Treatment strategies for neurodegenerative diseases based on trophic factors and cell transplantation techniques

  • B. J. Hoffer
  • L. Olson
Conference paper


Treatment strategies based on transfer of genes, molecules, or cells to the central nervous system are summarized. When neurons are already degenerated, functional compensation can be effected by grafts of syngeneic or allogenic tissue to the target area. This technique is undergoing clinical trials in Parkinson’s disease. Before degeneration has occurred, it may be possible to rescue “stressed” neurons, and stimulate terminal outgrowth using treatment with neurotrophic factors. Such approaches, with an emphasis on the NGF family of neurotrophins and their receptors, are reviewed. Finally, new molecular biology techniques may permit the transfer of genes directly into non-dividing cells of the central nervous system. These three approaches may have a more general applicability, and become important not only in neurodegenerative diseases, but also in other afflictions of the nervous system such as ischemia, stroke and injury.

While axonal regeneration is an effective and clinically important mechanism in the peripheral nervous system, it is a well-established fact that long nerve fiber pathways do not regenerate in the adult mammalian central nervous system. The reason for this difference long remained unknown, but the elegant experiments of Aguayo and collaborators (David and Aguayo, 1981) have demonstrated that adult CNS axons are able to elongate efficiently if given the appropriate environment, such as a section of peripheral nerve. The discrepancy between regenerative capacity in CNS and PNS has at least three possible bases: (1) production of neurotrophic factors by Schwann cells but not oligodendroglial cells, (2) the production of nerve growth inhibitory factors by oligodendroglial but not Schwann cells, or (3), scar formation to a greater extent in the CNS than in the PNS. It now appears as if all three possibilities are true. There are relatively effective regenerative mechanisms for peripheral nerve injury, but the extreme complexity of the central nervous system and precise regulation of central connectivity has led to an absence of such regenerative capacity. As longevity has increased in modern society, the need for reparative intervention for neurodegenerative diseases has increased commensurately.

While research during the last two decades has not yet provided us with methods to effectively stimulate regeneration of long fiber tracts in the central nervous system, it has led to the development of two other principal repair strategies. The first is a cell replacement strategy; neurons that have been lost can sometimes be functionally replaced by other cells such as embryonic neurons which are implanted, not at the original site of such nerve cell bodies, but directly into their axonal target regions. With this strategy one avoids the necessity of regenerating a long axon pathway, obviously with loss of the original circuitry, but there is a gain of new nerve terminals. The second approach is applicable before neurons have died, and focuses on prevention of “stressed” neurons from dying and stimulation of nerve terminals from remaining neurons using neurotrophic factors. Obviously, these two principles can be combined. In the following, we shall discuss some of the recent animal research for treatment with grafts and growth factors, as well as comment upon ongoing clinical trials.

One may look at reparative strategies as various ways of transfering molecules or cells to the brain to obtain long-lasting effects. Thus molecular and cellular transfer techniques fundamentally differ from current treatment strategies of neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Current treatments attempt to increase dopamine and cholinergic neurotransmission, respectively, by pharmacological means such as administering a dopamine precursor, an acetylcholinesterase inhibitor, or various direct and indirect agonists. These treatments may be somewhat effective as long as the drugs are taken regularly, but the positive effects disappear immediately upon drug withdrawal. Moreover, tolerance and side effects are common problems.


