New Treatment Promotes Nerve Regeneration and Sensory Function in Some CMT Patients
JD Griffith, MS
October, 2003, American Neurological Association Meeting, San Francisco -A small study, presented by Dr. Zarife Sahenk, of Ohio State University, shows promise for Charcot-Marie-Tooth Disease (CMT). The pilot trial of genetically engineered human neurotrophin-3 (NT-3), a nerve growth factor being developed by Regeneron Pharmaceuticals, Inc., yielded statistically significant clinical improvements in neuropathy impairment and demonstrated nerve regeneration in the four patients treated with Charcot Marie-Tooth Disease, Type 1A (CMT-1A). "NT-3 is the first clinically significant treatment for Charcot-Marie-Tooth Disease," Dr. Sahenk's group concluded, "and may also benefit patients with other inherited neuropathies."
In an interview with Neurology Today, Dr Sahenk, elaborated: "Results from this pilot study need to be substantiated with a large, multi-center clinical trial." "But," she added, "the take-home message for the clinical neurologist is that hereditary neuropathies, traditionally considered a black hole without any avenues for treatment, deserve further clinical research efforts." Dr. Sahenk also implied that although the trial only involved patients with CMT-1A, the treatment may be useful for other types of CMT and neuropathies in general.
The eight patients in this pilot study tested DNA positive for CMT-1A, the most common type of CMT.
Charcot-Marie-Tooth Disease is subdivided into CMT type-1 (defects in the myelin sheath that surrounds the axon or nerve cell) and CMT type-2 (degeneration of the axon or nerve cell itself) (Dyke PJ, Lambert, EH, Arch Neurol 1968 18:603-18).
Most CMT-1A is caused by an extra copy of gene on chromosome 17, of the gene that codes for peripheral myelin protein 22 (PMP22). In nerves outside the brain and spinal chord, the myelin sheath is formed by Schwann cell membranes, which wrap in concentric layers around the nerve cell. Because of the duplication of the PMP22 gene (3 copies of the gene instead of 2), an excess of PMP22 is produced in the Schwann cells, which disrupts the normal formation and compaction of myelin, the fatty substance that surrounds nerve cells, and dramatically increases the speed of impulse conduction. Problems with the myelin sheath, an electrical insulator, can result in a slowing of nerve conduction velocity (the speed the nerve impulse travels along the nerve). Nerve conduction velocity (NCV) is one of the characteristics that differentiate demyelinating, CMT type 1(slowed NCV) from axonal, CMT type 2 (normal or near normal NVC (Dyke PJ et al 1968). The CMT clinical symptoms of muscle atrophy (wasting) and loss of sensation are the result of length-dependent degeneration of the nerve cell itself, not from slow nerve conduction (Sahenk Z, 1999, Shy et al., 2000).
Neurotrophins May Help Patients and Other Diseases
Neurotrophin-3 is a neurotrophin (from the Greek trophe-nourishment), a family of short amino acids chains (small proteins), which support neuronal development, survival and plasticity in the developing and adult brain and peripheral nervous system. Neurotrophins are secreted by their targets (muscles, other neurons or other structures) and are detected by specific receptors on the membranes of nerve cells. NT-3 is essential for the formation and viability of Schwann cells, which form the myelin sheath surrounding neurons in the peripheral nervous system. The first neurotrophin studied, nerve growth factor (NGF), was discovered in the early 1950s by Rita Levi-Montalcini and Stanley Cohen, who were awarded 1986 Nobel Price in Physiology and Medicine for their work. Other members of the neurotrophin family have since been discovered; including brain-derived neurotrophic factor (BDNF), neurotrophin- 3 (NT-3) neurotrophin 4 (NT-4/5) and glial cell derived neurotrophin factor (GDNF).
Neurotrophins' ability to stimulate neuron growth and support the survival of adult nerve cells has made them a major target for drug development. Early optimism for neurotrophins as a miracle cure for a range of disease has waned, but the potential for therapeutic use is still exciting. Neurotrophins are currently being investigated as potential therapies for wide variety of conditions, including CMT, ALS (Lou Gehrig's Disease), Alzheimer Disease, Parkinson's Disease, Huntington's Disease, Bi-polar Disorder and neuropathic pain.
Treatment vs. Placebo
The study enrolled eight patients with CMT-1A and randomly selected four patients to receive the NT-3, and four patients to receive the placebo. The study was double blind; neither the investigator nor the patient knew who received NT-3 or the placebo. The patients injected themselves with NT-3 or the placebo three times per week for six weeks and the results were evaluated.
- Using the Mayo Clinic Neuropathic Impairment Score (NIS) (Dyke et al. 1980), which summarizes muscle weakness and decreased sensation corrected for age, sex and physical fitness, significant improvements were reported in the NT-3 group in NIS and sensory tests (pin prick, vibration and cold temperature) but not in the placebo group.
- The pegboard test measures a patient's ability to move their arms, hands, fingers and finger dexterity by counting the number of pegs that can be inserted into a board in specified time. Pegboard performance significantly worsened in the placebo group, but was unchanged in the NT-3 group.
- Sural nerve biopsy is an invasive procedure used frequently in the past as a diagnostic tool and to distinguish between CMT-1 and CMT-2. It involves the removal of a small piece of the sural nerve, a pure sensory nerve, easily accessible behind the ankle or at the lower part of the leg, for microscopic examination. Now, due to the availability of genetic testing for diagnosis, such nerve biopsies are scarce, which is probably fortunate for the patient but unfortunate for the study of the disease. The nerve fiber regeneration was studied by comparing sural nerve biopsies before and after six months of treatment. The results of the study were impressive with myelinated nerve fiber regeneration in the patients receiving NT-3 but not in the control group. The investigators found a significant increase in small myelinated fibers and more solitary myelinated per square millimeter in the NT-3 group.
The investigators also measured NCV in the patients before and after the study and found no significant change. Dr. Sahenk said this result was not unexpected because partial nerve regeneration would not be expected to significantly improve NCV.
We want to thank Dr. Sahenk and the other investigators for their continued excellent research and much appreciated interest in CMT. The study was supported by The Neuropathy Association and Regeneron Pharmaceuticals, Inc.