Genetic Engineering & Biotechnology News

DEC 2017

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Genetic Engineering & Biotechnology News | | DECEMBER 2017 | 23 from the patient from a number of tissues, can be readily expanded in culture, and have been shown to have positive clinical outcomes in a number of trials. These cells are multipotent, meaning they can become different tissue-type cells (e.g., fat, bone, car- tilage) with a predisposition to convert into specific tissue types depending on the source tissue from which they were first isolated. Methods to control or change this predis- position are key to exploiting them to repair tissue in cell therapies. Using IntraStem, we can program the gene expression of MSCs to differentiate them efficiently into bone cells (Figure 1). 17 Importantly, this technique can overcome the cellular inclination to form alternative tissues (e.g., cartilage) directly at the level of gene expression. Using this approach to deliver recombinant transcription factor pro- teins (e.g., RUNX2) means we do not geneti- cally modify the cells, unlike gene therapy. This can now be exploited for programming MSCs when developing strategies for repair- ing bone trauma and disorders. Relatedly, human MSCs can have low proliferative capacity and readily senesce in certain patient groups (e.g., diabetics and the elderly). Locate has recently embarked on a program using IntraStem to amplify their numbers, overcome proliferative shortfalls, and expedite production of therapeutically relevant numbers. The aim is that this per- sonalized therapy will then be administered into patients using the TAOS system to fur- ther enhance clinical outcomes. Simple Transfection with Low Effect on Cell Viability The IntraStem technology can be adapted to condense and deliver nucleic acids to cells and therefore find use as a transfection re- agent. We have shown that IntraStem pep- tides can be engineered to form nanocom- plexes' of mRNA and pDNA, which can be used to transfect a wide variety of cell types. These formulations have recently been tested in preclinical lung-delivery models. When compared to Product B, post-transfection cell-proliferation rates are preserved more significantly, allowing serial gene delivery to be achievable (Figure 2). The cytocom- patibility of the reagent therefore suits appli- cations whereby the cells are sensitive to ef- fects of chemical or physical methods of gene delivery. Interested transfection can be used in hydrogels (for tissue engineering and re- generative medicine), for in vivo delivery of gene therapy, and for human tissue ex vivo. The technology has also been shown useful in the generation of induced pluripotent stem cells (iPSCs) using episomal vectors (Figure 3), and in the delivery of gene-editing tech- nologies to iPSCs to correct genes or gener- ate disease models. Conclusions The IntraStem peptide system allows the intracellular delivery of a multitude of therapeutic molecules across a wide range of cell types and culture contexts. In addi- tion, its production and use require no spe- cialist equipment and can be scaled to high- throughput to large transfection formats. The ability to efficiently deliver molecules ranging from antibodies, nucleic acids, and nanoparticle formulations using IntraStem will be a useful tool in contributing to the development of more effect treatments and allow the better understanding of disease states and stem cell differentiation. Karen Weintraub Over the course of his career, Tom Crawford, M.D., has held 70 babies he knew would miss every major milestone. They would never roll over, walk, or speak their first word. They would die before reaching the age when their healthy peers were outgrowing diapers. Now Dr. Crawford, a neurologist at Johns Hopkins University Medical Center, is pretty certain he'll never have to tell another family that their child is destined for the same fate. Two treatments for spinal muscular atro- phy (SMA), the neurodegenerative disease he has dedicated his career to addressing, have completely altered the treatment landscape. "It's like the elimination of polio," he says, though, like other medical profession- als, he stops short of calling either of the new therapies a "cure." Two papers and an editorial in the current issue of the New England Journal of Medicine outline the two different approaches to treating the worst form of SMA. One of the therapies, generically called nusinersen and marketed as Spinraza by Ionis Pharmaceuticals and Biogen, an RNA-altering antisense oligonucleotide, was approved by the FDA in late 2016. The second treatment, which is at an earlier stage of research, is a gene replacement therapy meant as a one-time treatment to add back the missing SMN1 gene that makes a protein of the same name. Without that protein—which Spinraza generates a different way—the brain can't send messages to the motor neurons that link it to muscles, and the nerves and muscles atrophy. Patients with SMA produce very