Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's Disease in the U.S., is a devastating degenerative disease of the central nervous system, in which motor neurons die. Motor neurons are the nerve cells that innervate peripheral muscles and control our movements. Like most other nerve cells, motor neurons are not known to retain the potential to divide and replenish in the mature brain. They may die because of high oxidative stress and programmed cell death known as apoptosis. High oxidative stress results from an increase in free radicals. Free radicals are highly-reactive oxidative chemicals that can fatally damage the cell. On the other hand, apoptosis is a self-destruction mechanism of the cell that is triggered when the concentration of the excitatory neurotransmitter glutamate reaches abnormally high levels in the extracellular space. Therefore, therapies that lower free radicals and block the action of glutamate may offer benefits in the treatment of ALS.
Still we do not understand why the oxidative stress increases for motor neurons in ALS and why the extracellular glutamate reaches apoptotic levels. The motor neurons constitute the only nerve cells that reside inside the central nervous system, but make direct contact with cells outside. Perhaps, their endings pick up extrinsic molecules that increase their vulnerability in conjunction with a genetic predisposition.
Patient advocacy groups have recently petitioned the U.S. Food and Drug Agency to allow the compassionate use of Iplex developed by INSMED Inc. in terminally ill ALS patients. Amy Harmon reports the story of one family involved in her post for The New York Times published May 16, 2009. Iplex (mecasermin rinfabate) is a product of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) and has been used in th past to stimulate disrupted body growth in children. IGF-1 is known to promote proliferation and stifle apoptosis in cancer cells (Yu and Rohan, 2000). IGFBP-3 regulates IGF-1 action. Notably, it counteracts the growth factor's suppression of apoptosis. The protein may also inhibit tumor growth and stimulate apoptosis independent from IGF-1. Recent experience in Italy suggests that Iplex improves the condition of patients with ALS. How the drug interacts with motor neuron cell death is unclear at this point. Perhaps, the sum of its opposing effects slows the death of motor neurons. A lot more research needs to be done.
It is difficult to judge the wisdom of opting for such treatment, when the cause of the disease is entirely unknown. Faced with profound uncertainty, we are only left with hope.
- According to Esha Dey's post on Reuters dated Jun. 25, 2009, phase II clinical trials showed that Iplex failed to significantly improve the condition of patients with myotonic muscular dystrophy (MMD). An Insmed press release specifies that 69 patients were treated over 6 months in a randomized, double-blind, placebo-controlled study. MMD is recognized as a genetic disorder. In contrast to ALS, the modified genes affect muscle cell function (07/24/09).
- Learn about ALS from people who live with it. The acounts were recorded for The New York Times series "Patient Voices: A.L.S.", produced by Karen Barrow and published Oct. 19 (10/10/23).
- A recent study of Kaspar and others (2005) supports the contention above that IGF-1 may facilitate nerve cell survival in ALS. The researchers showed in a transgenic mouse model for ALS that physical exercise or delivery to the central nervous system of the gene for IGF-1 slowed the progression of the disease. Both treatments combined had a synergistic effect on function and survival (10/25/09).
- As of Jul. 29, 2009, Insmed has put clinical trials with Iplex on hold. The drug has been unavailable to new patients since then. The company ascertains that current supplies will suffice to maintain the treatment of patients who were already enrolled in ongoing trials for another two years. No new decisions have been announced to date (12/22/09).
- The route of administration may be crucial to the effectiveness of Iplex in the treatment of ALS. A recent study with 330 ALS patients showed that subcutaneous injection of IGF-1, the main component of Iplex, did not statistically significantly improve the condition of the participants (Sorensen and others, 2008) compared with participants administered a placebo. A compound must cross the blood-brain barrier to affect motor nerve cells. Perhaps, too little IGF-1 reached the motor nerve cells to initiate a detectable effect. However, other routes of drug delivery may be more efficacious than subcutaneous injections. For example, rabies viruses are neurotropic. That is, the virus is taken up by the endings of motor nerve cells, transported into their cell bodies and further retrogradely into the nerve cells innervating the motor nerve cells. In the process of the disease, the virus multiplies in the nerve cell bodies, causing severe encephalitis and, ultimately, death. Because of its retrograde transport, rabies virus is used in animals to examine nerve cell circuitry (Taber and others, 2005). It is conceivable that deactivated forms of the virus can be used as vehicle to shuttle drugs like Iplex into the central nervous system. Herpes simplex viruses possess similar neurotropic properties and may constitute another option (03/19/10).
- Yesterday, NPR's Talk of the Nation (Science Friday) broadcast a segment on recent advances in stem cell research entitled "Stem Cell Research Update". New studies are discussed that provide evidence that glia cells derived from human stem cells implanted into rats after spinal cord injury help functional recovery (Sharp and others, 2010). The senior investigator of the study believes that one day in the near future stem cells can be used to replace nerve cells lost in neurodegenerative diseases. The therapy may be promising with diseases in which the causes are well understood. By contrast, the cause for motor neuron cell death in ALS is completely unknown. Hence, replacing them with new ones derived from stem cells may be short-lived (05/22/10).
- If you are considering stem cell therapy, you may find the information on the International Society for Stem Cell Research site helpful (07/26/10).
- Kaspar BK, Frost LM, Christian L, Umapathi P, Gage FH (2005) Synergy of insulin-like growth factor-1 and exercise in amyotrophic lateral sclerosis. Ann Neurol 57:649-655.
- Sorenson EJ, Windbank AJ, Mandrekar JN, Bamlet WR, Appel SH, Armon C, Barkhaus PE, Bosch P, Boylan K, David WS, Feldman E, Glass J, Gutmann L, Katz J, King W, Luciano CA, McCluskey LF, Nash S, Newman DS, Pascuzzi RM, Pioro E, Sams LJ, Scelsa S, Simpson EP, Subramony SH, Tiryaki E, Thornton CA (2008) Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurol 71:1770-1775.
- Sharp J, Frame J, Siegenthaler M, Nistor G, Keirstead HS (2010) Human embryonic stem cell-derived oligodendrocyte progenitor cell transplants improve recovery after cervical spinal cord injury. Stem Cells 28: 152-163.
- Taber KH, Strick PL, Hurley, RA (2005) Rabies and the cerebellum: New methods for tracing circuits in the brain. J Neuropsychiatry Clin Neurosci 17:133-139.
- Yu H, Rohan T (2000) Role of the Insulin-Like Growth Factor Family in Cancer Development and Progression. JNCI J Natl Cancer Inst 92:1472-1489.