William H. Frey II, Ph.D.

Professor, Department of Neurology, Pharmaceutics, and Oral Biology

Alzheimer's Research Center

E-MAIL: alzheimr@umn.edu

Research Interests:

Dr. William H. Frey II is the Founder and Co-Director of the Alzheimer's Research Center at Regions Hospital, Professor of Pharmaceutics and faculty member in Neurology, Oral Biology and Neuroscience at the University of Minnesota and consultant to the pharmaceutical and biotechnology industry.
Dr. Frey's non-invasive intranasal method for bypassing the blood-brain barrier to rapidly delivery and target therapeutic agents to the brain along the olfactory and trigeminal neural pathways while reducing systemic exposure and unwanted side effects has captured the interest of both pharmaceutical companies and neuroscientists.  The intranasal insulin treatment he developed for Alzheimer’s disease has been shown in multiple clinical trials to improve memory in both Alzheimer’s patients and normal adults. The intranasal therapeutic (stem) cell treatment he discovered has been shown to bypass the blood-brain barrier to treat Parkinson's, stroke, neonatal ischemia, multiple sclerosis and subarachnoid hemorrhage in animal models of these disorders.

Selected Publications:

(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.) Dhuria, S.V., Hanson, L.R.,

Frey, WH 2nd (2015) Noninvasive intranasal stem cells bypass the blood-brain barrier to target the brain to treat Parkinson's disease, stroke, MS, brain tumors, cerebral ischemia, Alzheimer's and other CNS disorders. Journal of Nature and Science, Vol.1 No.1 e23 (Neuroscience)

Margarita Gutova, Davit Shahmanyan, BS candidate; Diana Oganesyan, BA candidate; Yelena Abramyants, RN; Lusine Danielyan, MD; William H Frey II, PHD; Vazgen Khankaldyyan, BS; Joseph Najbauer, PhD; Irina V Balyasnikova, PhD; Rex A Moats, PhD; Maciej S Lesniak, MD; Michael E Barish, PhD; Karen S Aboody, MD (2015) Intranasal delivery of therapeutic neural stem cells to target intracerebral glioma. Enliven: J Stem Cells Regen Med 1(1):007

R. Scott McIvor, Zhenhong Nan, Kelly M. Podetz-Pedersen, Kelley Kitto, Leah R. Hanson, Daniel A. Wolf, Karen Kozarsky, Carolyn A. Fairbanks, William H. Frey, Walter C. Low, Lalitha R. Belur (2014) Intrathecal and intranasal infusion of adeno-associated virus vector: non-invasive routes of administration achieving corrective levels of iduronidase expression throughout the brain for gene therapy of mucopolysaccharidosis type I. Mol Gen and Metab 111(2):S75–S76

Danielyan L, Beer-Hammer S, Stolzing A, Schäfer R, Siegel G, Fabian C, Kahle P, Biedermann T, Lourhmati A, Buadze M, Novakovic A, Proksch B, Gleiter CH, Frey WH 2nd, Schwab M. (2014) Intranasal delivery of bone marrow derived mesenchymal stem cells, macrophages, and microglia to the brain in mouse models of Alzheimer's and Parkinson's disease. Cell Transplant. 23, Supplement 1, pp. S123–S139

Fine JM, Forsberg AC, Renner DB, Faltesek KA, Mohan KG, Wong JC, Arneson LC, Crow JM, Frey WH 2nd, Hanson LR (2014) Intranasally-Administered Deferoxamine Mitigates Toxicity of 6-OHDA in a Rat Model of Parkinson's Disease. Brain Research 1574:96-104

Jared M. Fine, Daniel B Renner, M.S.; Anna C Forsberg, B.A.; Rachel A Cameron, B.A.; Benjamin T Galick, B.A.; Clinton Le, B.A.; Patrick M Conway, B.A.; Benjamin M Stroebel, B.A.; William H Frey II, Ph.D.; Leah R Hanson, Ph.D. (2014) Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation. Neurosci. Lett. 584:362-367

Michael H. Rosenbloom, Terry R. Barclay, Maria Pyle, Brian L. Owens, Amanda B. Cagan, Christopher P. Anderson, William H. Frey II, Leah R. Hanson (2014) A Single-Dose Pilot Trial of Intranasal Rapid-Acting Insulin in Apolipoprotein E4 Carriers with Mild–Moderate Alzheimer's Disease. CNS Drugs 28:1185–1189.

