Q: What do you consider to be the most impor­tant recent finding (or findings) regarding the role of neurotrophins in neurodegeneration?

YB: With regard to neurodegeneration, the most important, recent finding has been the realization that the neurotrophin receptor p75, which is expressed by many developing neu­rons, reappears in a number of pathological sit­uations in the adult, including spinal cord lesions and epilepsy. In the case of the spinal cord, this up-regulation has now been causally linked with the death of neurons and of oligo­dendrocytes (supportive brain cells), as well as with inhibition of axonal elongation. Myelin-associated inhibitors of axonal elongation bind to a receptor that uses p75 as a co-receptor to transduce a signal that leads to a lack of axonal regrowth. Understanding the roles played by specific receptors in neurodegeneration is a crucial step toward developing drugs that specifically interfere with the pathways activated by these receptors.

Q: Since neurotrophins appear to play critical roles in synapse development, to what extent might these fundamental developmental mechanisms be recapitulated to help treat neurological disease?

YB: Neurotrophins, especially brain-derived neurotrophic factor (BDNF), are increasingly recognized as having neurotransmitter-like prop­erties in the central nervous system, including a role in synaptic development and transmission. There is also solid evidence that BDNF is a necessary component of the phenomenon des­ignated long-term potentiation. While our knowledge is entirely derived from cellular and animal models, it has recently been shown in humans that the most common genetic varia­tion of the bdnf gene leads to deficits in some forms of memory, in particular so-called episod­ic memory. This genetic variation, referred to as a polymorphism, leads to an amino acid substi­tution that seems to interfere with the secretion of BDNF. Incidentally, it is of note that this particular study was designed to test a possible rela­tionship between the bdnf gene polymorphism and schizophrenia, a correlation that could not be established. At present, it is unclear if other, less frequent mutations of the bdnf gene have been identified. Also, knowledge about the vari­ous promoters of this gene is still fragmentary so that it remains unclear as to what kind of poly­morphism may exist in regulatory sequences of the gene.

Q: How important will neurotrophin manipula­tion/regulation be to harnessing the potential of stem cells for therapeutic benefit?

YB: With regard to stem cells, one of the most important roles played by neurotrophins may be their ability to assist in the generation of stem cells. Recent work in rodents has shown that increased levels of BDNF lead to increased numbers of neurons derived from endogenous stem cells in the adult brain. It is unclear at this point if BDNF supports the division of precur­sor cells, or, what appears more likely based on results in the peripheral nervous system, if BDNF prevents the death of newly generated neurons. Treatment aimed at increasing the lev­els of endogenous BDNF may be beneficial for a number of reasons, not least because of the intriguing emerging link between BDNF and depression. Most treatments for depression increase BDNF levels in the brain, suggesting the possibility that increased numbers of newly born neurons may constitute part of the expla­nation as to how anti-depressants work.

One of the most important roles played by neurotrophins may be their ability to assist in the generation of stem cells.

Q: What is the biggest challenge (or challenges) to translating basic advances in our understanding of neurotrophins into clinically feasible therapies?

YB: A major difficulty in using basic knowledge about neurotrophins is that these proteins can­not simply be injected in the hope that they will restore functions. This strategy has been very successful with regard to the generation of blood cells. For example, erythropoietin is now widely used as a very effective way to increase the generation of red blood cells, and granulo­cyte colony stimulating factor is also hugely suc­cessful as a means to increase the proliferation of a sub-type of white blood cells. Both sub­stances are proteins, like neurotrophins. But the central nervous system is encapsulated within the blood-brain barrier, a fairly impermeable tis­sue that isolates it from the surrounding milieu. While necessary for proper functioning, this bar­rier effectively excludes large components such as the neurotrophins. Also, the neurotrophins have so many different actions that just increas­ing their levels in the brain, even if this were possible, may not always be desirable. This may cause for example epilepsy or even the death of neurons under certain conditions. Also, inap­propriate connections may be formed as a result of the growth-promoting properties of the neu­rotrophins. One approach that may be more fea­sible and attractive would be to specifically increase the transcription of the neurotrophin genes in areas of interest. In this regard, it is of significance that certain anti-depressants increase transcription of the bdnf gene. It thus seems that small drugs that can be taken orally increase the transcription of genes like bdnf, and that this may explain part of their mode of action. How to selectively increase gene tran­scription in specific areas of the nervous system remains a difficult problem at this point.

Q: What are the areas to watch in the year ahead in neurotrophin research?

YB: In the years to come it will be important to try to correlate various forms of polymorphisms in the neurotrophin genes with psychiatric dis­eases, including depression, in particular. Also, much more needs to be done on the regulation of the transcription of the neurotrophin genes. Likewise the role of neurotrophins in the gener­ation of stem cells is poorly understood, as is the generation of new neurons in areas of the brain such as the cerebral cortex. With regard to axonal elongation after lesion, it will be impor­tant to see the extent to which blocking signals that inhibit axonal elongation may help restore function. Finally, the links between neu­rotrophins and Alzheimer’s need to be explored. There are a number of reports indicating poten­tially important correlations between, for exam­ple, the levels of BDNF and of NGF (nerve growth factor) in the brain of Alzheimer’s patients and in animal models of the disease. Also, the role of the neurotrophin receptor p75 in binding with and being activated by toxic peptides such as A beta (beta amyloid, the pro­tein implicated in Alzheimer’s) and a fragment of the protein involved in prion diseases needs to be explored.

