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Preclinical Data from Isis, UCSD Shows Antisense Infusion Effective for ALS; Phase I Hinges on Cash

Researchers from Isis Pharmaceuticals and the University of California, San Diego, published this week preclinical data showing that antisense oligonucleotides targeting a protein associated with familiar amyotrophic lateral sclerosis significantly slowed disease progression when administered via intraventricular infusion.
According to Isis, the findings support continued development of an antisense-based treatment for ALS, which the company anticipates moving into human testing within a year with help from medical device giant Medtronic, which is providing infusion pumps.
However, further development of the ALS therapy is contingent on the company finding sufficient funding, Isis’ Senior Vice President of Research Frank Bennett told RNAi News.
Familial ALS is a neurodegenerative condition characterized by the accumulation of mutant proteins in the central nervous system. According to the ALS Association, about 20 percent of all cases of familial ALS are caused by mutations in the gene that produces the protein superoxide dismutase 1.
Writing in a study appearing this week in the online edition of The Journal of Clinical Investigation, the researchers suggest that targeting SOD1 in patients carrying mutant forms of the gene can reduce levels of disease-causing protein and curb the progression of this form of the disease.
Following this strategy, the UCSD and Isis researchers created a 20-mer antisense oligo — which featured phosphorothioate modifications and 2′-O-(2-methoxy)ethyl substitutions on the sugars of the first and last 5 nucleotides — targeting rat SOD1.
The antisense agent was then “continuously pumped into the right lateral ventricle of a normal rat via a catheter surgically implanted through the skull and connected to an osmotic pump imbedded subcutaneously,” the researchers wrote in JCI.
An analysis of brain and spinal cord tissues collected after 14 days of treatment revealed significant antisense concentrations in the brain, brain stem, and all levels of the spinal cord. Follow-on infusions conducted with a tracking oligo confirmed these findings, while infusions in non-human primates demonstrated uptake in “the brain parenchyma relevant to neurodegenerative diseases, including the hippocampus, substantia nigra, pons, and cerebellum,” the researchers noted.
Additional experiments demonstrated that continuous infusion of an SOD1-targeting antisense oligo significantly suppressed endogenous rat SOD1 mRNA.
Based on these findings, “the next step was to develop an oligonucleotide that would knock down human SOD1 … to test whether the oligos are protective in an ALS model,” Timothy Miller, a UCSD researcher and co-author of the paper, told RNAi News this week.
This antisense oligo “suppressed mRNA and protein in vivo both after intraperitoneal administration and following intraventricular infusion for one month into … transgenic rats,” the paper’s authors wrote.
“Oligonucleotide treatment to lower mutant human [SOD1] accumulation in the rat ALS model was initiated at 65 days of age” — about 30 days before the age of disease onset — ”and rats were monitored for changes in weight, clinical signs of weakness, and survival,” according to the paper.
While both the timing of disease onset and early disease as measured by weight loss were similar between infusions of the antisense oligo, saline, and an oligo control, the antisense therapy slowed disease progression to give the treated rats a 37-percent extension of the typical 27-day disease duration after onset.

The antisense oligo “suppressed mRNA and protein in vivo both after intraperitoneal administration and following intraventricular infusion for one month into … transgenic rats.”

According to the authors, the findings indicate that their therapeutic approach to ALS “provides an effective method for gene down-regulation,” and takes advantage of a delivery method that not only allows for widespread distribution of the antisense agent throughout the central nervous system, but provides a simple means of regulating or stopping treatment in the event of unforeseen side effects.
Further, they note that antisense oligos may prove more effective than siRNAs since “the more rapid turnover of siRNAs — even when modified to enhance stability — requires infusion of substantially higher dosages to target even relatively rare mRNAs in the CNS. Moreover, since siRNAs obligatorily bind to and can saturate components required for endogenous small RNA pathways, this can produce serious off-target consequences.”
Toward the Clinic
Given the encouraging results from the rat experiments, Miller said that the next step for the researchers is to conduct toxicity studies, with an eye to beginning human trials within a year.
“We think these oligonucleotides are safe, and Isis has used these … peripherally in more than 500 patients,” he said. “But we obviously need formal toxicology testing in animals to make sure that these drugs are safe before we move to phase I trials.”
Miller said that the first phase I trial would evaluate the safety of the SOD1-targeting antisense oligo, delivered via an implantable infusion pump provided by Medtronic, in about 16 patients who have the SOD1 mutation and are symptomatic.
“We will probably do a test dose first, without implanting the pump, to make sure that [the patients] tolerate” the treatment, he said. “Then … we’ll put in the pump.”

“At the same time, we have to be mindful that we’re a very small biotech company and have to watch how we spend our own money. For external costs, we need to find funding.”

Eventually, Miller said, the antisense therapy might be tested in patients who have the SOD1 mutation but have not yet developed ALS. However, whether this is pursued will depend on the therapy’s safety profile.
Miller noted that the planned clinical development of an SOD1-targeting antisense drug, however, assumes “our funding continues to come through.”
According to Isis’ Bennett, the limited market for ALS therapies makes it unlikely that Isis could secure a bigger partner for the program, and therefore finding funding for the effort has been a challenge.
“For this particular indication … we’re talking about, at most, 300 to 500 patients in the US, and maybe an equal number in markets where you could sell a drug like this,” he said. Based on these figures, “I would anticipate [it] would be very difficult to get large pharma or even a large biotech interested.
“We have been fortunate that the ALS Association has stepped up and paid for the primate studies,” he noted, adding that additional help has come in the form of a commitment from Medtronic to provide pumps for clinical studies. However, “we’re still short from what it’s going to take to file an IND, so we have grants in with other agencies that will hopefully come through. It’s easily a couple million dollars to get to the point where we’re testing patients,” he said.
Bennett said that Isis remains committed to the ALS project, noting that “we’re putting internal labor into this project, as well as providing all the IP and expertise this project needs to go forward.
“At the same time, we have to be mindful that we’re a very small biotech company and have to watch how we spend our own money,” he added. “For external costs, we need to find funding.”
Should Isis find that funding, Bennett said Miller’s time-to-clinic projection of one year is accurate.
“We’re anxious to move this project along,” he said. “Keep your fingers crossed that the funding comes in.”

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