Seminar: Developing Therapies for motor neuron diseases.

I've been meaning to start this blog for quite some time now. The basic point is that I have too many thoughts; I can end up talking too much and making way too many tangent conversations.
I've created this blog for me to summarize certain seminars I attend, papers I read and just blab about my work/things that interest me. Not only will I be able to clear my mind but I am hoping some will read this and have questions/answer my questions/comment.

Disclaimer:: I do not think I have any literary abilities. Please do not focus on my writing capabilities or grammatical errors.

Here it goes:

Today I attended a talk hosted by the Motor Neuron Center at Columbia University Medical Center. The speaker was Brian Kaspar from Ohio State University, he presented a short talk on his lab's work on Gene therapeutics targeting SMA and ALS.
He began the talk introducing the general problems with targeting diseases in the CNS; the blood brain barrier, diversity of cell types, magnitude of the amount of cells from the Brain reaching down throughout the spinal cord, etc. Kaspar then introduced Adeno-associated viral vectors (AAV). AAV is a virus naturally found in humans and nonhuman primates, it has no known pathological responses and can integrate into post-mitotic cells. Once infected in cells it integrates it's genomic information stably for long term trans gene expression (on Chromosome 19). With these attributes it sounds like an awesome vehicle to use when searching for ways to deliver gene therapies to various live systems. Currently there are clinical trials ongoing for Cystic fibrosis and Parkinson's disease.
The trick is figuring out which family member of the virus to use, how to administer it, when to administer it and what are the effects of the trans gene expression. For example, some familial genetic disorders present themselves because of a lack of a certain gene's expression (therefore, lack of a certain protein). Some gene therapies have a long list of issues in clinical trials because of the body's natural immune response to a protein it has never 'seen' before - even if that protein can rescue the disease over time - one would still need to battle the immune system to allow it. In light of this issue, another problem occurs = lack of focus on efficacy. FDA clinical trials usually focus on the safety of the treatment but not the efficiency to alleviate the disease. Moving on...
The lab initially started testing AAV6-GFP (green fluorescent protein) and AAV8-GFP through tail vein injection but had no success in penetrating the blood brain barrier to the CNS. However, when they tested AAV9 they were very successful in finding GFP expression in a robust amount of astrocytes all over the nervous system and some neurons. Astrocytes are mainly born a few days postnatal. With this in mind they tried to target mostly neurons by injecting intravenously through a facial vein visible postnatal 1 and 2 (tails are too small then). The result was great GFP expression in the dorsal root ganglia and motor neurons throughout the spinal cord and various neurons in the brain (neocortex, hippocampus, cerebellum).
Both scenarios present possible good routes for therapies against either SMA (neonatal injection) and ALS (adult tail injection). SMA is luckily known to be attributed to a loss in the SMN1 gene expression. Therefore, animals affected by SMA have at some point 'seen' smn1 protein physiologically speaking. Using an SMA mouse model, they tested the ability of AVV9-SMN1 treatment to rescue the disease phenotype. In short, they were successful in finding that the treated SMA mice compared to untreated SMA controls were able to become stronger and eventually live normal mouse life spans (tested through muscle growth, behavior, electrophysiology, and life span). However, SMA semi-adult mice (they only live about 15 days) past neonatal do not response similarly to the treatment, as the mice age the AAV starts targeting mainly astrocytes and less neuronal populations which ends up not rescuing the illness.
The Kaspar lab is now testing this gene therapy on non-human primates and having great success. They plan to move forward with human clinical trials.
They are also doing a lot of work on ALS, but I'm tired of writing about it for now. Need to do some image analysis.

Very exciting stuff in terms of possible treatment options.

Here is a link to their recent paper about AAV9 injections: http://www.nature.com/nbt/journal/v27/n1/abs/nbt.1515.html