HD Lighthouse Contributing Editor's Comment: This is the first of a series of essays about approaches to treatment.

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Posted to the HDL: 14 Dec 2005

Neurotrophins to the Rescue

There have been several recent articles detailing the importance of neurotrophins in Huntington's. Neurotrophins are molecules that have been shown to promote neuron development, health, and survival. These molecules act as signals that exert significant control over the switch that triggers life and death pathways in cells.

More than twenty neurotrophins have been described. Making it more complicated, each neurotrophin has differing activities in various cell subtypes and brain areas. The following is a brief review of three neurotrophins, Brain Derived Neurotrophin (BDNF), Neurotrophin-4/5 and Fibroblast Growth Factor 2; those recently in the news. They all are candidates for therapy in HD.

Brain Derived Neurotrophic Factor (BDNF)

BDNF is the neurotrophin that appears to be particularly important for the survival of medium spiny neurons (MSN), which are the cells most affected by Huntington's. It has been shown that MSN cells don't manufacture BDNF, but instead rely on cortical nerve cells for its necessary supply of this essential neurotrophin.

It is known that normal (wild type) huntingtin protein is an important promoter of BDNF. In Huntington's disease, levels of normal huntingtin protein and BDNF are decreased. In addition, mutant huntingtin protein interferes with BDNF at three critical levels; its manufacture, transport, and delivery across the cortical-striatal nerve junction.

Up-to-date information on BDNF and its many roles in Huntington's can be found in a review article in Nov. 2005 Nature Reviews by Cattaneo et.al. In this article the authors detail much that is known about normal huntingtin protein function including its many roles in promoting healthy levels of BDNF. Normal huntingtin protein stimulates BDNF production in cortical cells, transport along paths which connect the cortical cells to medium spiny neurons, its release between these cells at the synapse, and its uptake into spiny neurons. In Huntington's disease, levels of both normal huntingtin protein and BDNF are decreased.

The critical importance of cortical BDNF for maintaining the health of medium spiny neurons is shown in recent work by Dr. Z. Baquet et.al in April 2005 J. Neuroscience. The authors describe work done on mice that are genetically engineered to be deficient in BDNF production only in cortical neurons. These mice, whose genetic defect is only BDNF deficiency, gradually develop striatal cell damage in a pattern very similar to HD mice. Further, these BDNF deficient mice develop motor abnormalities similar to HD mice. These results suggest that BDNF deficiency is a major factor in the pathology of Huntington's.

Making matters worse, mutant huntingtin protein further interferes with decreased levels of BDNF at many critical levels; its manufacture, transport, and delivery across the cortical-striatal nerve junction. 2001 Science 2004 Cell

Several studies have shown the protective effect of delivering BDNF to the striatum of HD models. Zucatta, et.al, in 2005 Pharmacol Res. provide the following reference summary and presents further detailed results of their research confirming the protective benefit of BDNF.

Reference	Application	Animal HD model	Results
Perez-Navarro et al. [26]	Grafting of cell lines expressing BDNF	Quinolinic acid rat model	Promotion of the survival of striatal neurons
Alberch J et al. [27]	Transplantation of cells genetically engineered with BDNF	Quinolinic acid rat model	Protection of striatal projection neurons and basal ganglia circuits
Ryu JK et al. [41]	Transplantation of human neural stem cells expressing BDNF	3-nitropropionic rat model	Improvement in motor performance and protection of striatal neurons
Kells AP et al. [28]	Adeno-associated viral (AAV) vector mediated gene delivery of BDNF	3-nitropropionic rat model	Provision of neuronal protection
Canals JM et al. [29]	Subcutaneous delivery with minipump	R6/1mouse model	Reversion of the loss of the enkephalinergic phenotype in R6/1 and improvement of motor dysfunctions

The references in the above table are links are to a site that requires a subscription

Neurotrophin-4/5

This molecule primarily targets and promotes the survival of striatal "interneurons". Interneuron cells provide support to the medium spiny neurons. While interneurons are relatively spared in Huntington's, increasing the supportive function of these cells is protective of the more vulnerable medium spiny neurons. In a recent article by Ducray, et.al 2005 J. Neurochem, the authors describe the benefit of neurotrophin-4/5 when administered to mouse models of HD They found that both interneurons and medium spiny neurons were protected (in cell cultures). NT-4/5 has been shown to be neuroprotective in quinolinic mouse models by Perez-Navarro, et al in 2000 Neuroscience.