Nerve Growth Factor Neurotrophic Factor Schwann Cell Dopamine Neuron Adult Mammalian Central Nervous System 
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  1. Backlund E-O, Granberg PO, Hamberger B, Knutsson E, Martensson A, Sedvall G, Seiger A, Olson L (1985) Transplantation of adrenal medullary tissue to striatum in parkinsonism. First clinical trials. J Neurosurg 62: 169–173PubMedCrossRefGoogle Scholar
  2. Barde YA (1990) The nerve growth factor family. Prog Growth Factor Res 2: 237–248PubMedCrossRefGoogle Scholar
  3. Bothwell M (1991) Keeping track of neurotrophin receptors. Cell 65: 915–918PubMedCrossRefGoogle Scholar
  4. David S, Aguayo A (1981) Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats. Science 214: 931–993PubMedCrossRefGoogle Scholar
  5. Ebendal T (1992) Function and evolution in the NGF family and its receptors. J Neurosci Res 32: 461–470PubMedCrossRefGoogle Scholar
  6. Engele J, Schubert D, Bohn M (1991) Conditioned media derived from glial cell lines promote survival and differentiation of dopaminergic neurons in vitro: role of mesencephalic glia. J Neurosci Res 30: 359–371PubMedCrossRefGoogle Scholar
  7. Ernfors P, Ebendal T, Olson L, Mouton P, Strömberg I, Persson H (1989) A cell line producing recombinant nerve growth factor evokes growth responses in intrinsic and grafted central cholinergic neurons. Proc Natl Acad Sci USA 86: 4756–4760PubMedCrossRefGoogle Scholar
  8. Friden PM, Walus LR, Musso GF, Taylor MA, Malfroy B, Starzyk RM (1991) Antitransferrin receptor antibody and antibody-drug conjugates cross the blood-brain barrier. Proc Natl Acad Sci USA 88: 4771–5PubMedCrossRefGoogle Scholar
  9. Gaul G, Lubbert H (1992) Cortical astrocytes activated by basic fibroblast growth factor secrete molecules that stimulate differentiation of mesencephalic dopaminergic neurons. Proc R Soc Lond B 249: 57–63CrossRefGoogle Scholar
  10. Hoffer BJ, Leenders KL, Young D, Gerhardt G, Zerbe GO, Bygdeman M, Seiger A, Olson L, Stromberg I, Freedman R (1992) Eighteen-month course of two patients with grafts of fetal dopamine neurons for severe Parkinson’s disease. Exp Neurol 118: 243–252PubMedCrossRefGoogle Scholar
  11. Leibrock J, Lottspeich F, Hohn A, Hofer M, Hengerer B, Masiakowski P, Thoenen H, Barde YA (1989) Molecular cloning and expression of brain-derived neurotrophic factor. Nature 341: 149–152PubMedCrossRefGoogle Scholar
  12. Levi-Montalcini R (1987) The nerve growth factor 35 years later. Science 237: 1154–1162PubMedCrossRefGoogle Scholar
  13. Lin L-F, Doherty D, Lile J, Bektesh S, Collins F (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260: 1130–1132PubMedCrossRefGoogle Scholar
  14. Lindvall O, Rehncrona S, Brundin P, Gustavii B, Astedt B, Widner H, Lindholm T, Bjorklund A, Leenders KL, Rothwell JC, Frackowiak R, Marsden C, Johnels B, Steg G, Freedman R, Hoffer B, Seiger Å, Bygdeman M, Strömberg I, Olson L (1989) Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson’s disease. A detailed account of methodology and a 6-month follow-up. Arch Neurol 46: 615–631PubMedGoogle Scholar
  15. Nagata K, Takei N, Nakajima K, Saito H, Kohsaka S (1993) Microglial conditioned medium promotes survival and development of cultured mesencephalic neurons from embryonic rat brain. J Neurosci Res 34: 357–363PubMedCrossRefGoogle Scholar
  16. O’Malley E, Sieber B, Black I, Dreyfus C (1992) Mesencephalic type I astrocytes mediate the survival of substantia nigra dopaminergic neurons in culture. Brain Res 582: 65–70PubMedCrossRefGoogle Scholar
  17. Olson L (1988) Grafting in the mammalian central nervous system: basic science with clinical promise. In: Magistretti P (ed) Discussions in neurosciences. FESN, GenevaGoogle Scholar
