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Applied Genetic Technologies Corporation

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Patent
Applied Genetic Technologies Corporation | Date: 2017-02-22

This invention relates generally to a codon optimized nucleic acid encoding a retinitis pigmentosa GTPase regulator (RPGR) protein. The nucleic acid has enhanced stability during plasmid production relative to a wildtype cDNA encoding the RPGR protein. The invention also relates to expression cassettes, vectors, and host cells comprising the codon optimized nucleic acid. Methods for preparing a recombinant adeno-associated (rAAV) expression vector comprising the codon optimized nucleic acid sequence are also provided. The nucleic acids, expression cassettes, vectors, and host cells provided may be useful in the large scale production of rAAV expression vectors for gene therapy applications.


BALTIMORE, May 09, 2017 (GLOBE NEWSWIRE) -- Researchers at the Casey Eye Institute, the Retina Foundation of the Southwest, the Kellogg Eye Center and Applied Genetic Technologies Corporation (NASDAQ:AGTC), a biotechnology company conducting human clinical trials of adeno-associated virus (AAV)-based gene therapies for the treatment of rare diseases, reported results from a study of the natural history of X-linked retinoschisis (XLRS) and the impact of carbonic anhydrase inhibitors (CAIs) on disease progression. The data were presented this week at ARVO 2017, the Association for Research in Vision and Ophthalmology Annual Meeting, taking place in Baltimore from May 7-11. Maria A. Parker, M.D., Senior Project Manager at the Casey Eye Institute at the Oregon Health and Science University, presented the data in a poster titled “Natural History and Effect of Carbonic Anhydrase Inhibitor Use in X-Linked Retinoschisis” (Abstract #1490). XLRS is characterized by abnormal splitting of the layers of the retina, resulting in poor visual function in young boys, which can ultimately result in legal blindness in adult men. The study was designed to characterize the natural history of XLRS and to determine the effect of CAIs on retinal function and structure in XLRS patients. This observational study enrolled 56 patients six years of age and older (average 30.0 years) with a confirmed mutation in the RS1 gene. Of the 56 patients, 18 had no CAI use prior to or during the study (Group A), 18 had previously used CAIs and continued to do so during the study (Group B) and 20 had no history of CAI use but began these medications at the start of the study (Group C). All patients underwent functional [best corrected visual acuity (BCVA)] and structural [macular cystic cavity volume (CCV) calculated from spectral domain optical coherence tomography] evaluations at baseline, 6, 12 and 18 months, and Group C patients underwent additional exams at 1 and 3 months after starting CAI therapy. There were no significant differences in BCVA or CCV within each group at subsequent evaluations compared with baseline values. Comparison of Group C with Groups A and B at each follow up examination also showed no statistically significant differences in BCVA or CCV, although there was a suggestion of improved visual acuity in Group C earlier in the study. Researchers conclude that these results demonstrate that XLRS is stable over an 18-month time period and that topical CAI use was not associated with improvement in visual function or macular cyst volume at one year. However, they also noted that some individuals treated with CAIs demonstrated notable improvements at earlier time points, suggesting that these medications may have more nuanced effects. “There are limited data available on the natural course of XLRS, or the impact of using CAIs on disease progression, likely because XLRS is a rare condition,” said Sue Washer, President and CEO of AGTC. “This lack of information is one hurdle to overcome as we develop new treatment approaches. We believe these study results are an important advance in our understanding of the natural progression of XLRS, and will enhance our efforts to develop our AAV-based XLRS gene therapy candidate, which is currently being evaluated in a Phase 1/2 clinical trial.” AGTC is currently enrolling patients in a clinical trial for its XLRS product candidates, as part of the company's collaboration with Biogen. Patients and caregivers interested in participating in or learning more about this trial may learn more at www.agtc.com/patients-and-caregivers or by contacting advocacy@agtc.com. AGTC is a clinical-stage biotechnology company that uses its proprietary gene therapy platform to develop products designed to transform the lives of patients with severe diseases, with an initial focus in ophthalmology. AGTC's lead product candidates are designed to treat inherited orphan diseases of the eye, caused by mutations in single genes that significantly affect visual function and currently lack effective medical treatments. AGTC's product pipeline includes ophthalmology programs in X-linked retinoschisis (XLRS), X-linked retinitis pigmentosa (XLRP), achromatopsia, wet age-related macular degeneration, and our optogenetics program with Bionic Sight. AGTC's non-ophthalmology programs include its adrenoleukodystrophy program and its otology program, which is in pre-clinical development, and the company expects to advance several otology product candidates into clinical development in the next few years. Each of AGTC's XLRS, XLRP and adrenoleukodystrophy programs is partnered with Biogen. AGTC employs a highly-targeted approach to selecting and designing its product candidates, choosing to develop therapies for indications having high unmet medical need that it believes are clinically feasible and present commercial opportunities. AGTC has a significant intellectual property portfolio and extensive expertise in the design of gene therapy products including capsids, promoters and expression cassettes, as well as, expertise in the formulation, manufacture and physical delivery of gene therapy products. This release contains forward-looking statements that reflect AGTC's plans, estimates, assumptions and beliefs. Forward-looking statements include information concerning possible or assumed future results of operations, business strategies and operations, preclinical and clinical product development and regulatory progress, potential growth opportunities, potential market opportunities and the effects of competition. Forward-looking statements include all statements that are not historical facts and can be identified by terms such as "anticipates," "believes," "could," "seeks," "estimates," "expects," "intends," "may," "plans," "potential," "predicts," "projects," "should," "will," "would" or similar expressions and the negatives of those terms. Actual results could differ materially from those discussed in the forward-looking statements, due to a number of important factors. Risks and uncertainties that may cause actual results to differ materially include, among others: no gene therapy products have been approved in the United States and only two such products have been approved in Europe; AGTC cannot predict when or if it will obtain regulatory approval to commercialize a product candidate; uncertainty inherent in the regulatory review process; risks and uncertainties associated with drug development and commercialization; factors that could cause actual results to differ materially from those described in the forward-looking statements are set forth under the heading "Risk Factors" in the Company's Annual Report on Form 10-K for the fiscal year ended June 30, 2016, as filed with the SEC. Given these uncertainties, you should not place undue reliance on these forward-looking statements. Also, forward-looking statements represent management's plans, estimates, assumptions and beliefs only as of the date of this release. Except as required by law, we assume no obligation to update these forward-looking statements publicly or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, even if new information becomes available in the future.