Fibroblast Growth Factor 2

Jin, et.al in 2005 Science has recently shown that fibroblast growth factor 2 (FGF-2) stimulates development of new spiny neurons from stem cells already present in the brain. When given to R6/2 model of Huntington's at the time of symptom development, FGF-2 prompted stem cells to migrate to striatum and form functioning new spiny neurons. This effect was a 150% increase in neuron cell proliferation. The authors further showed that new cell development was associated with benefit in motor abnormalities as well as decreased nuclear aggregates. R6/2 life span was expanded by 20%.

It is especially exciting that this growth factor got into brain using a subcutaneous route. This is an extremely important characteristic for translating into therapy for HD people because direct brain delivery would not be necessary.

Neurotophin Therapy Available Now

There is no question that neurotrophins promote brain health. While the experts are working on translating these scientific findings to pharmacologic therapy for HD, there are other ways to raise BDNF. Dietary restriction, exercise, and environmental stimulation are cost effective and associated with a protective elevation in BDNH levels. Curcumin, various SSRI antidepressants, and atypical neuroleptics are also associated with a similar elevation.

Pharmacologic Neurotrophin Therapy: Delivery is Critical

However, greater success for HD therapy will likely require larger pharmacologic dosing of BDNH or other neurotrophins which must be delivered using surgically invasive techniques to the area of brain (or spinal fluid around the brain) damaged by Huntington's. FGF-2 may be the exception, but systemic side effects may interfere with subcutaneous administration of the agent.

Direct infusion into brain, using tiny catheters and implanted pumps, was used in the recent Amgen Parkinson's study. The pressures used in these systems are critically important because it controls dosing. The Parkinson's study may have been flawed due to inadequate pump pressure/dosing. Another system used is neurotrophin gene delivery by viral vectors. Most likely, gene transfer therapy will require direct delivery to brain.

NeurotrophinCell

A relatively new biotechnology company has pioneered another product and delivery system for neurotrophins. Living Cell Technologies with U.S. headquarters in Rhode Island, filed for a Pre-IND with the FDA for its NeurotrophinCell product for use in Huntington's earlier this year. Their first meeting with the FDA occurred just a few weeks ago, to seek approval for proceeding to Phase I clinical trials in people. They should know in January 2006 whether they can procede to human trials.

NeurotrophinCell contains choroid plexus cells harvested from pigs. Choroid plexus cells are located at the junction of brain and spinal fluid and are natural producers of neurotrophins which are released into adjacent brain and spinal fluid that surrounds the brain. These specialized pig cells are placed inside a tiny biopolymer capsule that allows for release of neurotrophins, and is engineered to protect from host immune response. Capsules are injected into brain using tiny catheters: There is no need for continued infusion. This product also supplies a physiologic "cocktail"? balance of neurotrophic factors.

This company has used "quinolinic acid"? animal models (rats and monkeys) for studies of Huntington's. In Nov. 2004 Neuroreport, scientists from this company published a rat study showing striatal cell preservation in the group that received the capsules prior to quinolinic acid injection. In August 2005, they reported on work still not published using monkeys as the mammal model. Those treated with capsules containing transplanted cells had only 1/5 the damage when compared to the untreated group; an impressive 80% neuroprotective benefit.

My Three Comments

Mutant Huntington protein produces a myriad of interrelated cellular abnormalities. Researchers separate these abnormalities into groups which include (among others) transcription, excitotoxicity, energy production, inflammation, and neurotrophins. Unfortunately no single system has yet been shown dominant. And so far, drugs targeting each of these groups show about the same (relatively small) benefit. If one (or more) such systems were found to be more important to promoting the disease, then targeting that system for therapy would have greater effect on alleviating the disease. Neurotrophins might prove to be that system.

Though BDNF appears most important, the right combination of trophins is likely to be better. In this sense, the approach taken by Living Cell Technology (LCT) may be exciting.

But realistically, Living Cell Technology will need to show long term safety of the capsule and long-term viability of choroid cells, before their approach moves beyond Phase I trials. But isn't it impressive how quickly this biotechnology company has moved; from a natural resource of cells; to research findings in rodent and mammal models; to working towards clinical trials in people. Perhaps, with safety demonstrated, 2006 will see this moving farther still. We can hope.

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