All Roads

It has been known for some time that chronic neuroinflammation is a primary driver of disease in ALS and its "cousins" Alzheimers, Parkinsons, etc. Many attempts have been made to address it by using anti-inflammation drugs without success. Recently a study was published using a "prodrug" in animal models of Alzheimer's and Huntington's diseases. In this study, the drug 2-(3,4-dimethoxybenzenesulfonylamino)-4-(3-nitrophenyl)-5-(piperidin-1-yl)methylthiazole (JM6) inhibited the action of KMO, which is involved in the metabolism of tryptophan. This causes tryptophan to metabolize into kynurenic acid (KYNA), a neuroprotective substance, instead of quinolinic acid (QUIN), a neurotoxic substance. This degradation of tryptophan is called the kynurenine pathway (KP). It is one of the major regulatory pathways of the immune response and is known to be active in neuroinflammation. In HD, AD, and PD (Parkinson) there is decreased KYNA and increased QUIN. In multiple studies, changing the KYNA/QUIN balance in favor of KYNA is neuroprotective via a variety of methods.

Of interest to the ALS Community is that the same imbalances are seen in ALS. Strong evidence suggests that dysregulation of the KP leads to the type of neuronal damage from chronic neuroinflammation seen in many neurodegenerative diseases. In vitro testing with rodent motor neuron cells revealed a functional KP, that degeneration increased with duration and magnitude of exposure of QUIN, and that KYNA was protective against damage to neurons. It is known that QUIN is an NMDA receptor agonist (activator) and that KYNA is an antagonist (inhibitor). NMDA receptor-mediated excitotoxicity via calcium (Ca+) influx is a known cause of motor neuron death in ALS. This means that inhibition of KMO (aka kynurenine 3-hydroxylase) should be beneficial in ALS as well. Fortunately, K3H/KMO has been characterized for some time. In a study done in 2000, KMO (referred to as K3H) was found to be inhibited by Cl- (chloride). Luckily for PALS, there is already a chlorine drug in trial. This drug creates Taurine Chloramine (TauCl) which modulates the pro-inflammatory response seen in ALS, and also appears capable of rerouting KP to a beneficial product rather than harmful.

From the above it appears that previous attempts at modulating neuroinflammation failed because they were targeting symptoms rather than underlying cause (like treating a headache with aspirin when the cause is a tumor). By boosting the body's endogenous TauCl production a clearly malfunctioning immune response can be guided to its secondary, nurturing, state. At the same time, multiple targets identified in ALS can be struck with a single weapon: Excitotoxic calcium influx from glutamate receptors (currently treated with little effect by Riluzole), mitochondrial distress (currently the target of other drugs in trial), and the neuroinflammation which is one of the main drivers of disease progression in ALS.

While all roads may lead to Rome, it appears that in neurodegenerative disease they may lead to KP moderation by chloramines.

Growing Grass

A few weeks ago, Professor Stephen Hawking was quoted in The Guardian newspaper saying "there is no Heaven; it's a fairy tale." Shortly after, two radio "shock jocks" in the Houston market decided to take issue with Professor Hawking's words by belittling his condition and questioning his abilities. I won't repeat their attack, but it was immature and offensive to all people affected by ALS. In response to their attack, a Facebook group was formed to boycott the radio personalities and the advertisers on their network of stations. The goal was formed to not just demand an apology but to make this a teachable moment by demanding that the parent company, Clear Channel, also air multiple PSAs. In addition, Clear Channel agreed to a 30-minute interview featuring Steve Perrin, the CEO of ALS-TDI. All of the boycott group's demands were met. This marks a major event in awareness for ALS. An organized grassroots movement was formed via social network tools and used those tools to achieve a goal long-sought in the community. This is only the beginning, and a perfect example of the kind of the cooperative relationship we need to foster with media, local and national.

Cell Mates

In 2006, mouse fibroblasts were successfully transformed from a fully differentiated state to a state of pluripotency. These cells were designated induced pluripotent stem cells (iPSC).Since that news, human cells were successfully transformed and techniques to increase the safety and efficiency of production have been found. Other techniques have been developed which can correct genetic defects in iPSCs with the eventual goal of repairing or replacing defective tissues.

iPSCs still have issues to be resolved such as:

• certain methods of inducing pluripotency are tumorigenic
• iPSCs appear to have "memory" of their original cell type
• there is some data showing that iPSCs express certain proteins on their surface resulting in immune rejection even in cells donated from the host's own tissue
• other complications such as efficiency (allowing sufficient numbers of cells to be generated within a clinically acceptable time at a clinically acceptable cost).