William H. Frey II (2014) Intranasal Insulin: A potential therapeutic for post-traumatic stress disorder and Alzheimer's. Minnesota Physician XXVIII(3):16-17

William H. Frey II (2013) Post-traumatic stress disorder: New approach may help prevent, as well as treat, this devastating disorder. Minnesota HealthCare News

Jessica Freiherr, Manfred Hallschmid, William H Frey II, Yvonne Brünner, Colin D Chapman, Christian Hölscher, Suzanne Craft, Fernanda G De Felice, Christian Benedict (2013) Intranasal Insulin as a Treatment for Alzheimer's Disease: A Review of Existing Basic Research and Clinical Evidence. CNS Drugs 27:505-514

William H. Frey II (2013) Intranasal insulin to treat and protect against PTSD. The Journal of Nervous and Mental Disease 201(7):638-639

Chapman CD, Frey WH II, Craft S, Danielyan L, Hallschmid M, Schioth HB, Benedict C (2013) Intranasal Treatment of Central Nervous System Dysfunction in Humans. Pharm Res 30(10):2475-2484

Wolf DA, Hanson LR, Aronovich EL, Nan Z, Low WC, Frey WH 2nd, McIvor RS. Lysosomal enzyme can bypass the blood-brain barrier and reach the CNS following intranasal administration. Mol Genet Metab. 2012 May;106(1):131-4.

William H. Frey II. (2012) Minnesota Physician XXVI(2): 24-25 Special Delivery: Intranasal treatments bypass blood-brain barrier to treat Alzheimer’s and other brain disorders.

Fine, JM, Baillargeon, AM; Renner, DR; Hoerster, NS, Tokarev, J, Colton, S; Pelleg, A, Andrews, A, Sparley, KA, Krogh, KM; Frey, WH; Hanson, LR (2012) Experimental Brain Research 219(3):381-90 Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1α, and phosphorylates GSK3β in P301L tau transgenic mice.

Leah R. Hanson, Jared M. Fine, Dan B. Renner, Aleta L. Svitak, Rachel B. Burns, Thuhien M. Nguyen, Nathan J. Tuttle, Dianne L. Marti, S. Scott Panter and William H. Frey (2012) Intranasal delivery of deferoxamine reduces spatial memory loss in APP/PS1 mice. Drug Deliv. and Transl. Res.

Dan B. Renner, William H. Frey II, Leah R. Hanson (2012) Neuroscience Letters (accepted & in press) Intranasal Delivery of siRNA to the Olfactory Bulbs of Mice via the Olfactory Nerve Pathway.

Dan B. Renner, Aleta L. Svitak, Nathan J. Gallus, Marna E. Ericson, William H. Frey II and Leah R. Hanson (2012) Journal of Pharmacy and Pharmacology (in press & online) Intranasal delivery of insulin via the olfactory
nerve pathway.

Leah R. Hanson, Jared M. Fine, John D. Hoekman, Thuhien M. Nguyen, Rachel B. Matthews, Paula M. Martinez, Jens Pohl, and William H. Frey II (2012) Drug Delivery 19(3):149-54 Intranasal Delivery of Growth/Differentiation Factor 5 to the Central Nervous System.

Helgi B. Schiöth, William H. Frey II, Samantha J Brooks, Christian Benedict (2012) Expert Review of Clinical Pharmacology 5(1):17-20 Insulin to treat Alzheimer’s disease: Just follow your nose?

Helgi B. Schiöth, Suzanne Craft, Samantha J. Brooks, William H. Frey II, Christian Benedict (2012) Molecular Neurobiology (Accepted & In Press) Brain insulin signaling and Alzheimer`s disease: Current evidence and future directions.

Zhongwu  Liu, PhD; Yi Li, MD; Li Zhang, MD; Hongqi Xin, Phd; Yisheng Cui, MD; Leah R Hanson, PhD; William H Frey II, PhD, Michael Chopp, PhD (2012) Neurobiology of Disease 45(2):804-809 Subacute Intranasal Administration of Tissue Plasminogen Activator Increases Functional Recovery and Axonal Remodeling after Stroke in Rats.

Gomez D.,  Martinez JA, Hanson LR, Frey WH II and Toth C (2012) Frontiers in Bioscience S4, 74-89 Intranasal Treatment of Neurodegenerative Diseases and Stroke.

Frey, W.H.II. (2011) AAPS Newsmagazine 7:14-18 Intranasal Delivery of CNS Therapeutics.

Danielyan, Lusine; Schäfer, Richard; von Ameln-Mayerhofer, Andreas; Bernhard, Felix; Verleysdonk, Stephan; Buadze, Marine; Lourhmati, Ali; Klopfer, Tim; Schaumann, Felix; Schmid, Barbara; Koehle, Christoph; Proksch, Barbara; Weissert, Robert; Reichardt, Holger; van den Brandt, Jens; Buniatian, Gayane; Schwab, Matthias; Gleiter, Christoph, Frey, William. (2011) Rejuvenation Research 14(1):3-16. Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson’s disease.

