Amyotrophic Lateral Sclerosis (ALS) (Lou Gehrig's Disease)
Emerging Medical Therapies
Stem cells, immature cells that can differentiate into specialized adult cells, may represent the next generation of ALS therapy.
However, due to federal restrictions on stem cell therapy as well as the difficulty of designing studies, very few trials have been conducted to date on the treatment of ALS with stem cells. Those that have been conducted, however, are encouraging and early trials show great promise. Researchers have found the following:
- Bone marrow derived “stem-cell transplantation in the motor cortex delays ALS progression and improves quality of life” (Martinez 2009).
- Direct injection of bone marrow derived stem cells into the frontal motor cortex (a brain region) of human ALS patients is generally safe and well tolerated (Martinez 2012).
Researchers have also experimented with the use of stem cells that express beneficial growth factors as a way of comprehensively treating ALS (Suzuki 2008; Lunn 2009). This therapy offers the potential to alter the course of ALS in afflicted patients.
TAR DNA-binding protein 43 (TDP-43) and FUS (fused in sarcoma)
Research has identified the cellular protein TDP-43 as an important factor in the cause of ALS, especially the sporadic forms (Mackenzie 2007). TDP-43 binds DNA and RNA in cells, including motor neurons. Aggregates of TDP-43 are found in the motor neurons of patients with ALS, suggesting that they may contribute to ALS pathogenesis. Identification of TDP-43’s involvement in ALS rapidly fueled a breakthrough discovery of an additional causative mutation in the gene encoding another RNA/DNA binding protein called FUS (fused in sarcoma) (Kwiatkowski 2009; Vance 2009). Because both of these proteins have been implicated in ALS, they may represent a novel pathway by which the motor neurons are damaged. This has also opened up the potential for gene therapy, allowing researchers to try to replace defective genes with functional ones, thus slowing or reversing the loss of motor neurons associated with ALS (Lagier-Tourenne 2009; Hester 2009). Researchers are also searching for ways to inhibit TDP-43 aggregation using chemicals such as methylene blue and latrepirdine (Yamashita 2009).
IGF-1 and Growth Hormone
Insulin-like Growth Factor-1 (IGF-1) is a potent modulator of neuronal growth and function. This neurotrophic factor has the ability to protect neurons both in the central and peripheral nervous system. Researchers have examined the possibility in cell and animal models that IGF-1 could be an effective therapeutic treatment for ALS (Sakowski 2009). Human studies, however, have produced mixed results. Whereas one study found some slowing of the progression of ALS in patients treated with IGF-1 injections (Nagano 2005), others found that subcutaneous (under the skin) injections are not effective in ALS patients (Sorenson 2008). However, the lack of effect with subcutaneous injections could be due to an inability to access the central nervous system. Intraspinal cord delivery has shown promise in animal models (Franz 2009). The use of retroviruses as a potential delivery method for administering IGF-1 to ALS patients has also shown promise (Lepore 2007).
Similarly, growth hormone (GH) may be related to ALS as one trial found that ALS patients had impaired GH secretion compared to healthy controls (Morselli 2006). However, the potential therapeutic value of GH replacement therapy needs further investigation as a recent clinical trial found no improvement in ALS patients receiving GH compared to placebo (Sacca 2012).
- Arimoclomol is an investigational drug that improves the expression of “heat shock proteins”, thereby helping prevent the accumulation of misfolded proteins. Comprehensive in vivo and in vitro studies demonstrated its effect in the prevention of neuronal loss and promotion of motor neuron survival, even after the onset of symptoms. Clinical trials have reported good safety and tolerability (Phukan 2010).
- Ceftriaxone, a commonly used antibiotic, may also be able to treat ALS by improving reuptake of glutamate. When used in an animal model of ALS, ceftriaxone delayed loss of neurons and muscle strength, thus increasing survival (Rothstein 2005).
- Dexpramipexole is under development by Knopp Neurosciences and Biogen Idec as a potential neuroprotective therapy for ALS (Cheah 2010). While it has been shown to be safe and well tolerated (Bozik 2011), more research needs to be done to determine its efficacy.
- Another new medication which is currently being studied in clinical trials is TRO19622 (clinicaltrials.gov 2010). TRO19622 is a cholesterol-like molecule and displays remarkable neuroprotective properties both in vitro and in vivo. TRO19622 is expected to preserve existing neuronal function by delaying or even stopping further progression of the disease. TRO19622 has been granted orphan drug designation status for the treatment of ALS in the USA. This status allows the opportunity to seek ‘fast track’ review by the FDA (Trophos.com 2012).