Delivery of Therapeutic Proteins Into the Nervous System

  • Quantitative assessment of the permeability of peptides and proteins at the blood-brain barrier and blood-nerve barrier
  • Protein modifications to increase permeability at the blood-brain barrier and blood-nerve barrier: glycation, polyamine modification (putrescine, spermine, spermidine), ubiquitin modification
  • Delivery of therapeutic proteins across the blood-brain/nerve barriers after systemic administration for the treatment of neurodegenerative diseases
  • Proteins targeted for delivery: neurotrophic factors, anti-oxidant enzymes (superoxide dismutase, catalase), leptin, peptides that inhibit amyloidogenesis, interferons, cytokines, antibodies, interleukins, etc.
  • In vivo targeting of Alzheimer's amyloid plaques for diagnostic imaging
  • Pre-clinical animal models to demonstrate efficacy of our delivery technology include:

    Animal Models

    Therapy

    Transgenic mouse model of FALS with a point mutation of Gly 93 Ala in SOD

    Antioxidant enzymes

    Transgenic mouse models of Alzheimer's disease that overexpress human Ab protein

    Peptides that inhibit amyloidogenesis, antioxidant enzymes, antibodies to Aβ

    Obesity

    Leptin

    Diabetic neuropathy: Modulation of DRG trkA and p75 NGF receptors after peripheral axotomy

    NGF

    Four-vessel occlusion model of cerebral ischemia (stroke)

    Anti-oxidant enzymes

Selected references

Manuscripts: 93, Abstracts: 130

  • Poduslo JF, Curran GL: Increased permeability across the blood-nerve barrier of albumin glycated in vitro and in vivo from patients with diabetic polyneuropathy. Proc Natl Acad Sci USA 89:2218-2222, 1992.
  • Poduslo JF, Curran GL, Berg CT: Macromolecular permeability across the blood nerve and blood brain barriers. Proc Natl Acad Sci USA, 91:5705-5709, 1994.
  • Poduslo JF, Curran GL: Glycation increases the permeability of proteins across the blood-nerve and blood-brain barriers. Molecular Brain Res, 23:157-162, 1994.
  • Poduslo JF, Curran GL: Permeabilities at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Molecular Brain Res, 36:280-286, 1996.
  • Poduslo JF, Curran GL: Polyamine modification increases the permeability of proteins at the blood-nerve and blood-brain barriers. J Neurochem, 66:1599-1609, 1996.
  • Poduslo JF , Curran GL: Increased permeability of superoxide dismutase at the blood-nerve and blood-brain barriers with retained enzymatic activity after covalent modification with the naturally occurring polyamine, putrescine. J Neurochem, 67:734-741, 1996.
  • Wengenack TM, Curran GL, Poduslo JF: Postischemic, systemic administration of polyamine-modified superoxide dismutase reduces hippocampal CA1 neurodegeneration in rat global cerebral ischemia. Brain Res, 754:46-54, 1997.
  • Wengenack TM, Curran GL, Poduslo JF: Therapeutic strategies for the non-invasive treatment of Alzheimer's disease by polyamine-modified neurotrophic factors and antioxidant enzymes with increased permeability at the blood-brain barrier. Alzheimer's Disease: Biology, Diagnosis and Therapeutics, K Igbal et al., eds. John Wiley & Sons, 1997.
  • Poduslo JF , Curran GL, Haggard JJ, Biere AL, Selkoe, DJ: Permeability and residual plasma volume of human, Dutch variant, and rat amyloidb-protein 1-40 at the blood-brain barrier. Neurobiology of Disease, 4:27-34, 1997.
  • Wengenack TM, Curran GL, Olson EE, Poduslo JF: Putrescine-modified catalase with preserved enzymatic activity exhibits increased permeability at the blood-nerve and blood-brain barriers. Brain Res., 767:128-135,1997.
  • Poduslo JF, Curran GL, Gill JS: Putrescine-modified NGF: Bioactivity, pharmacokinetics, blood-brain/nerve barrier permeability, and nervous system biodistribution. J Neurochem, 71:1651-1660, 1998.
  • Poduslo JF, Curran GL, Frangione B, and Soto C: b -sheet peptide inhibitor of Alzheimer's amyloidogenesis with increased BBB permeability and resistance to proteolytic degradation in plasma. J. Neurobiology, 39:371-382, 1999.
  • Reinholz MM, Haggard JJ, Curran GL, and Poduslo JF: Plasma pharmacokinetics, nervous system biodistribution and biostability, and spinal cord permeability at the blood-brain barrier of putrescine-modified catalase in the adult rat. Experimental Neurol. 159:191-203, 1999.
  • Reinholz MM, Merkle CJ, and Poduslo JF: Therapeutic benefits of putrescine-modified catalase in a transgenic mouse model of familial amyotrophic lateral sclerosis. Experimental Neurol. 159:204-216, 1999. 1
  • Poduslo JF, Curran GL, Sanyal B, and Selkoe DJ: Receptor mediated transport of human amyloid b-protein 1-40 and 1-42 at the blood-brain barrier. Neurobiology of Disease, 6:190-199, 1999.
  • Wengenack TM, Curran GL, and Poduslo JF: Targeting of Alzheimer's amyloid plaques. Nature Biotechnology, 18:868-872, 2000.
  • Burguera B, Counce ME, Curran GL, Jensen MD, Lloyd RV, Cleasy MP, and Poduslo JF. Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats. Diabetes, 49:1219, 2000.
  • Wengenack TM, Whelan S, Curran GL, Duff K, and Poduslo JF: Quantitative histological analysis of Alzheimer's amyloid deposition in APP, PS1 transgenic mouse brain. Neuroscience, 101:939-944, 2000.
  • Poduslo JF, Whelan SL, Curran GL, and Wengenack TM: Therapeutic benefit of polyamine-modified catalase as a scavenger of hydrogen peroxide and nitric oxide in FALS transgenics. Annals of Neurology, 48:943-947, 2000.
  • Poduslo JF, Curran GL, Wengenack TM, Malester B, Duff K: Permeability of proteins at the blood-brain barrier in the normal adult mouse and double transgenic mouse model of Alzheimer's Disease. Neurobiology of Disease, 8:555-567, 2001.
  • Poduslo JF, and Curran GL: Amyloid b-peptide as a vaccine for Alzheimer's disease involves receptor-mediated transport at the blood-brain barrier. NeuroReport 12:3197-3200, 2001.
  • Poduslo JF, Wengenack TM, Curran GL, Wisniewski T, Sigurdsson EM, Borowski BJ, Jack CR, Jr: Molecular targeting of Alzheimers amyloid plaques for contrast-enhanced magnetic resonance imaging. Submitted, 2001.