A report on drug development in neuromuscular diseases as of January 2009
In the era of molecular biology, the drug development process has moved from a “let’s try it and see what happens” approach to a scientifically based process of discovery and application.
For many of the diseases in MDA’s program, drug discovery begins with gene discovery — identifying a gene that, when flawed, causes a disease.
Composed of chemicals called nucleotides, which form DNA, a gene is the instruction manual for a cell’s manufacture of a specific protein. If something goes wrong in the instructions, the protein is either not made or is made in such a way that it performs poorly or has harmful effects.
Gene discovery may lead to attempts at gene replacement therapy. But genes also allow scientists to break the code of a disease, which may lead them to other treatment strategies.
The drug development process
Potential therapies start out in “preclinical” development, meaning experiments in test tubes and animals before they move into human testing.
The U.S. Food and Drug Administration requires extensive preclinical studies in the laboratory, including in animal models of the disease to be treated, to eliminate experimental compounds that have obvious toxicities before they’re used in humans.
Human testing of experimental drugs is a three-part process: Phase 1 studies generally are small and designed only to test safety and tolerability, sometimes in healthy volunteers. Phase 2 trials involve larger numbers of participants and analyze preliminary efficacy of the compound against the disease being treated. Phase 3 studies are larger still and are undertaken to further establish efficacy, evaluate unwanted or unexpected effects and determine optimal dosage levels.
The stem cell option
Replacing failing nerve and muscle cells remains an attractive option for many neuromuscular diseases, although there are significant barriers to cell transplantation. Using a person’s own cells means the genetic flaw in them has to first be corrected. Using donated healthy cells means the immune system has to be subdued so it doesn’t reject them.
Scientists hope understanding the fundamentals of nerve- and muscle-cell development eventually will lead to the identification and laboratory replication of cells that are sufficiently immature (“stemlike”) to integrate into existing tissue without alerting the immune system, but also mature enough to develop into the type of tissue into which they have integrated.
Spinal muscular atrophy
Perhaps nowhere has a gene discovery been more useful in treatment development than in spinal muscular atrophy (SMA).
In the 1990s, the identification of mutations in a chromosome-5 gene that became known as SMN1 were identified as the primary cause of the disease. But at about the same time, the existence of a neighboring gene, ultimately called SMN2, was identified as nearly the same as SMN1 and able to partially compensate for flawed or missing SMN1 genes. Scientists also learned that people have varying numbers of SMN2 genes, and that, in general, the more SMN2 genes people with SMA possess, the better their motor function is.
While delivering SMN1 genes to nerve cells has been considered as a treatment strategy in SMA, an attractive alternative for researchers has been to try to augment or change the output of SMN protein from SMA patients’ existing SMN2 genes. Many different strategies are under way toward this goal.
In addition, it may be possible to deliver genes that code for proteins that protect nerve cells even if they don’t replace the SMN protein.
The gene that, when flawed, causes Friedreich’s ataxia, was identified in the 1990s, and the protein made from its DNA was dubbed frataxin.
It soon became clear that, without frataxin, iron builds up in the mitochondria, the microscopic energy factories inside cells. Ultimately, it disables these structures and kills nerve cells.
Those findings led to strategies such as coenzyme Q10 and idebenone, which help mitochondria withstand the iron overload; iron-binding compounds, to reduce mitochondrial iron levels; and approaches to increase frataxin production from flawed genes.
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Duchenne/Becker muscular dystrophies
They soon learned the dystrophin protein is located near the membrane that surrounds each muscle fiber and that it helps keep the membrane intact. That gave them a whole new range of drug development targets, such as dystrophin substitutes like utrophin and membrane sealants like poloxamer 188.
Understanding how specific genetic errors in the dystrophin gene cause dystrophin deficiency has in recent years led to strategies that cause cells to ignore certain DNA instructions and pay attention to others. Stop codon read-through and exon skipping are two such strategies.