Researchers at the University of Delaware have discovered a novel technique - that acts like a "spell-checker" for correcting a misspelling in the DNA code - to repair the defective gene that causes spinal muscular atrophy (SMA).
This hereditary neuromuscular disease is the number-one genetic killer of children under two years old.
Babies born with Type 1 SMA, the most severe form of the disease, can't walk, crawl, sit unsupported, lift their heads, or breathe normally. Fifty percent die before their second birthday.
The research is published in the Jan. 14 online edition of Experimental Cell Research. The study was supported by $477,500 in National Tobacco Settlement funds to the state of Delaware. The research grant was awarded through the Delaware Health Fund.
“Think of it like a spell-check program--we're erasing the wrong letter in the DNA code and putting the right one in,” said Eric Kmiec, professor of biological sciences at UD.
Kmiec, who holds 14 patents for gene-editing technologies at the University, collaborated with research scientist Darlise DiMatteo and undergraduate Stephanie Callahan on the discovery in his laboratory at the Delaware Biotechnology Institute.
The technique has shown promising results in tests in mice and is now poised for development by OrphageniX Inc., based in Wilmington, Del. The start-up company was incorporated in 2005 to commercialize UD-patented technologies for repairing genes that cause rare, hereditary, “orphan” diseases, so named because they have not been “adopted” by the pharmaceutical industry for the development of treatments.
According to the Families of Spinal Muscular Atrophy, an international, nonprofit organization, the disease affects one in 6,000 babies born, and one in 40 people is a genetic carrier.
A genetic 'bandage'
Spinal muscular atrophy is caused by a mutation in the SMN1 gene, which affects the motor neurons, the nerve cells in the spinal cord that control the muscles of the rib cage and limbs, which are essential for breathing, swallowing, sitting and walking.
Each gene is made up of a length of DNA, a code composed of the four chemical units that make up the genetic alphabet: A for adenine, G for guanine, C for cytosine and T for thymine.
In spinal muscular atrophy, a defect occurs in the SMN1 gene. There's a letter out of place--a T (thymine) occurs where there should be a C (cytosine). As a result, the gene doesn't make a protein that the motor nerves in the spinal cord need to survive, which leads to the gradual atrophy, or wasting, of the muscles.
To replace the function of the defective SMN1 gene, the UD research team used a gene in the human body that is nearly an exact copy (SMN2). Then they introduced a small fragment of this healthy gene's DNA--a genetic “bandage” referred to as an oligonucleotide--into a diseased cell, triggering the cell to heal itself.
Tests of the technique in mice with spinal muscular atrophy, conducted by Jackson Laboratory in Bar Harbor, Maine, showed “very promising results” with the development of healthy muscle in the animals, Kmiec said.
“Babies with SMA die early in life,” Kmiec noted. “But if we can deliver the healing agent to the appropriate cell, we can help address this horrible disease. We're not looking at a cure, but we hope this technique could lead to a series of treatments that could alleviate the symptoms and improve the quality of life of patients,” Kmiec said.
The technique, known as targeted gene alteration (TGA), is among a group of UD-patented technologies under development by OrphageniX, a pre-clinical development stage biotechnology company that has moved quickly out of the starting gate since its launch in February 2007.
“OrphageniX plans to develop a treatment for spinal muscular atrophy with help from expert consultants in the field,” Michael Herr, chief executive officer, said.
The development of a treatment for SMA would advance to clinical testing within a year from funding by either investors or commercial collaborators, Herr noted.
Patients with the less severe, Type III form of spinal muscular atrophy would be targeted for initial human trials. Although individuals with Type III SMA suffer from a range of muscle weakness and fatigue quickly, the disease generally is not life-threatening at this stage.
Herr said that OrphageniX is committed to helping people by commercializing scientific breakthroughs, but he noted that, “we must also provide an adequate return to investors for OrphageniX to succeed.”
Truly translational research
For his latest research to be truly “translational,” extending from the lab bench to the bedside, Kmiec said it has been critical to involve people like Darlise DiMatteo, who have a keen understanding of spinal muscular atrophy.
DiMatteo, who joined Kmiec's research team a year ago, formerly worked at Nemours Alfred I. duPont Hospital for Children, where she conducted research studies of muscular dystrophy and SMA for more than a decade. The world-renowned children's hospital continues to be an important partner on the project, Kmiec said.