Sunday, 15 July 2012

Current Research Highlights

I was having a read around the other week, and I found a link on the rareconnect website to this article:

The article, written by Allen Bernard (whose daughter has HSP), is based on his discussions with five of the world's leading HSP researchers: 
  • Dr. Craig Blackstone at the National Institutes of Health in Bethesda, Maryland; 
  • Dr. Evan Reid at the University of Cambridge in the UK;
  • Dr. Gerardo Morfini at the University of Illinois, Chicago;
  • Dr. Joanna Bakowska at Loyola University, Chicago; and 
  • Dr. Michael Hanna at the Texas A&M University, Commerce.
Of course, its difficult to abbreviate a 13 page document into a single blog post, but here we go - I've lifted various paragraphs from the document here:

Researchers working on hereditary spastic paraplegia, better known as HSP, know more today than ever before. They are uncovering new linkages between the proteins that are at the heart of the disorder all the time. If you rewind the clock just five years, almost nothing was known about the proteins involved in HSP, how they interacted, what they did or why they did it. Since then much has been learned. If you go back 10 years, some of the proteins involved where just being uncovered. Go back 15 and HSP was almost a complete mystery.

One of things that HSP has going for it from a treatment point of view is the proteins like atlastin are fundamental to how cells work. Because of this, cell biologists are becoming increasingly interested in studying them so they can increase their knowledge of basic biology. This greatly expands the base of very smart people exploring what these proteins do and how they do it. For a very rare disease like HSP, this is like hitting a walk-off homerun because it opens the door to unlooked-for-discoveries by researchers outside of the HSP field that could lead to significant breakthroughs in how HSP is understood and treated.

Researchers are finding more and more targets - functions like axonal transport and structures called microtubules, for example - to focus on for potential treatments.  To find a 'wonder drug', you might think that money is the end all, but perhaps the biggest inhibitor to finding a treatment is lack of good animal models.

While HSP-like symptoms can be created in mice, for example, the phenotype that mice exhibit is less severe than in people and, therefore, harder to measure. Also, mice are just a few inches from head to tail while the cells involved in human HSP are up to a meter long. Mice also take a long time to mature. So when you work with mice, it can take up to a year or more for symptoms to show. 

That is why researchers often turn to fruit flies, which share the majority of their genes with humans (they just have fewer variations of them) and they reproduce very quickly so you can see results much sooner. But, fruit flies are not people. They can point you in the right direction; give you an idea of what to look for or what questions to ask but they won't serve as a stand in for us. 

Researchers like Dr. Morfini also work with squid since their axons can be removed, viewed under a microscope, and react to HSP similarly to our own. Squid have long been used to study other central nervous system (CNS) diseases like ALS and Parkinson's so a lot is known about their basic structure. 

This makes squid an important source of information since 99 percent of a motor neuron cell is actually made up of its axon. So axonal transport, or the movement of molecules and proteins up and down the long thin tube that is the axon, is also considered by many in the field to be an good place to look for a cause of HSP. Any disruption of this very finely tuned architecture could result in disease.

HSP could be a a "Gateway Disease," a disease that leads to treatments and cures for some of today's most intractable illnesses. There are  conditions like Charcot Marie Tooth Type 2b and some neuropathies (a loss of sensation in the feet and hands that can lead to amputations) that involve the same proteins as HSP and yet, on the outside, look completely different. This is the type of thing that gets researchers from other fields interested because there must be something very fundamental going on.

ALS and its cousin primary lateral sclerosis (PLS) also have something in common with HSP because of proteins. So, at some point in the future, a researcher in one of these fields or an HSP researcher could uncover a strong bond that could lead to a treatment for both. Multiple sclerosis (MS) is another disease where there appears to be some overlap but all of these connection need to be explored much more deeply.

Current research highlights:
Bone Morphogenic Protein (BMP) signaling

One of the more promising areas of research is being pursued by Dr. Reid at the University of Cambridge. He and his team are looking at something called the BMP signaling. While BMP stands for bone morphogenic protein, what's really important is it appears that atlastin (SPG3A), spastin (SPG4), maspardin (SPG21), spartin (SPG20), and NIPA1 (SPG6) are all part of the same functional pathway within the motor neuron. 

BMP signaling appears to play a key role in how axons grow and what they look like as they branch out into synapses. It is this distal end of the axon, the one at the base of the spine, that connects the neurons in your motor cortex to your legs. If BMP signaling causes HSP's symptoms, then you have a target to go after with drugs. Dr. Reid strongly believes this could be the case but more research needs to be done; particularly in animals; especially in mammals.

Endoplasmic Reticulum (ER)

Dr. Blackstone's work has led to the realization that spastin, atlastin, REEP1, reticulon2 and possibly NIPA1 are all involved in shaping a very important organelle inside the cell called endoplasmic reticulum (ER). And this is extremely important from a cell biology point of view because the ER sits at the heart of cell function and is believed to run the length of the axon.

Indeed, before the discovery of atlastin, no one really understood why the ER looked the way it did. Now, HSP has opened a window into this most essential part of the cell. A gateway, if you will, to this and many other areas of cellular function that are now better understood because of HSP.

Casein kinase  2 (CK2)

Working together, the research teams of Dr. Morfini and Dr. Peter Baas at Drexel University in Philadelphia have found a potential target for a treatment of SPG4, spastin. Like Dr. Reid, their findings are preliminary but, if they pan out, they might provide a new framework for the development of treatments that may help prevent motor neuron degeneration in HSP. 

Their findings indicate that the protein kinase CK2, which regulates the activity of other proteins, is abnormally activated by mutant forms of spastin. Abnormally activated CK2, in turn, negatively affects yet other proteins that are involved in the movement of materials along the axons in an important cellular process referred to as “axonal transport”

Like many other protein kinases, CK2 is a drugable target. What's exciting about Drs. Morfini's and Baas’s work is that CK2 has been studied for decades, so it is very well understood and there are currently cancer drugs in Phase I of the FDA approval process today to regulate it.

Thursday, 5 July 2012

Another new arrival - and cord blood storage

An update - a couple of weeks ago my wife gave birth to our second son. Double trouble in a few years, I'm sure!

We repeated the decision that we took for our first son, and decided to get the cord blood stored again. As a reminder for the first decision:

One of the things which the genetics team said back at the beginning was that if we had two children, one with and one without the condition, then (provided there was a treatment available) the stem cells of the one without may be more of use to the one with. This info now becomes relevant.

In case anyone is interested, we used cells 4 life The process was much easier this time as they now offer a phlebotomy service too. If anyone is thinking of doing this, then as a referral from an existing customer gets you (and me) a £50 Marks and Spencer voucher. Drop me a line....

Naturally, the HSP angle is still in the blue sky thinking zone, but there may be other uses for these as we go. Only the passing of the years will tell.