George J. Francis, Leah R. Hanson, Jose A. Martinez, Wei Q. Liu, Douglas W. Zochodne, William H. Frey II, Cory Toth. (2011) J Neuropathology and Experimental Neurology 70(5):323-39 Motor endplate innervation loss in diabetes and the role of insulin.

Benedict, C., Frey W.H.2nd, Schiöth, H.B, Schultes, B., Born, J., Hallschmid, M. (2011) Experimental Gerontology 46(2-3):112-115 Intranasal insulin as a therapeutic option in the treatment of cognitive impairments.

Dhuria SV, Hanson LR, Frey WH 2nd. Intranasal delivery to the central nervous system: mechanisms and experimental considerations. J Pharm Sci. 2010 Apr;99(4):1654-73.

Johnson, N., Hanson, L.R. and Frey, W.H.II (2010) Molecular Pharmaceutics 7(3):884-893 Trigeminal pathways deliver a low molecular weight drug from the nose to the brain and orofacial structures.

Frey, W.H.II. and Danielyan, L. (2010) Drug Delivery Technology 10(1):39-41, Intranasal Delivery of Stem Cells & Genetically Engineered Cells to the Brain.

Alcalá-Barraza, S., Lee, M., Hanson, L., McDonald, A., Frey, W., McLoon, L. (2010) J. Drug Targeting 18(3):179-190, Intranasal Delivery of Neurotrophic Factors BDNF, CNTF, EPO and NT-4 to the CNS.

Lusine Danielyan, Roman Klein, Leah R. Hanson, Marine Buadze, Matthias Schwab, Christoph H. Gleiter, William H. Frey II. (2010) Rejuvenation Research 13(2-3):195-201 Protective effects of intranasal losartan in the APP/PS1 transgenic mouse model of Alzheimer's disease.

Dhuria SV, Hanson LR, Frey WH 2nd. Intranasal drug targeting of hypocretin-1 (orexin-A) to the central nervous system. J Pharm Sci. 2009 Jul;98(7):2501-15.

Dhuria SV, Hanson LR, Frey WH 2nd. Novel vasoconstrictor formulation to enhance intranasal targeting of neuropeptide therapeutics to the central nervous system. J Pharmacol Exp Ther. 2009 Jan;328(1):312-20. Epub 2008 Oct 22.

Thorne RG, Hanson LR, Ross TM, Tung D, Frey WH 2nd. Delivery of interferon-beta to the monkey nervous system following intranasal administration. Neuroscience. 2008 Mar 27;152(3):785-97.

Frey, W.H. II. Novel vasoconstrictor formulation to enhance intranasal targeting of neuropeptide therapeutics to the central nervous system. J Pharmacol Exp Ther. 2009 Jan;328(1):312-20.

Hanson, Leah R. and Frey, William H II Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. (2008) BMC Neuroscience 9 Suppl 3:S5

Martinez J., Francis G., Liu W., Ramji, N., Pradzinsky, N., Fine J., Wilson, M., Hanson, L.R., Frey, W.H.II , Zochodne D., Gordon T., Toth C. (2008) Neuroscience 157(4):908-925 Intranasal Delivery of Insulin and a Nitric Oxide Synthase Inhibitor in an Experimental Model of ALS .

Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA, Plymate SR, Cherrier MM, Schellenberg GD, Frey II WH , Craft S . (2008) J Alzheimers Dis. 13(3):323-31. Intranasal Insulin Administration Dose-Dependently Modulates Verbal Memory and Plasma Amyloid-beta in Memory-Impaired Older Adults.

Thorne, R.G., Hanson, L.R., Ross, T.M., Frey W.H. II (2008) Neuroscience 152(3):785-797 Delivery of interferon-ß to the monkey CNS following intranasal administration.

Hashizume R., Ozawa T., Gryaznov S.M., Bollen A.W., Lamborn K.R., Frey W.H. II , and Deen D.F. (2008) Neuro-oncology 10: 112-120 New Therapeutic Approach for Brain Tumor: Intranasal Delivery of Telomerase Inhibitor GRN163 into Intracerebral Glioblastoma Xenografts

Ross T., Zuckermann R., Reinhard C., Frey W.H. II (2008) Neurosci. Lett. 439:30-33. Intranasal administration delivers peptoids to the rat central nervous system.

Francis, G., Martinez J., Ramji N., Liu W., Xu K., Fine J., Tuor U., Glazner G., Hanson L.R., Frey, W.H. II , Toth C. (2008) Brain 131:3311-3334 Intranasal Insulin Prevents Cognitive Decline, Cerebral Atrophy and White Matter Changes in the Diabetic Brain.

Thorne, R.G., Hanson, L.R., Ross, T.M., Frey W.H. II (2008) Neuroscience 152(3):785-797 Delivery of interferon-ß to the monkey CNS following intranasal administration.

William Frey