Genetic Engineering & Biotechnology News

JUL 2017

Genetic Engineering & Biotechnology News (GEN) is the world's most widely read biotech publication. It provides the R&D community with critical information on the tools, technologies, and trends that drive the biotech industry.

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34 | JULY 2017 | | Genetic Engineering & Biotechnology News oped by Renova Therapeutics. This therapy, called RT-100, has promise as "a single-dose treatment designed to safely improve heart function," says Jack Reich, Ph.D., Renova's CEO and cofounder. The therapy's Ad5. hAC6 adenovirus vector effectively delivers the AC6 gene via cardiac catheterization (an outpatient procedure) directly into the arter- ies. This AC6 is then taken up by the heart, resulting in better myocyte function and im- proved calcium handling. Dr. Reich indicates that Renova has other products in its pipeline. RT-200, which de- livers Urocortin 2, is designed to increase insulin sensitivity and glucose disposal. It could be used to treat several cardiovascular and metabolic diseases. RT-300 is meant to deliver the Urocortin 3 gene, to correct CHF with pulmonary hypertension. RT-400, a peptide infusion treatment with stresscopin hormone, is being evaluated for its ability to treat acute decompensated heart failure (ADHF). Rare, but Not Overlooked There are at least 7,000 different rare dis- eases that affect around 300 million people worldwide with around 200,000 cases in the United States alone. Several pharma- ceutical and biotech companies are working tirelessly to find ways of curing or at least alleviating the distressing symptoms of these often-forgotten diseases. One such company is Audentes Therapeu- tics. It has four programs in its development pipeline that show promise in using gene therapy to correct and improve, or even cure, a few rare diseases. The company's AT132 program is meant to treat X-linked myotu- bular myopathy (XLMTM), an extremely rare disease that affects approximately 1 in 50,000 newborn males worldwide and is characterized by severe muscle weakness and impaired respiratory function. AT132 targets the MTM1 gene. Correct- ing the mutant via gene therapy can result in the upregulation of myotubularin, which is involved in the development and mainte- nance of muscle cells. Matthew Patterson, Audentes' cofounder, CEO, and president, emphasizes the importance of using the right vector: "It is extremely important that we use vectors at the correct dose so that it can effec- tively pass through the liver's filtration system and reach the designated target gene." Other programs at Audentes include AT342, which targets the UGT1A1 gene to treat Crigler-Najjar syndrome; AT307, which targets the CASQ2 gene to treat CASQ2- related catecholaminergic polymorphic ven- tricular tachycardia (CPVT); and AT982, which targets the GAA gene to upregulate an enzyme called acid alpha glucosidase for the treatment of Pompe disease. More Than Meets the Eye Achromatopsia, a nonprogressive and he- reditary retinal disorder, is characterized by decreased vision, increased photosensitivity, and a marked absence of color vision. It af- fects about 1 in every 33,000 people world- wide and can cause several grades of incom- plete-to-complete color vision loss depending on the level of cone photoreceptor function. To develop a treatment for achromatop- sia, Applied Genetic Technologies Corpora- tion (AGTC) is working on AAV-based tech- nology that could also be effective against disorders such as X-linked retinitis pigmen- tosa (XLRP), X-linked retinoschisis (XLRS), and wet age-related macular degeneration (wet-AMD). "When considering a single disorder, there are a number of factors that could lead to dif- ferent levels of effectiveness in different pa- tients," comments Mark Shearman, Ph.D., AGTC's chief scientific officer. "Some disor- ders, like XLRS, are monogenic, which means they are caused by mutations in a single gene. That said, mutations in different regions of the gene involved are known to result in vary- ing changes to its function. Treating patients at different stages of the disorder could also influence how effective a therapy might be. Others, like achromatopsia, have been linked to several genes and a mutation in just one gene can cause the disorder." In certain cases, there could be multiple gene therapy product candidates, one or more for each of the genes that are associated with the disorder. Each of the gene therapies should be expected to have a unique poten- tial effectiveness, dictated by the role that the gene plays in the visual process. ACHM is caused by mutations in any of at least six genes, and gene therapy product candidates are in clinical development for patients who have mutations in two of these genes (CNGA3 and CNGB3, which account for 75% of the patient population). Many Helpers Make Light Work Targeting