'Milk-Making' Molecule Lengthens Life Span in SMA Mice

Treatment with the protein prolactin improved motor function and enhanced survival time in mice with a disease resembling severe SMA

Article Highlights:
  • Treatment with a molecule called prolactin has been shown to slow weight loss, improve motor function and increase life span in mice with a disease resembling severe spinal muscular atrophy.
  • Prolactin works via manipulation of the SMN2 gene.
  • It's long been thought that a successful therapeutic strategy for SMA could be targeting the SMN2 gene so that increased levels of SMN protein would be produced.
by Amy Madsen on August 8, 2011 - 3:02pm

The administration of a protein called prolactin has been shown to slow weight loss, improve motor function and increase life span by approximately 70 percent in mice with a disease resembling a severe form of spinal muscular atrophy (SMA).

Prolactin is a hormone whose primary function is to promote milk production in women who are breastfeeding.

Prolactin receptors are located in numerous places in the body, including the ovaries, heart, lungs, adrenal glands, skeletal muscle and some areas of the central nervous system (CNS). Importantly, the prolactin molecule is able to cross the blood-brain barrier and get into the CNS.

The findings were reported online July 25, 2011, in the Journal of Clinical Investigation, by a team of scientists including Faraz Farooq and former MDA grantee Alex MacKenzie, both at the University of Ottawa and the Apoptosis Research Center at the CHEO Research Institute in Ottawa, Ontario, Canada. (Read Prolactin increases SMN expression and survival in a mouse model of severe spinal muscular atrophy via the STAT5 pathway.)

Prolactin 'upregulates' the needed SMN protein

The underlying molecular cause of SMA is a deficiency in a protein called SMN (for survival of motor neurons), which leads to the death of muscle-controlling nerve cells in the spinal cord.

The researchers showed that in mice injected with prolactin, the molecule significantly upregulated the SMN gene expression, meaning it increased the levels of the needed protein, via manipulation of the SMN2 gene.

Human cells also showed increased production of SMN protein when treated with prolactin.

It's long been assumed that targeting the SMN2 gene and prompting increased production of SMN protein would be a successful therapeutic strategy in SMA, and proof of concept for the strategy has been accomplished in several previous studies in the last decade.

For more about experimental treatments in development for SMA, many with MDA support, see SMA: Wider 'Window of Opportunity' for Treatment?, Quest News Online, Aug. 4, 2011.

SMN2 can function as a 'backup' for the SMN1 gene

Humans have two nearly identical genes from which SMN protein can be produced: SMN1 and SMN2. SMA results when mutations render SMN1 genes incapable of providing instructions for full-length SMN protein molecules.

Some full-length SMN protein can be made from SMN2 genes, which are thought of as "backup" SMN genes. However, the amount is generally not enough to compensate for nonfunctional SMN1 genes. The more SMN2 genes a person has (the numbers vary), the more full-length SMN he or she can produce, and the milder the disease course of SMA is likely to be.

Many therapeutic strategies for SMA are based on increasing full-length SMN protein production from SMN2 genes.

Prolactin is one of a number of agents that has been shown to cause an increase in the production of full-length SMN protein from what normally would be considered the backup source of genetic instructions for this protein. It appears to work by activating what is known as the JAK-STAT5 pathway.

Meaning for people with SMA

Further testing is needed to translate the prolactin findings from mice to humans. However, the study team suggests that prolactin's SMN-elevating effects may prove even more powerful in humans than in mice. They say prolactin has the potential to benefit people who already exhibit symptoms of SMA.

Prolactin also has previously been tested for its ability to help mothers of premature infants produce milk, and it's been found to be safe in this context. Because it's been tested in people, its development as a potential SMA therapy may move more quickly than a drug that has never been tested in humans.

The researchers reported that data support the testing of prolactin in clinical trials.

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