G-Whiz

Holy dancing cow! Today I was playing with my Google account and finally set up a G-Mail account. I then noticed a "Call Phone" link that connected me to Google Voice. While this isn't new by any means, since it was free for USA domestic and Canada, I decided to install the web browser add-on. Within a few minutes I was placing phone calls to friends. Imagine their surprise... The default setup comes across as "CLIENT_ONLY" which might be ignored by people with Caller-ID (most of my calls went to voicemail at first). So a few more minutes later I had "upgraded" my Google Voice account with a brand new mobile phone number in my desired area-code and linked it to my house land-line so people can call me if I am offline. Calls to my Google Voice number which go to voicemail are placed in an inbox I can access via my Google Voice or email. The voice quality on both ends was reported to be quite good. Calls were very easy for me to make. I cued up my opening lines so that as soon as the remote end answered I could hit "Speak" on my assisted communication device and identify myself. I had originally intended to use this in emergencies if I couldn't otherwise alert a caregiver (note that this is NOT suitable for dialing 9-1-1) but after my test calls went so well I decided that I have a "new" communication method for talking to my more patient friends. I had used Skype in the past, but Skype is only free for computer-to-computer calls, not to regular cell or land-line phones. I was able to do all of this with my eye-tracking system with relative ease. If you have control over your eye-tracking assisted communication device and can install software, I recommend trying this out to see if it works for you. UPDATE: Configuration instructions are in the Comments section.

Jury Duty

As many of you know, I have two previous posts about a drug in trial called NP001 (see "Salty Dog" and "All Roads"). In the past few days ALSA released a statement about this trial. I thank ALSA for doing this service for pals in spreading the word about this trial. Recent research seems to finally hold real promise of effective treatment for ALS, the realization of over a century of work. However, until we have the hard data all we have is promise and hope (which while powerful are still ineffective treatments for real disease). It is the responsibility of eligible PALS to become "jurors" in these trials and help us all to find the facts which can free us from the death sentence which Fate has issued.

Brainstorm Coming

Some more very good news for PALS in the USA: Brainstorm is bringing it's stem cell clinical trial to the US! This technology, named NurOwn, uses a patient's own mesenchymal stem cells to produce little factories for neurotrophic factors (proteins that nourish and strengthen neurons). This would provide a constant and lifetime production of support for the neighboring neurons, a much more effective approach than drugs which are only present for a short time or may be reduced or blocked by the Blood-Brain-Barrier. Note that this is not a replacement therapy, but rather one to help feed and protect existing neurons. You can read about the trial protocol here. For recently diagnosed patients they will inject into muscles to try to take advantage of axonal uptake in the hope that this will preserve the axon and its attachment to the muscle (neuromuscular junction). Patients in later stages of disease will have an injection into the spine to treat the neurons' cell bodies directly.

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.