cancer cells that have spread to several organs of the body is difficult. Targeted radiation therapy or chemotherapy tends to destroy not only the cancer cells but also nor- mal cells. Turning to gene therapy to selective- ly deliver therapeutic genes into these cancer cells on a larger scale and eliminating them in one fell swoop is the ultimate goal of Tocagen. Using two products, Toca 511 and Toca FC, the company plans on developing an ef- fective combination therapy that could hit the cancer hard. Toca 511 is an injectable retroviral replicating vector (RRV) that pro- vides the genetic material to encode a pro- drug activator enzyme, cytosine deaminase (CD), which is derived from yeast and has no human counterpart. It is selectively delivered to only cancer cells, thus producing the CD protein in each cell. Part two of this therapy involves a pill called Toca FC, which contains 5-fluorocy- tosine (5-FC) that converts to the anticancer agent 5-FU in the presence of CD protein. Toca FC kills not only the cancer cells, but also the myeloid-derived suppressor cells (MD- SCs), which suppress the immune system, and tumor-associated macrophages (TAMs). Harry Gruber, M.D., cofounder and for- mer CEO of Tocagen, talks about the use of gamma-retroviruses: "The advantage of us- ing a gamma-retrovirus (as opposed to the lentivirus) is that it cannot enter the nucleus on its own. This makes it selective to divid- ing cells only, and since cancer cells are rap- idly dividing, [gamma-retroviruses] help in spreading the virus and its genetic informa- tion. They live in defective cells that lack an innate immunity, and due to this selectivity, they are designed to be universally geared to- ward only cancer cells." Dr. Gruber also mentioned that Toca 511/ FC received the FDA's Breakthrough therapy designation, which expedites drug development. The field of gene therapy has come a long way since its inception. Early failures and setbacks forced researchers back to the drawing board to figure out how viral vec- tors could be accepted by the human body, which ordinarily rejects foreign particles. Researchers also had to learn how such vec- tors could reach specific targets and deliver foreign DNA that could be integrated into the genome. This dance between therapy and the innate immune system is getting more complex, but is also showing its true beauty within the complexity. Gene Therapy Continued from page 32 Translational Medicine The Audentes Therapeutics portfolio consists of four programs, each of which applies adeno- associated virus gene therapy technology. Programs that are entering clinical-phase testing include AT132, a therapy for X-linked myotubular myopathy (XLMTM), and AT342, a therapy for Crigler- Najjar syndrome. CRISPR-based gene therapy involves repair- ing a disease-causing DNA mutation in the somatic cells of a patient. While there is great interest in this approach, one potential ob- stacle is how to test the efficacy of the pro- posed therapy in an effective manner. Ideally, a CRISPR/Cas9-based therapy not only must efficiently modify the target DNA sequence, but also needs to be delivered in the right tissue at the right amount and lack side effects. It is therefore desirable for researchers not only to evaluate the DNA repair efficiency of the therapy, but also to test delivery methods, dosing, and potential side effects/off-targets in different tissues. As opposed to other therapeutic ap- proaches (such as kinase inhibitors), gene therapy acts on a biological feature— namely, a defined genomic sequence—that is highly species-specific and usually even patient-specific. Since non-genetically modi- fied animal models such as mouse, rat, or monkey will likely not have the same target sequence in their genomes, they cannot be used to test the therapy. "One way that Taconic Biosciences and other model providers are overcoming this limitation is by introducing a human se- quence into the mouse genome via genomic humanization," says Adriano Flora, Ph.D., associate director, scientific program man- agement, Taconic Biosciences. "Genomic hu- manization involves replacing a mouse gene with a portion of or the entire human gene, or adding to the mouse genome a sequence corresponding to the human gene of interest." By introducing a human gene bearing the patient-specific mutation, model provid- ers can create a model of human disease to test the efficacy of the gene therapy in vivo, continues Dr. Flora. "An example of this ap- proach is reported in a Nature publication describing the application of such a model. While this model was used to test zinc finger nucleases, an alternative to CRISPR, it dem- onstrates the value of genomic humaniza- tion as a means to overcome the limitations of testing gene-editing therapies. n Making CRISPR/Cas9 Gene-Therapy Testing Viable in Animal Models

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