Some of these issues are already being addressed and quite frankly the pace of research has been astonishingly rapid. iPSCs are already being used to model disease and aid drug discovery. Due to the novelty of cell-based therapies and the fact that implanted cells are difficult or impossible to remove (unlike dosages of drugs which can be ceased in the event of adverse reaction), regulatory hurdles are necessarily high. However, as more trials are performed giving more data on safety these hurdles can be lowered somewhat and/or more easily surmounted. There are cell-based therapies already in or going through the regulatory process for trials using a variety of stem cell types. Not only do these prospective treatments face regulatory hurdles, they must also cross the Valley of Death of pharmaceutical research. Some researchers are finding ways of doing this on their own with intellectual property partnerships, and the NIH has been working to bridge the gap with new programs such as TRND.

This is a very exciting time for regenerative medicine.

FUS and ALS: What's the Connection?

A very interesting article from the MDA. Discusses some exciting work regarding the role of FUS in ALS. The article also mentions TDP43 and a possible convergence in the pathologies of both.

The Cost of Breath

Despite having a "fatal illness", with a little technology and someone to keep an eye on me for the inevitable adjustments, I can live until age draws the final curtain on the story of my life. My quality of life remains high regardless of my current certain physical limitations. There is nothing wrong with my mind: I am still as intellectually productive as ever. Nothing would please me more than to earn my own keep (and I am not alone in this desire), but people classified as terminally ill don't appear to be considered viable members of the workforce. So I volunteer my time to raise awareness and try to understand relevant research, sharing what I learn with others (a part of my previous career and the genesis of this blog). I find this work fulfilling and it keeps my opinion of my quality of life quite high, focusing on accomplishment rather than loss. Those close to me can attest that I can get cranky between projects when I have nothing to do so I try to stay busy. As I am quadriplegic I must use a computer system that tracks my eye movement to approximate the use of a mouse. With this computer I write and respond to email and online chat offering technical advice and answering questions from other PALS, scour the Web for research information, create videos to promote awareness, created a website (with coding assistance from a friend far more skilled than I), and play with my home computer network among other projects. The decision to vent or not is a highly personal one with many factors contributing to the decision. I chose to live on a vent for a few reasons. First, I had finally recently achieved real happiness in life and didn't want the dream-come-true to end so soon. Second, I saw some hope on the horizon with the state of research into the disease and possible ways to overcome it and I still hold this view more than ever. Last, and important to my perception of quality of life, I still had a contribution to make to the world and I have only grown more intense in that belief. I am simply not done living, with all which that experience entails. But my every breath now comes at a price. Because I cannot move to assist myself I must have an able-bodied person within hearing distance of any alarms or signals from my equipment. The skill requirements aren't high and can be taught in a weekend, but nevertheless someone must be alert and on duty 24/7. Family is often preoccupied by the demands of daily living, volunteers are few and far between, and government assistance is non-existent for people in my condition. The one factor which should NOT be involved in deciding whether to live on a vent is the cost of attendants. Medicare will not provide for in-home attendants. There are even very few institutions which will take people on mechanical ventilation and hospice is not an option due to the vent being a life support device. With the enormous wealth floating around our for-profit healthcare system it is astounding that no insurance (not even my high-end corporate policy) will cover the cost of attendants. So my only option, given my desire to live, is to become a beggar on an offramp of the information superhighway. This is terribly humiliating to me.

Nerd Factor Five

As an Information Technology professional I tend to accumulate equipment. I have a couple of old laptops lying around (some dating back to 1998). One of the slightly newer ones I connected to my TV via the external SVGA port (with an associated stereo sound cable connected to the headphone jack). Now I can stream Netflix and other online content to my big flatscreen TV while not using up the resources on my communication system. For independence I installed VNC which gives me full control over the remote machine. All I need is someone to power on the laptop and I am up and running. Currently I am watching live surfing being streamed from Bells Beach, Australia. Think I'll crack a Foster's and enjoy!

More Press

As many of you may already know, I was recently featured in an article in the Santa Cruz Sentinel. There was a lot of information to cover and I applaud Laura for getting it all in there. I did want to clarify some points: First (and least), I was the web group sysadmin for Lutris, building and maintaining the internal and external web infrastructure, and the I.T. manager for Mercedes-Benz Research & Development. Second, regarding vents, my point was that due to the costs involved, many never have a choice. Some make a choice not to vent, and I respect that. However, due to the financial expense, for many the choice is made for them regardless of their desire. This deprives the world of many potentially productive and engaged people, and is an ongoing concern of mine.