A drug candidate for SMA: PTK-SMA1

Paratek Pharmaceuticals and Families of Spinal Muscular Atrophy announced that a jointly funded drug development program for Spinal Muscular Atrophy has been awarded a multi-million dollar cooperative agreement from NINDS.
The five-year cooperative agreement encompasses pre-clinical drug development up to the time of an Investigational New Drug Application (IND) to the FDA. The program is focused on developing a novel small molecule of the tetracycline family, PTK-SMA1, from within Paratek's propriety compound library. The potential for success of the drug candidate is evaluated at key stages of the development using quantitative go/no-go milestones that have been established in the agreement between Paratek and the NINDS. The Krainer Laboratory at Cold Spring Harbor Laboratory and the Hastings Laboratory at Rosalind Franklin University are also key collaborators in the program and will also receive funding under the NINDS cooperative agreement.

The compound under investigation at Paratek is intended to correct RNA splicing of a low functioning back-up gene to SMN1 called SMN2, which will in turn increase SMN protein levels. The first publication from the drug discovery collaboration at Paratek Pharmaceuticals is a study appeared online in the journal Science Translational Medicine on November 4th, “Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for Spinal Muscular Atrophy”; the scientists report the activity of PTK-SMA1 in mouse models of SMA and in cells isolated from SMA patients. This is the finding of a research collaboration involving Adrian Krainer, Ph.D., of Cold Spring Harbor Laboratory (CSHL) and scientists from Paratek Pharmaceuticals and Rosalind Franklin University of Medicine and Science. Unlike previously identified molecules that stimulate SMN production, the tetracycline-like compound is a unique therapeutic candidate in that it is a small molecule that specifically alters RNA splicing by directly targeting the splicing reaction. The researchers confirmed that this effect of PTK-SMA1 on RNA splicing and exon inclusion ultimately results in increased levels of full-length and functional SMN protein. The compound boosted protein levels in cells isolated from SMA patients and cultured in lab dishes. The scientists also proved its ability to work in vivo by injecting it into mice carrying a human SMN2 gene. The mice showed more than a 5-fold increase in human SMN protein levels within a week of treatment.

“PTK-SMA1 is the only small molecule known to specifically alter RNA splicing by directly and solely targeting the splicing reaction,” says Krainer. Other molecules that affect splicing also affect other cellular processes, thus diluting their potency, and potentially increasing the risk of side effects. PTK-SMA1 has the added advantage of being a derivative of tetracyclines, which are nontoxic and have demonstrated safety in humans. The team is excited about having such a promising therapeutic candidate for SMA treatment and plans to next focus on two key issues: finding out exactly how PTK-SMA1 redirects RNA splicing and finding a way to get it across the blood-brain barrier and into the affected neurons in the spinal cord.

"At Families of SMA we are excited that our $2 Million initial investment at an early stage of this project has provided the preliminary data to leverage larger funding amounts from NIH. We feel this grant award is wonderful validation of the Families of SMA research funding program and more specifically of Paratek’s promising drug program for SMA", said Jill Jarecki Ph.D., Research Director at Families of SMA.
“The Families of SMA drug discovery strategy is to invest funds to enable companies to begin early-stage programs for this orphan disease, and as programs progress to later stages, we look for funding to transition from non-profit to commercial and government sources. Clearly Paratek’s program is a successful demonstration of that approach", said Kenneth Hobby, President at Families of SMA.
Dr. Stuart B. Levy, M.D., Paratek's Vice Chairman, Chief Scientific Officer and co-founder, stated, "We are very grateful for the support of FSMA, which has helped get us to this exciting moment. We are encouraged that through the NINDS funding, we shall identify a drug candidate for this devastating disease."
John D. Porter, Ph.D., Program Director for the Paratek award at NINDS, stated, “This award was made through the NINDS Cooperative Program in Translational Research, a novel, milestone-driven program that solicits ideas for therapies from disease communities, evaluates those ideas through peer review, and both optimizes and assesses candidate therapies at each stage of development. This cooperative project combines the corporate resources and expertise of Paratek, the research experience of the academic investigators, the focus, insights, and funding of the Families of SMA, and the funding and project management experience of NINDS staff. It represents a powerful strategy for developing new therapies for SMA and other diseases.”

Families of SMA and SMA Europe (through SMA Trust), a consortium of European SMA advocacy groups, have also co-funded a recent grant award to Paratek Pharmaceuticals for their Spinal Muscular Atrophy drug program. This award will cover aspects of the program not funded by the NINDS allocation, including funding to the laboratory of Dr. Louise Simard at the University of Manitoba.

(sources: CSHL, Paratek and FSMA websites)