Southwestern Medical Center in Dallas and Joseph Miano at the University of Rochester (N. Y.) led a team that has shed new light on how myocardin turns down the genes that cause a cell to become skeletal muscle and activates those that cause it to become smooth muscle.

The description of a previously unrecognized role for myocardin in repressing the skeletal muscle maturation program has “important implications for understanding the molecular underpinnings” that determine which kind of muscle cell a stem cell will become, the investigators say.

Understanding the forces involved in ensuring that stem cells become the kind of muscle that’s needed will be helpful for development of cell-based therapies for muscle disease. (See “Moving Away From the Blasts of the Past,” page 34.)

HDAC inhibitors quiet
immune response by
boosting regulatory cells

A class of compounds known as histone deacetylase (HDAC) inhibitors, which cause genetic instructions to be interpreted by cells as “open” (ready to be followed as recipes for proteins), can apparently cause an increase in numbers and activity levels of so-called T-regulatory cells, natural quieters of an immune response.

Inducing immunologic tolerance to transplanted cells or proteins from one person to another or quieting an unwanted immune response to one’s own cells and proteins (the root cause of so-called autoimmune diseases) are usually accomplished with drugs that suppress the immune system, sometimes with serious side effects.

But in recent years, it’s become clear that the body has its own mechanisms to control a potentially damaging immune-system response and that some of these can be harnessed by biomedicine to increase the acceptance of transplanted tissues (for instance, in muscle-cell transplantation) and treat autoimmune disease.

Wayne Hancock at Children’s Hospital of Philadelphia and the University of Pennsylvania, coordinated a team of researchers who offer evidence supporting this strategy in an Oct. 7 online publication in Nature Medicine.

Through mouse experiments, the authors show that an HDAC inhibitor such as trichostatin could be beneficial in inflammatory bowel disease and possibly other

autoimmune diseases. (Myositis, myasthenia gravis and Lambert-Eaton syndrome are autoimmune neuromuscular diseases.)

Other experiments in mice, they say, show that treatment with an HDAC inhibitor and the immunosuppressant rapamycin (which spares the T-regulatory cells) might be an attractive strategy for transplant recipients. (Cell and gene transfer strategies to treat genetic neuromuscular diseases pose some of the same immunologic obstacles as do organ transplant procedures.)

The authors say their studies “show important new mechanisms by which HDAC inhibitors can modulate inflammatory and immune responses in vivo [in living organisms] through their effects on naturally occurring T-regulatory cells” and that the findings “constitute an important, previously uncharacterized and therapeutically relevant mechanism of action.”

 

Giovanna Spinella, a consultant to the U.S. National Institutes of Health’s Office of Rare Diseases, and Vitaly Mathyuishenko, from Families of SMA Ukraine, examine the software that the TREAT-NMD database will use.

TREAT-NMD goes global

Some 50 representatives of the Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) communities in Europe, North America, Australia and Japan convened in Montpellier, France, Nov. 7 through 9, to address the need to identify patients with specific gene mutations who may be eligible to participate in forthcoming clinical trials. MDA Medical and Science Editor Margaret Wahl represented MDA.

A major goal of the meeting was to assess obstacles to collecting information about patients in various countries and combining it into a global database under the auspices of TREAT-NMD (Translational Research in Europe — Assessment and Treatment of Neuromuscular Diseases).

SMA groups hear biotech
presentations, plan trials

Representatives of four spinal muscular atrophy (SMA) advocacy groups — MDA, Fight SMA, Families of SMA and the SMA Foundation — met in Bethesda, Md., Sept. 28 and 29 to hear presentations from the National Institute of Neurological Disorders and Stroke (part of the National Institutes of Health, or NIH) and from biotechnology companies and others interested in drug development for SMA.

Sharon Hesterlee, MDA’s vice president of translational research, represented the Association.

The Patient Advisory Group of the International Coordinating Committee for SMA Clinical Trials, under the auspices of NIH, organized the meeting.

Among the presenters were NIH, Tikvah Therapeutics, deCODE Genetics, Paratek Pharmaceuticals, Trophos, MethylGene and PTC Therapeutics.

Most of the drug development research is aimed at increasing production of SMN, the protein needed but deficient in SMA, either by changing the way cells process instructions from a gene known as SMN2, or by increasing the stability of the protein made from the SMN2 gene.

Several candidate compounds were discussed. Among them were analogs (chemical relatives) of indoprofen; sodium phenylbutyrate; quinazoline analogs; tetracycline analogs; TRO19622; and histone deacetylase (HDAC) inhibitors.

Also discussed were the establishment of standardized end points ( measurements of strength and other aspects of the disease) and the development of a large, unified network of institutions for the conduct of SMA clinical trials.

The Patient Advocacy Group also released SMA standard of care guidelines in September. (See Research Updates, November-December.)

This group and the International Coordinating Committee encourage all SMA-affected families to join the International SMA Patient Registry. For details go to www.mda.org, click on Clinical Trials, then select Spinal Muscular Atrophy from the drop-down menu. Or contact Connie Garland at Indiana University at (317) 274-5745 or cjgarlan@iupui.edu. q