William H. Frey

Research Interests:

BYPASSING THE BLOOD-BRAIN BARRIER WITH INTRANASAL DELIVERY TO TREAT ALZHEIMER’S DISEASE, STROKE AND OTHER CNS DISORDERS

For decades the blood-brain barrier has prevented the use of many therapeutic agents for treating central nervous system (CNS) disorders. I have developed a noninvasive, intranasal method of bypassing the blood-brain barrier to deliver therapeutic agents to the brain and spinal cord. This method allows drugs that do not cross the blood-brain barrier to be delivered to the CNS. It also directly targets drugs that do cross the blood-brain barrier to the CNS, eliminating the need for systemic delivery and thereby reducing unwanted systemic side effects. Delivery from the nose to the CNS occurs within minutes along both the olfactory and trigeminal neural pathways. Delivery occurs by an extracellular route and does not require that the drugs bind to any receptor or undergo axonal transport. 

Intranasal delivery to the CNS has been reviewed in Drug Delivery Technology 5(4):64-72, 2005.  Insulin-like growth factor-I (IGF-I) has been delivered to the brain and spinal cord by this route [Thorne, Neuroscience 127:481-496, 2004.]  Intranasal IGF-I given up to four hours after stroke markedly reduces infarct volume and improves neurological function [Liu, Journal of Stroke and Cerebrovascular Diseases 13(1):16-23, 2004.]  Intranasal erythropoietin also protects against focal cerebral ischemia [Yu, Neuroscience Letters 387:5, 2005.]   Intranasal NGF has been shown to successfully treat Alzheimer's disease in a transgenic mouse model [Capsoni, PNAS 99(19):12432-12437, 2002 and De Rosa, PNAS 102(10):3811-3816, 2005.]  Intranasal neurotrophins have also been shown to stimulate neurogenesis in adult animals [Jin, Ann. Neurol. 53:405-409, 2003].  Finally, Gozes has used intranasal delivery to target NAP and ADNF to the brain to treat anxiety and neurodegeneration.  [Alcalay, Neuroscience Letters 361:128-131, 2004; Gozes, JPET 293(3):1091-1098, 2000.]  

The peptide hypocretin-1 is intranasally targeted to the brain and spinal cord [Hanson, Drug Delivery Technology 4(4):66-71, 2004].  Banks has demonstrated that intranasal exendin is delivered directly to the brain and improves memory, cognition and neuronal survival [Banks, JPET 309:469-475, 2004 and During, Nature Med. 9:1173-1179, 2003].  Proteins such as interferon beta-1b have been intranasally delivered to the CNS [Ross et al., J. Neuroimmunol. 161:66-77, 2004].     

Shingaki [Drug Delivery System 14(5):365-371, 1999] has shown that intranasal methotrexate reduces brain tumor size in animals, suggesting effective chemotherapy with reduced side effects.  [Also see F. Wang, Drug Delivery Technology 4(1):48-55, 2004.]  Hashizume [AANS 2006] reported intranasal GRN163, a polynucleotide inhibitor of telomerase, doubles life span in rats with glioma.  Intranasal drug targeting to the brain of the chemotherapeutic raltitrexed is about 100-fold greater than with i.v. administration [Wang, Cancer Chemother. Pharmacol., 2005].  In humans, initial trials of intranasal perillyl alcohol have shown reduction in size of malignant brain tumors (glioblastoma) [C.O. da Fonseca, et al., Surg. Neurol. 65:S1:2-S1:9, 2006].  In another study using a low molecular weight therapeutic agent, S.S. Panter reported dramatic preconditioning and protection of the brain against stroke with intranasal deferoxamine at the 2005 Society for Neuroscience Annual Meeting.  Intranasal delivery can also target gene therapy to the CNS [R. Draghia, Gene Therapy 2:418-423, 1995; F. Lemiale, et al., J. Virol. 77:10078, 2003; A. Jerusalmi, et al., Mol. Therapy 8(6):886, 2003; J. Laing, et al., Mol. Therapy 13(5):870-881, 2006; and I-K. Han, et al., J. Mol. Med., 2006 (available online)].

Intranasal delivery of neuropeptides to the CSF in humans has been documented by Born [Nature Neuroscience 5(6): 514-516, 2002].  Intranasal insulin improves memory and mood in healthy adults [Benedict, Psychoneuroimmunol. 29:1326-1334, 2004] and improves memory in patients with Alzheimer's disease without altering blood levels of insulin or glucose [Reger, Neurobiology of Aging 27(3):451-458, 2006.]  Twenty-one days of intranasal insulin significantly improved verbal memory in Alzheimer's patients [Craft, ICAD, 2006.]  Intranasal oxytocin has been found to increase trust in humans following direct delivery from the nose to the brain (Kosfeld, Nature 435:673-676, 2005.)

Intranasal leptin reduces food consumption and body weight in animals [Schulz, Endocrinol. 145:2696, 2004] and reduces appetite [Shimizu, Int. J. Obesity 29:858, 2005].  Intranasal insulin reduces body fat in men [Hallschmid, Diabetes 53:3024-3029, 2004].  Intranasal PT-141 has been successfully used in humans to treat erectile dysfunction by acting at melanocortin receptors in the hypothalamus which are involved in both appetite and sexual response.  This method does not require any modification of the therapeutic agent and does not require that the drug be coupled to any carrier.  The method can deliver a wide variety of therapeutic agents to the CNS, including both small molecules and macromolecules as described above.  [The URL for the latest published review of intranasal delivery to the brain is given below.]

http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=357

The Alzheimer’s Research Center, located in St. Paul, Minnesota, was first established in 1977 by Dr. William H. Frey II, one of the original editors of the Journal of Alzheimer’s Disease. Major funding from the National Institutes of Health followed in 1978. One of the earliest Alzheimer’s research centers in the United States, our center maintains one of the nation’s largest human dementia brain banks, with over 2,000 cases of individuals who have died from Alzheimer’s disease and related dementing illnesses, such as Lewy body dementia, multi-infarct dementia, Parkinson’s disease, etc.  Analysis of the center’s brain bank has resulted in important clinicopathologic findings.

