12 August 2003. Though repairing or replacing dying tissue remains a distant goal for neurodegenerative diseases such as Alzheimer's and amyotrophic lateral sclerosis (ALS), research reported in last Friday's Science and yesterday’s Nature Medicine seems to take us one, albeit small, step towards that elusive goal.
Reporting in Science, Fred Gage and colleagues at The Salk Institute for Biological Studies, La Jolla, and Johns Hopkins University, Baltimore, reveal that they can delay the progression of ALS and prolong life in mouse models by delivering appropriate growth stimuli to neurons in the central nervous system (CNS).
Getting such neurotrophic factors directly into the CNS has proven problematic in the past (see, for example, ARF related news story
on treating Parkinson's disease with GDNF), but first author Brian Kaspar and colleagues used a back-door approach to delivery based on a particularly useful property of adeno-associated viruses (AAVs).
AAVs, it turns out, migrate from the synapses of neuromuscular junctions up through axons and into the neuronal nucleus, a process called retrograde transport. Kaspar and colleagues used these viruses to retrogradely deliver neurotrophic factors, including insulin-like growth factor 1 (IGF-1) and glial cell line-derived growth factor (GDNF), into the CNS of mice suffering from ALS. These animals, carrying a mutation in their superoxide dismutase gene, usually show the first symptoms of the disease at around 90 days. However, when Kaspar injected the quadricep and intercostal muscles of these animals at day 60 with IGF-1-laden viruses, disease began, on average, 31 days later; GDNF delayed symptoms by 16 days. In addition, IGF-1 prolonged the life of the diseased animals by about 37 days (160 days average lifespan with treatment vs. 123 days without). The treatment also worked prophylactically, though not as well. Administered at 60 days, IGF-1 prolonged life by about 24 days, while GDNF extended survival by seven days.
The IGF treatment in particular seems promising as a therapeutic. Not only did the mice survive longer, but they also had overall improved health, maintaining their body mass and muscle strength. However, IGF has been used to only marginal success in human ALS trials (see Mitchell et al., 2002). This lack of success may be due in part, write the authors, "to limited delivery of the protein to the target neurons," adding that the use of AAV vectors would circumvent the half-life and stability issues that plague protein therapeutics.
Exactly how IFG-1 protects the mice is uncertain, but Kaspar and colleagues noted reduced apoptosis in the treated animals. This may be due to greater activity of the protein kinase Akt, which is known to reduce cleavage of caspase 9, one of the key steps in the apoptotic pathway. The authors recorded almost 40 percent higher levels of phosphorylated, active Akt and 60 percent lower levels of cleaved caspase 9 in the spinal cords of treated animals.
Akt is also a key component in a new therapy for cardiac muscle repair pioneered by Victor Dzau and colleagues at the Brigham and Women's Hospital, Boston. In today's Nature Medicine, Dzau and colleagues report that mesenchymal stem cells genetically engineered to express Akt can effectively regenerate damaged heart muscle and restore cardiac function.
First author Abeel Mangi and colleagues used retroviruses to transfect purified rat mesenchymal stem cells (MSC) with the gene for murine Akt, the assumption being that the kinase would make the cells more viable by protecting them against apoptosis. This, indeed, appeared to be the case, because the authors found an almost 80 percent reduction in programmed cell death in the transfected cells. Mangi and colleagues then tested the Akt-enhanced cells in vivo, transplanting them into rat hearts that had suffered myocardial infarction.
The results were dramatic. When Mangi injected infarcted hearts with MSCs expressing the LacZ gene, about 13 percent of the damaged heart tissue was repaired, but stem cells expressing Akt led to an almost complete recovery of myocardial tissue. Furthermore, the Akt-MSCs restored function-ventricular systolic pressure jumped from 150 mmHg to 200 mmHg, close to the normal of about 225 mmHg.-Tom Fagan.
Kaspar BK, Llado J, Sherkat N, Rothstein JD, Gage FH. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 2003 August 8;301:839-842. Abstract
Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, Dzau VJ. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med. 2003 Sep;9(9):1195-201. Epub 2003 Aug 10. Abstract