Combination therapy as the best approach for damaged spinal cords BY ANNA GRIFFITH :
Ever since the 1940s, when researchers discovered that nerves of the spinal column can grow, scientists have tried to devise ways to coax the cells to overcome damaged areas and thereby defeat paralysis, organ degeneration and other problems associated with injury to the central nervous system. Removing scar tissue with drugs, laying down scaffolds and inserting cells have all been tried with varying degrees of success. Recent achievements, such as the restoration of some ability to walk in rodents, and other findings indicate that rather than a single approach, all may be the key. “A combination of drugs and cells gives better results than just any one of the components on their own,” says Naomi Kleitman, a program director at the Nat ional Institutes of Health’s National Institute of Neurological Disorders and Stroke.
Injury to nerves produces inflammation, ion imbalance, scar tissue and cysts filled with cerebrospinal fluid, which damage additional neurons and create a barrier against neuron growth. A lesion just one millimeter wide can increase to five to 10 millimeters, too large a gap for neurons to bridge. Surviving neurons often lose myelin, the insulation needed for reliable and quick signal transmission. About 200,000 people in the U. S. live with spinal cord injury.
Several compounds now in phase 1 clinical testing may counteract growth-blocking elements. Bio Axone Therapeutic in Quebec found that 30 percent of patients improved after receiving Cethrin, a drug thought to counteract inhibition.
Novartis has ATI-355, an antibody against the inhibitory protein NOGO. Researchers have shown in preclinical tests that an enzyme isolated from bacteria, chondroitinase, dissolves scar tissue.
Besides removing inhibition, scientists are promoting the growth of new neurons. Until five years ago, they could not control the fate of stem cells. Now, using proteins and other chemicals that guide nervous system development and trigger cell differentiation, such as retinoic acid and sonic hedgehog protein, they can direct stem cells to secrete growth factors or to become essential neural components: spinal motor neurons for treating paralysis, myelin-producing oligodendrocytes for multiple sclerosis, or dopamine-producing cells for Parkinson’s. Pending safety studies, Geron, a biotechnology company in Menlo Park, Calif., plans to file for FDA approval of human stem cell trials later this year. “Perhaps stem cells are the breakthrough we’re looking for,” says nerve regeneration pioneer Lloyd Guth, who retired from the University of California, Irvine, and now lives in Williamsburg, Va.
The final “connector” could be biological scaffolding. These structures would orchestrate the actions of various cells and growth factors while creating a physical bridge for the exquisitely complex and precise process of regenerating the central nervous system. Samuel Stupp, director of the Institute for Bio-Nanotechnology in Medicine at North- western University, has designed peptides that self-assemble into nano fibers many thousandths the size of a human hair. The prevalence of a specific sequence of amino acids, dubbed IKVAV (for isoleucine, lysine, valine, alanine and valine), on the outer surfaces of the scaffold promotes neuron growth.
In rats, the scaffold trapped stem cells, signaled them to replicate and guided their differentiation into neurons while suppressing the formation of scar-forming glial cells. Scientists at the Massachusetts Institute of Technology and Hong Kong University used a similar peptide scaffolding to restore vision to surgically blinded hamsters. Such therapies may also be adapted to treat stroke and neurodegenerative disorders.
Research by neurologist Douglas Kerr of Johns Hopkins University shows the benefit of combining treatments. His team used stem cells, drugs to remove scar tissue, and a combination of growth factors and signaling cues to re-create an environment reminiscent of early nervous system development. Animals receiving treatments missing just one component of the cocktail showed no sign of recovery. Kerr and his colleagues are testing human embryonic stem cells in pigs and will continue doing so for several years before seeking approval for human trials. Combined treatment studies “are the most important of them all,” Guth says, and worth the effort to determine precise dosage, timing and combination of drugs to avoid harmful interactions.
There is still a long way to go. Many studies have restored paralyzed rats’ ability to walk, but Guth notes that rats (and cats) can walk nicely with just 5 to 10 percent of their spinal cord intact. And if the spinal cord is severed early in life, before inhibitory connections are made, the animals retain the simple reflex of walking. They can walk even though they lack substantial input from the brain—“like a chicken with its head cut off,” Guth says, a feat he doubts humans could replicate.
Motor and sensory pathways may need their own treatments. Besides requiring different growth factors, motor fibers may just need to regrow far enough to connect with a neural network within the spinal cord responsible for walking reflexes, whereas sensory fibers may need to travel all the way to the brain, Kleitman notes.
Clinical treatment should proceed with caution. Natural growth inhibition after injury occurs to protect against harmful rewiring, and patients in a few clinical studies now have pain because regenerating neurons grew the wrong way. Predicting a cure for paralysis is unfair to the public, Guth says: “A breakthrough, by definition, is an unanticipated event; however, because of the recent tremendous activity in the field, we have to be optimistic that a breakthrough will happen.”