little SMN protein. The severity of the disease is linked to some genetic differences that influ- ence the amount of protein produced. Both therapies seem to be equally effec- tive at getting patients' bodies to produce the SMN protein, though each approach has its strengths and weaknesses, according to Jill Jarecki, Ph.D., who is chief scientific officer at Cure SMA, an advocacy group. FDA-ap- proved Spinraza is further along the research pipeline, but it must be delivered via a spinal tap four times a year; the investigational gene therapy, which is being marketed by AveXis, of Bannockburn, IL, offers the promise of a one-and-done treatment, she says. "There's a need for multiple approaches," Dr. Jarecki says, adding that there are also two oral drugs being developed to treat SMA, one by Roche and the other by Novartis. All the activity makes this is an incred- ibly exciting time for the SMA field, but she doesn't want to raise false hopes, or neglect the 8,000–10,000 American children who are too old to benefit from these new therapies. The new study of Spinraza, led by Rich- ard Finkel, M.D., of Nemours Children's Hospital in Orlando, FL, found that the ear- lier a child with SMA gets adequate amounts of SMN protein, the better off he or she will be. This makes sense, because motor neu- rons cannot be resurrected or grow back, so more damage suffered prior to treatment translates into worse symptoms later on. To ensure that no one will ever be too old for effective therapy again, doctors, drug com- panies, patient advocates and families are now pushing to add SMA to the list of diseases screened for at birth. Such a screen was never necessary before there was treatment, but now it has taken on tremendous urgency, says Dr. Crawford, who was not involved in either pa- per, but who has been involved in other trials of the Spinraza therapy and is now recruiting participants for a new trial of the gene therapy. The gene therapy, called AVXS-101, uses a virus to infect virtually every cell in the body and adds a working copy of the SMN1 gene. This new gene sits inside the cells, but does not incorporate into the child's DNA; it's es- sentially a supplemental gene, according to Jerry Mendell, M.D., who led the research at Nationwide Children's Hospital in Columbus, OH, where the gene therapy was developed. All 15 children in the gene therapy trial were alive at 20 months and didn't require ventilation. Only 8% of untreated children with the most severe form of SMA typically escape ventilation by that age. The first three babies in the study received a dose of the gene therapy that was considered safe. But they saw only modest improvements. The other 12 babies received a higher dose and saw substantial change from the normal dis- ease course. All 12 can now sit, and 9 can sit for more than 30 seconds without assistance— a milestone never reached by any untreated SMA type 1 babies. Two have learned to walk, and all continue to improve, Dr. Mendell says. The virus caused only one minor side ef- fect—temporary inflammation in the liver— which is easily treated with steroids, Dr. Mendell says. One infant was turned away from the trial because he or she had already had been exposed to the adeno-associated viral vector used to deliver the gene therapy, and had developed antibodies to it. The virus was combined with a hybrid cytomegalovi- rus enhancer–chicken beta-actin promoter. It is not clear if the single dose of gene therapy will last forever, but so far, the signs are good. The first babies in the trial are still producing SMN three years after their treat- ment, Dr. Mendell says, and hemophilia pa- tients treated with gene therapy have an even longer track record. One of the big issues with both therapies is their cost. Spinraza is priced at $750,000 for the first year, when extra priming doses are needed, and $325,000 for each year af- ter that—apparently for the child's entire life. No price has yet been set for the gene therapy, but it's expected to reflect its benefit and the comparison with Spinraza. Both treatments are "pretty close to a cure," but not quite, Dr. Crawford says. Some damage from SMA may occur even before birth, and, he adds, "we're not going to make people in motorized wheelchairs get up and start running." Still, the progress has been remarkable. "I started out with this being the worst, most hopeless disease," notes Dr. Crawford, but luck has repeatedly been on the side of re- searchers and families. "Things have broken our way more than a couple of times." Gene Therapy Approach Pays Off for Babies Who Would Otherwise Have Died G E N E X C L U S I V E Breakthrough for Spinal Muscular Atrophy Bioprocessing James E. Dixon, Ph.D., is senior research fellow, stem cell technologies; and Robin Quirk, Ph.D. (rquirk@locatetherapeutics), is CEO of Locate Therapeutics. Website: References available online. Tutorial Photo of Braeden Farrell, who has spinal muscular atrophy (SMA). Biogen

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