BALTIMORE, May 09, 2017 (GLOBE NEWSWIRE) -- Researchers at the Casey Eye Institute, the Retina Foundation of the Southwest, the Kellogg Eye Center and Applied Genetic Technologies Corporation (NASDAQ:AGTC), a biotechnology company conducting human clinical trials of adeno-associated virus (AAV)-based gene therapies for the treatment of rare diseases, reported results from a study of the natural history of X-linked retinoschisis (XLRS) and the impact of carbonic anhydrase inhibitors (CAIs) on disease progression. The data were presented this week at ARVO 2017, the Association for Research in Vision and Ophthalmology Annual Meeting, taking place in Baltimore from May 7-11. Maria A. Parker, M.D., Senior Project Manager at the Casey Eye Institute at the Oregon Health and Science University, presented the data in a poster titled “Natural History and Effect of Carbonic Anhydrase Inhibitor Use in X-Linked Retinoschisis” (Abstract #1490). XLRS is characterized by abnormal splitting of the layers of the retina, resulting in poor visual function in young boys, which can ultimately result in legal blindness in adult men. The study was designed to characterize the natural history of XLRS and to determine the effect of CAIs on retinal function and structure in XLRS patients. This observational study enrolled 56 patients six years of age and older (average 30.0 years) with a confirmed mutation in the RS1 gene. Of the 56 patients, 18 had no CAI use prior to or during the study (Group A), 18 had previously used CAIs and continued to do so during the study (Group B) and 20 had no history of CAI use but began these medications at the start of the study (Group C). All patients underwent functional [best corrected visual acuity (BCVA)] and structural [macular cystic cavity volume (CCV) calculated from spectral domain optical coherence tomography] evaluations at baseline, 6, 12 and 18 months, and Group C patients underwent additional exams at 1 and 3 months after starting CAI therapy. There were no significant differences in BCVA or CCV within each group at subsequent evaluations compared with baseline values. Comparison of Group C with Groups A and B at each follow up examination also showed no statistically significant differences in BCVA or CCV, although there was a suggestion of improved visual acuity in Group C earlier in the study. Researchers conclude that these results demonstrate that XLRS is stable over an 18-month time period and that topical CAI use was not associated with improvement in visual function or macular cyst volume at one year. However, they also noted that some individuals treated with CAIs demonstrated notable improvements at earlier time points, suggesting that these medications may have more nuanced effects. “There are limited data available on the natural course of XLRS, or the impact of using CAIs on disease progression, likely because XLRS is a rare condition,” said Sue Washer, President and CEO of AGTC. “This lack of information is one hurdle to overcome as we develop new treatment approaches. We believe these study results are an important advance in our understanding of the natural progression of XLRS, and will enhance our efforts to develop our AAV-based XLRS gene therapy candidate, which is currently being evaluated in a Phase 1/2 clinical trial.” AGTC is currently enrolling patients in a clinical trial for its XLRS product candidates, as part of the company's collaboration with Biogen. Patients and caregivers interested in participating in or learning more about this trial may learn more at www.agtc.com/patients-and-caregivers or by contacting advocacy@agtc.com. AGTC is a clinical-stage biotechnology company that uses its proprietary gene therapy platform to develop products designed to transform the lives of patients with severe diseases, with an initial focus in ophthalmology. AGTC's lead product candidates are designed to treat inherited orphan diseases of the eye, caused by mutations in single genes that significantly affect visual function and currently lack effective medical treatments. AGTC's product pipeline includes ophthalmology programs in X-linked retinoschisis (XLRS), X-linked retinitis pigmentosa (XLRP), achromatopsia, wet age-related macular degeneration, and our optogenetics program with Bionic Sight. AGTC's non-ophthalmology programs include its adrenoleukodystrophy program and its otology program, which is in pre-clinical development, and the company expects to advance several otology product candidates into clinical development in the next few years. Each of AGTC's XLRS, XLRP and adrenoleukodystrophy programs is partnered with Biogen. AGTC employs a highly-targeted approach to selecting and designing its product candidates, choosing to develop therapies for indications having high unmet medical need that it believes are clinically feasible and present commercial opportunities. AGTC has a significant intellectual property portfolio and extensive expertise in the design of gene therapy products including capsids, promoters and expression cassettes, as well as, expertise in the formulation, manufacture and physical delivery of gene therapy products. This release contains forward-looking statements that reflect AGTC's plans, estimates, assumptions and beliefs. Forward-looking statements include information concerning possible or assumed future results of operations, business strategies and operations, preclinical and clinical product development and regulatory progress, potential growth opportunities, potential market opportunities and the effects of competition. Forward-looking statements include all statements that are not historical facts and can be identified by terms such as "anticipates," "believes," "could," "seeks," "estimates," "expects," "intends," "may," "plans," "potential," "predicts," "projects," "should," "will," "would" or similar expressions and the negatives of those terms. Actual results could differ materially from those discussed in the forward-looking statements, due to a number of important factors. Risks and uncertainties that may cause actual results to differ materially include, among others: no gene therapy products have been approved in the United States and only two such products have been approved in Europe; AGTC cannot predict when or if it will obtain regulatory approval to commercialize a product candidate; uncertainty inherent in the regulatory review process; risks and uncertainties associated with drug development and commercialization; factors that could cause actual results to differ materially from those described in the forward-looking statements are set forth under the heading "Risk Factors" in the Company's Annual Report on Form 10-K for the fiscal year ended June 30, 2016, as filed with the SEC. Given these uncertainties, you should not place undue reliance on these forward-looking statements. Also, forward-looking statements represent management's plans, estimates, assumptions and beliefs only as of the date of this release. Except as required by law, we assume no obligation to update these forward-looking statements publicly or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, even if new information becomes available in the future.


