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May 06, 2008
Looking for Magic in a Bottle
New Directions in Biology of Skeletal Muscle Conference
New Orleans April 27-30
I have been concentrating on Reauthorization of the MD-CARE Act, actually forgetting about the New Directions in Biology and Disease meeting in New Orleans. The Reauthorization is moving, though it is now important to go back to our champions in the House and Senate to thank them for their help and solicit advice to accelerate the process. To date, we have been meeting with more than 50 members of Congress Health LA (legislative assistants), members of the House Energy and Congress Committee (Committee of Jurisdiction), and Senate HELP committee.
Anyway, April is always a difficult month for me, bittersweet, filled with tears and joy all mixed together. Jenny’s birthday is April 11, she is 34. Chris’s birthday is April 14. He should be celebrating # 30. My mother-in-law died on April 18. Jenny is engaged as of April 26 to Kris Johnson, and we are all thrilled. Michelle’s birthday is April 27, she is 32. Michelle spent her birthday in Singapore in meetings. The April graph of joy and sorrow feels a bit like a trampoline.
The New Orleans Conference was amazing. It was a bit overwhelming to see and hear the collective brainpower in that room. The complexity of the muscular dystrophies is fascinating from a research perspective and heartbreaking at the other end, as we (parents/families/friends) observe the effect on muscle and function.
PPMD has supported this conference from its inception six years ago. This is the third New Directions conference. It is an outgrowth of the MD-CARE Act and perhaps the most significant conference on skeletal muscle biology in the world. In a certain sense, it is a temperature gauge, marking where we are at this place in time, identifying specific areas of promise, and the discovery of new pathways and new opportunities for research, drug development, and clinical trials on the horizon. It lays out a path of where we are going, what trials are on the forefront, what obstacles we need to think about as we move forward, and describes, in exquisite detail, the field of muscle research that is rapidly moving forward. It is designed to lay out potential treatments – that ‘magic in a bottle’, the small molecule or drug or chemistry that will assure us there is an end to the progression of Duchenne.
This conference is research driven, a bit different from the PPMD Annual Conference in that the discussions are highly scientific, discussing pathways and molecular structures, and always serves to remind me how intricate the human body is and how amazing that it works.
This year, the conference covered:
o Micro RNAs and their interaction – a perfectly synchronized orchestra of interactions and connections.
o Gene expression – the ability to understand what genes are over- or under-expressed in Duchenne and across disease states.
o How different genes expressed, up- or down-regulated and what we can learn from looking at a specific disease, as well as, looking across a spectrum of diseases.
I am enamored by the sheer brainpower of the room, the commitment, the dedication, the willingness to discuss and debate openly and honestly a given approach and how they might see this moving in the future.
In review –
1. Roles of Dystrophin:
Mechanical – transmit force from the contractile apparatus to the connective tissue/tendon.
Organizer – positions a number of proteins at the muscle membrane (nNos, ion channels, etc).
Signaling – plays a number of signaling roles, including a key role in calcium homeostasis.
2. Why is the muscle damaged when dystrophin is missing? Disruption of Calcium Homeostasis – Contractions (especially eccentric contractions such as walking up stairs, etc) cause the rupture of the muscle membrane which allows calcium inflow. There may also be increased flux through ion channels. Excessive calcium activates breakdown of muscle (via calpain and other proteases) and may trigger a cell death program. Cell death triggers an inflammatory response. Activation of the fibroblasts can lead to fibrosis which interferes with muscle regeneration.
3. What are the current recommended therapies in Duchenne? Steroids (Prednisone/Deflazacort), Idebenone*, Ace Inhibitors, and Beta Blockers.
*CoQ10 is not easily absorbed. Think of Idebenone as a second generation compound – better absorbed and more stable than CoQ10 with equal protection of the heart.
4. What is on the near horizon? Drugs that cause read-through of a nonsense codon (PTC124); chemistries that alter RNA splicing (Antisense oligonucleoties – AON or Exon skipping); therapeutic trials with protease inhibitors; drugs that decrease fibrosis; drugs to promote muscle repair and decrease damage; and drugs/biologicals that will increase the amount of Utrophin.
Drug Development with validated targets – Utrophin, Myostatin inhibition, IGF-1, Integrin, Serca 2A (cardiac specific), and potentially additional targets such as Sarcospan.
5. Anything else?
o RNA manipulation
o Viral directed exon skipping (U7-snRNA)
o Gene Replacement Therapy
o Stem Cells
o Mesantgioblasts
o Mesenchymal stem cells
o Bone Marrow derived (SP cells**)
o Muscle derived (SP cells**)
**SP cells arise from somites – transient blocks of tissue in the embryo that give rise to muscle, vertebrae, and the inner layer of skin cells called the dermis.
o Barriers to stem cell therapy involve delivery, cell fate, and expansion of the cells without losing their potential. Delivery of stem cells to every muscle of the body is a daunting task and one that has not been overcome in any animal model.
o Cell fate – Since environment instructs the cells, there is a question about the timing of the therapy. Will the therapy only work in early disease and what will the fate of cells that end up in tissue that is not muscle? Also, growing (expanding) sufficient stem cells and insuring that the cells will not lose their potential for rescue/regeneration remains a critical factor.
o Viral delivery of a truncated (micro/mini) dystrophin
o AAV/micro dystrophin or micro utrophin
o AAV/α-sarcoglycan
o AAV/γ-sarcoglycan
Barriers are coming down with regard to production of sufficient AAV, though other issues remain. They include the possibility of an immune response to the virus (viral vector) and clinical protocols will need to include immune suppression protocols. There is expressed concern about systemic delivery and the need to utilize muscle specific promoters to increase safety.
Finally, it is important to determine the functionality of micro dystrophins or micro utrophin in order to deliver the most efficient/functional protein as we approach viral mediated therapies.
Posted by ppmd at May 6, 2008 05:16 PM