Research conducted at the Alzheimer’s Research Center has resulted in a number of very important discoveries and many publications in peer-reviewed scientific and medical journals.  In addition, a number of patents have been granted by the United States Patent Office and European and Canadian patent offices on inventions developed by the center which are designed to improve the treatment of Alzheimer’s disease, stroke, and other neurologic disorders. The founder and director of the Alzheimer’s Research Center, Dr. Frey has been interviewed by major media both in the United States and abroad about his research discoveries.

Publications:

Leah R. Hanson and William H. Frey II.  Strategies for the prevention and treatment of neuroAIDS. Journal of Neuroimmune Pharmacology 2007 (in press).

Rintaro Hashizume, Tomoko Ozawa, Sergei M. Gryaznov, Andrew W. Bollen, Kathleen R. Lamborn, William H. Frey II, and Dennis F. Deen.  New therapeutic approach for brain tumor: Intranasal delivery of telomerase inhibitor GRN163 into intracerebral glioblastoma xenografts.  Neuro-oncology 2007 (submitted).

M.A. Reger, Ph.D.; G.S. Watson, Ph.D.; W.H. Frey II, Ph.D.;, L.D. Baker, Ph.D.; B. Cholerton, Ph.D.; M.L. Keeling, B.S.; D.A. Belongia, B.A.; M.A. Fishel, M.D.; S.R. Plymate, M.D.; G.D. Schellenberg, Ph.D.; M.M. Cherrier, Ph.D.; S. Craft, Ph.D.  Effects of intranasal insulin on cognition in memory-impaired older adults: Modulation by APOE genotype. Neurobiol. Aging 27(3):451-458, 2006.

Dhanda D.S., Frey II W.H., Leopol D., Kompella U.B.  Nose-to-brain delivery: Approaches for drug deposition in the human olfactory eptithelium.  Drug Delivery Technology 5(4):64-72, 2005.

Atamna H. and Frey WH II.  A role for heme in Alzheimer's disease: Heme binds amyloid and has altered metabolism.  PNAS 101:11153-11158, 2004.

Thorne R.G., Pronk G., Padmanabhan V., Frey W.H. II.  Delivery of insulin-like growth factor-I to the brain and spinal cord along olfactory and trigeminal pathways following intranasal administration.  Neuroscience 127:481-496, 2004.

Ross T.M., Martinez P.M., Renner J.C., Thorne R.G., Hanson L.R., Frey W.H. II.  Intranasal administration of interferon beta bypasses the blood-brain barrier to target the central nervous system and cervical lymph nodes: A non-invasive treatment strategy for multiple sclerosis.  Journal of Neuroimmunology 151:66-77, 2004.

Hanson L.R., Martinez P.M., Taheri S., Kamsheh L., Mignot E., Frey W.H. II.  Intranasal administration of hypocretin 1 (Orexin A) bypasses the blood-brain barrier and targets the brain: A new strategy for the treatment of narcolepsy.  Drug Delivery Technology 4(4):66-71, 2004.

Liu X-F., Fawcett J.R., DeFor T., Hanson L. and Frey W.H. II.  The window of opportunity for treatment of focal cerebral ischemic damage with noninvasive intranasal insulin-like growth factor-I in rats.  J. Stroke and Cerebrovascular Dis. 13(1):16-23, 2004.

Frey, W.H. II.  Intranasal delivery: Bypassing the blood-brain barrier to deliver therapeutic agents to the brain and spinal cord.  Drug Delivery Technology 2(5):46-49, 2002.

Fawcett J.R., et al.  Inactivation of the human brain muscarinic acetylcholine receptor by oxidative damage catalyzed by a low molecular weight endogenous inhibitor from Alzheimer's brain is prevented by pyrophosphate analogs, bioflavonoids and other antioxidants.  Brain Research 950:10-20, 2002.

Liu X-F., Fawcett J.R., Thorne R.G., DeFor T. and Frey W.H. II.  Non-invasive intranasal insulin-like growth factor-I reduces infarct volume and improves neurologic function in rats following middle cerebral artery occlusion. Neuroscience Letters 308:91-94, 2001.

Liu X-F., Fawcett J.R., Thorne R.G., DeFor T. and Frey W.H. II.  Intranasal administration of insulin-like growth factor-I bypasses the blood-brain barrier and protects against focal cerebral ischemic damage. J. Neurol. Sci. 187:91-97, 2001.

Thorne R.G. and Frey W.H. II.  Delivery of neurotrophic factors to the central nervous system: Pharmacokinetic considerations. Clinical Pharmacokinetics 40(12):907-946, 2001.

Kjome J.R., Swenson K.A., Johnson M.N., Bordayo E.Z., Anderson L.E., Klevan L.C., Fraticelli A.I., Aldrich S.L., Fawcett J.R., Venters Jr. H.D., Ala T.A., and Frey W.H. II.  Inhibition of antagonist and agonist binding to the human brain muscarinic receptor by arachidonic acid.  J. Mol. Neurosci. 10(3):209-218, 1998.

Chen X-Q., Fawcett J.R., Rahman Y-E., Ala T.A. and Frey W.H. II.  Delivery of nerve growth factor to the brain via the olfactory pathway.  J. Alzheimer’s Disease 1(1):35-44, 1998.

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http://www.pharmacy.umn.edu/pharmaceutics