  18. Olson L, Backlund E-O, Ebendal T, Freedman R, Hamberger B, Hansson P, Hoffer B, Lindblom U, Meyerson B, Strömberg I, Sydow O, Seiger Å (1991) Intraputaminal infusion of nerve growth factor to support adrenal medullary autografts in Parkinson’s disease: one-year follow-up of first clinical trial. Arch Neurol 48: 373–381PubMedGoogle Scholar
  19. Olson L, Nordberg A, von Holst H, Bäckman L, Ebendal T, Alafuzoff I, Amberia K, Hartvig P, Herlitz A, Lilja A, Lundgvist H, Långström B, Meyerson B, Persson A, Viitanen M, Winblad B, Seiger Å (1992) Nerve growth factor affects 11C-nicotine binding, blood flow, EEG, and verbal episodic memory in an Alzheimer patient. J Neural Transm [PD-Sect] 4: 79–95CrossRefGoogle Scholar
  20. Rosenberg MB, Friedmann T, Robertson RC, Tuszynski M, Wolff JA, Breakefield XO, Gage FH (1988) Grafting genetically modified cells to the damaged brain: restorative effects of NGF expression. Science 242: 1575–1578PubMedCrossRefGoogle Scholar
  21. Rousselet A, Fetler L, Chamak B, Prochiantz A (1988) Rat mesencephalic neurons in culture exhibit different morphological traits in the presence of media conditioned on mesencephalic or striatal astroglia. Dev Biol 129: 495–504PubMedCrossRefGoogle Scholar
  22. Schubert D, Heinemann S, Carlisle W, Tarikas H, Kimes B, Patrick J, Steinbach H, Culp W, Brandt B (1974) Clonal cell lines from the rat central nervous system. Nature 249: 224–227PubMedCrossRefGoogle Scholar
  23. Spencer DD, Robbins RJ, Naftolin F, Marek KL, Vollmer T, Leranth C, Roth RH, Price LH, Gjedde A, Bunney BS, Sass K, Elsworth J, Kier E, Makuch R, Hoffer P, Redmond Jr D (1992) Unilateral transplantation of human fetal mesencephalic tissue into the caudate nudeus of patients with Parkinson’s disease. N Engl J Med 327:1541–1548PubMedCrossRefGoogle Scholar
  24. Strömberg I, Wetmore CJ, Ebendal T, Ernfors P, Persson H, Olson L (1990) Rescue of basal forebrain cholinergic neurons after implantation of genetically modified cells producing recombinant NGF. J Neurosci Res 25: 405–411PubMedCrossRefGoogle Scholar
  25. Strömberg I, Björklund L, Johansson M, Tomac A, Collins F, Olson L, Hoffer B, Humpel C (1993) Glial cell line-derived neurotrophic factor is expressed in the developing but not adult striatum and stimulates developing dopamine neurons in vivo. Exp Neurol 124: 401–412PubMedCrossRefGoogle Scholar
  26. Thoenen H (1991) The changing scene of neurotrophic factors. Trends Neurosci 14:165–170PubMedCrossRefGoogle Scholar
  27. Wetmore C (1992) Brain-derived neurotrophic factor. Studies on the cellular localization and regulation of BDNF, related neurotrophins and their receptors at the mRNA and protein level. Thesis, Karolinska Institute, Stockholm, SwedenGoogle Scholar
  28. Wetmore C, Cao YH, Pettersson RJF, Olson L (1991) Brain-derived neurotrophic factor: subcellular compartmentalization and interneuronal transfer as visualized with antipeptide antibodies. Proc Natl Acad Sci USA 88: 9843–9847PubMedCrossRefGoogle Scholar
  29. Wetmore CJ, Cao Y, Pettersson RF, Olson L (1993) Brain-derived neurotrophic factor (BDNF) peptide antibodies: characterization using a Vaccinia virus expression system. J Histochem Cytochem 41: 521–533PubMedCrossRefGoogle Scholar
  30. Wetmore C, Bean AJ, Olson L (1994) Regulation of brain-derived neurotrophic factor (BDNF) expression and release from hippocampal neurons is mediated by non-NMDA type glutamate receptors. J Neurosci 14: 1688–1700PubMedGoogle Scholar
  31. Widner H, Tetrud J, Rehncrona S, Snow B, Brundin P, Gustavii B, Bjorklund A, Lindvall O, Langston JW (1992) Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). N Engl J Med 327: 1556–1563PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1997

Authors and Affiliations

  • B. J. Hoffer
    • 1
  • L. Olson
    • 1
  1. 1.Department of Pharmacology and PsychiatryUniversity of Colorado Health Sciences CenterDenverUSA

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