Q: What do you consider to be the most impor­tant recent finding (or findings) regarding the role of neurotrophins in neurodegeneration?

MT: Recent reports indicate that some growth factors are reduced in some human neurode­generative diseases, including Alzheimer's dis­ease, Huntington's disease, and others. Hence, replacing these growth factors in specific dis­eases could be therapeutically beneficial. A steadily building body of work from animal models of human disease strengthens the hypo­thetical rationale with which growth factors could be used to treat currently untreatable neurological disorders.

Q: Since neurotrophins appear to play critical roles in synapse development, to what extent might these fundamental developmental mechanisms be recapitulated to help treat neurological disease?

MT: In adult neurological disease, growth fac­tors have the potential to prevent or delay cell death, and to sustain or even strengthen existing synapses in the brain. The opposite side of the coin—that additional quantities of growth fac­tors could disturb the normal function of cells or synapses—has not been extensively explored to date. This hypothetical possibility must be kept in mind as therapeutic trials move forward.

Q: How important will neurotrophin manipula­tion/regulation be to harnessing the potential of stem cells for therapeutic benefit?

MT: Stem cells have recently been found to make growth factors, which may account for some of their potential therapeutic benefits (Exp Neurol, 2003;181:115-129). Conversely, different growth factors have been tested—with some success—for their ability to promote the differentiation of stem cells to more mature phenotypes that could then be utilized to rescue specific circuitry in human neurodegen­erative conditions. This work remains at an early pre-clinical stage of development, but has potential as future therapy for disease.

Q: What is the biggest challenge (or challenges) to translating basic advances in our understand­ing of neurotrophins into clinically feasible therapies?

MT: It is commonly recognized that nervous system growth factors have a remarkable poten­tial to prevent or reduce the rate of cell loss in progressive neurological conditions, including Alzheimer's disease, Parkinson's disease, ALS, Huntington's disease, and others. However, there are two key problems in delivering growth factors to the CNS effectively and safely. First, the growth factors must be injected directly into the brain to reach targeted cells, because they cannot gain access to the brain after peripheral injection (due to limitations imposed by the blood-brain barrier). Second, growth factors must be delivered to only those parts of the brain in which cells are degenerating. If broadly "flooded" throughout the brain, the growth fac­tors cause unacceptable side effects by stimulat­ing non-targeted cells.

… nervous system growth factors have a remarkable poten­tial to prevent or reduce the rate of cell loss in progressive neurological conditions…

Two approaches have recently been imple­mented in clinical trials to address the issue of effective and safe growth factor delivery to the brain.

In one approach, methods of gene therapy are used to locally deliver growth factors to spe­cific brain regions containing degenerating neu­rons. In a current clinical trial of nerve growth factor (NGF) gene therapy in Alzheimer's dis­ease, patients’ skin cells (fibroblasts) are geneti­cally engineered to make NGF, and the engi­neered cells are implanted into the brain adja­cent to the degenerating neurons. The engi­neered cells release the NGF locally, thereby accessing the degenerating cells without spread­ing the growth factor to the rest of the brain. Results of this first clinical trial will be reported at the 2004 annual meeting of the American Academy of Neurology in April.

In a second approach, growth factors are continuously infused directly into the brain at a low rate to target degenerating cells, without spreading the growth factor to the rest of the brain. Results of a preliminary infusion trial of the growth factor GDNF (glial-derived neurotrophic factor) directly into the brain in patients with Parkinson’s disease were reported in Nature Medicine in 2003. Although prelimi­nary, the trial showed encouraging data regard­ing possible improvement in Parkinsonian symptoms and brain metabolic activity. However, two of five patients had problems with the infusion hardware, suggesting that long-term growth factor infusions into the brain using continuous pumps may be problematic. As a proof-of-principle trial, however, the findings were potentially quite important. This approach is undergoing further clinical trials.

Either gene therapy or continuous infusions of growth factors directly into brain tissue may represent effective means for finally testing the very intriguing potential of growth factors to usefully treat human neurological disease.

Q: What are the areas to watch in the year ahead in neurotrophin research?

MT: The clinical trials of growth factor gene therapy and continuous infusions into brain tis­sue will continue to yield important informa­tion over the next few years. In addition, growth factors trials of gene therapy are planned to begin in Parkinson's disease in the next year. Trials of growth factor gene therapy may also begin in Huntington’s disease and ALS within the next two years.

A previous trial of peripheral subcutaneous injections of the growth factor IGF-1 (insulin­like growth factor-1) in ALS failed to show a consistent clinical benefit when reported a few years ago. The NIH will be sponsoring another trial of this peripheral subcutaneous injection method of IGF-1 in the near future, believing that more specific parameters can be devised for improving the efficacy of this simple but to date ineffective route of growth factor delivery.

Basic preclinical research will continue to be devoted to designing simplified growth factor molecules for access to the CNS after peripheral injection. However, a limitation of this approach will continue to be devising a means of restricting access of the growth factor to narrowly defined cellular targets.