides
- How it works: The small inhibitory peptide fragment, TFP5, passes through the Blood brain barrier and reduces activation of cyclin dependent kinase 5 (Cdk5) rescuing memory deficits and pathology
- Lead Inventors: Harish Pant (NINDS)
- Development Stage: In vitro (rat cortical neurons) and in vivo (double transgenic APP/PS1 AD model) demonstrating that TFP5 can ameliorate symptoms of AD without any evidence of toxicity
- Novelty: Highly specific inhibitory peptide-based therapy that passes the blood-brain barrier (BBB) and shows no signs of toxicity
- Clinical Application: Treatment of neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS)
General Description
An estimated 5.2 million Americans have Alzheimer’s disease (AD) in 2014. This includes approximately 11% of Americans over the age of 65. Currently, there is no treatment available today that slows or stops the decay of neurons in the brain that cause AD symptoms1. In addition, there are an estimated 0.5-1.5 million Americans living with Parkinson’s disease (PD) and currently no treatment exists that slows the progression of PD. PD is currently the 14th leading cause of death in the United States2. Finally, it is estimated that 20,000-30,000 Americans are living with Amyotrophic Lateral Sclerosis (ALS), and currently there is no known treatment for the disease and the average patient lives 3-5 years after symptoms develop3. Cyclin dependent kinase 5 (Cdk 5) has been implicated in all three diseases.
This invention discloses methods for treating neurodegenerative diseases by administering cyclin dependent kinase 5 (Cdk5) inhibitory peptides. Abnormally hyperactive Cdk5 has been shown to be associated with a variety of neurodegenerative disorders. Disclosed in this invention are isolated peptide fragments, pharmaceutical compositions and methods for use of such for treating subjects with a neurodegenerative disease, such as AD, PD, and ALS.
Scientific Progress
The invention describes use of novel cyclin dependent kinase 5 (Cdk5) inhibitory peptides to treat a range of neurodegenerative diseases including AD, PD, and ALS without any apparent phototoxicity. An inhibitory fragment, TFP5, disclosed in this invention, has been shown to ameliorate symptoms of AD in disease animal models without any evidence of toxicity. TPF5 is derived from a natural product, P5, but has been modified to cross the BBB. In particular, TFP5 treatment of rat cortical neurons reduced hyperactivation of Cdk5 upon neuronal stress and insults. Following intraperitoneal (ip) injection, TFP5 was capable of crossing the BBB and localizing within the brain where it was found to rescue memory deficits and pathology in a double transgenic mouse (APP/PS1) AD model.
Future Direction
- This invention provides a useful platform for developing additional peptides for treatment of neurodegenerative diseases; an important step is to prioritize other potential applications
- Future work needs to confirm results in animal models of ALS and PD
Strengths
- Derived from Natural Product
- Highly specific inhibitory peptide capable of passing BBB
- Shows no signs of toxicity in AD animal models
- May be used as basis to develop additional inhibitory peptides
- Potential to treat multiple neurodegenerative diseases including: Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS)
Weaknesses
- Need to confirm in vitro results in animal models of ALS and PD
Patent Status
US Patent Grant No. US 8597660 B2
Relevant Publications
B, K.B., et al., J Alzheimers Dis. 2014;39(4):899-909. [PMID: 24326517]
Shukla, V., et al., FASEB J. 2013 Jan;27(1):174-86. [PMID:23038754]
Inventor Bio
Harish Pant, PhD.
Dr. Pant received his M.A. and Ph.D. degrees in Physics from Agra University, Agra, India. His postdoctoral studies were conducted on the mechanisms of electron and ion transport in model membrane systems at the Department of Biophysics at Michigan State University. He joined the Laboratory of Neurobiology in the NIMH as a senior staff fellow in 1974 with Dr. Ichiji Tasaki where he studied the function of the axonal cytoskeleton in the squid giant axon. In 1979 he moved to the NIAAA extending his studies on the neuronal cytoskeleton and the effects of alcohol on its regulation. Dr. Pant moved to the NINDS, Laboratory of Neurochemistry in 1987 where he is presently chief of the section on Cytoskeleton Regulation. His laboratory is studying the mechanisms of topographic regulation of neuronal cytoskeleton proteins by post-translational modification, including the role of kinase cascades in normal brain and during neurodegeneration.
References
1. http://www.alz.org/downloads/facts_figures_2014.pdf
2. http://www.parkinsonsaction.org/news/cdc-lists-parkinsons-14th-leading-cause-death-america
3. http://wwwn.cdc.gov/als/whatisals.aspx