Patent
Applied Genetic Technologies Corporation | Date: 2016-11-23

This invention relates generally to a codon optimized nucleic acid encoding a retinitis pigmentosa GTPase regulator (RPGR) protein. The nucleic acid has enhanced stability during plasmid production relative to a wildtype cDNA encoding the RPGR protein. The invention also relates to expression cassettes, vectors, and host cells comprising the codon optimized nucleic acid. Methods for preparing a recombinant adeno-associated (rAAV) expression vector comprising the codon optimized nucleic acid sequence are also provided. The nucleic acids, expression cassettes, vectors, and host cells provided may be useful in the large scale production of rAAV expression vectors for gene therapy applications.


GAINESVILLE, Fla. and CAMBRIDGE, Mass., May 10, 2017 (GLOBE NEWSWIRE) -- Applied Genetic Technologies Corporation (NASDAQ:AGTC), a biotechnology company conducting human clinical trials of adeno-associated virus (AAV)-based gene therapies for the treatment of rare diseases, today announced financial results for the quarter ended March 31, 2017. “In the past quarter, we completed enrollment in the dose escalation portion of the Phase 1/2 clinical trial for our XLRS product candidate and are scheduling patients for enrollment in XLRS as well as for ACHMB3 and ACHMA3 Phase 1/2 clinical trials,” said Sue Washer, President and CEO of AGTC. “We are also looking forward to filing the IND for our XLRP program later in 2017 and continue to advance our preclinical programs in these potentially transformative therapies.” AGTC's lead product candidates are designed to treat inherited orphan diseases of the eye, caused by mutations in single genes that significantly affect visual function and currently lack effective medical treatments. AGTC's pipeline includes ophthalmology programs in X-linked retinoschisis (XLRS), X-linked retinitis pigmentosa (XLRP), achromatopsia (ACHM) caused by mutations in the CNGB3 and CNGA3 genes, wet age-related macular degeneration and an optogenetics program. AGTC is currently enrolling patients in a Phase 1/2 clinical trial for its XLRS product candidate as part of the company’s collaboration with Biogen. To date, the company has completed dosing in the first three groups. The company expects to provide a data update, across both safety and potential efficacy endpoints, for these first 12 patients this summer. The Data Safety and Monitoring Committee (DSMC) met recently to review the current safety data set including the most recent high-dose group and the Company has initiated enrollment in the expansion group at the high dose. The primary endpoint of this clinical trial is safety, and available data thus far have shown that AGTC’s XLRS product candidate has been generally well tolerated.  As previously disclosed, mild to moderate ocular inflammation occurred in the majority of treated patients and resolved either without treatment or after treatment with topical or oral corticosteroids. The frequency and intensity of inflammation to date has been similar at all three dose levels tested. A Phase 1/2 clinical trial evaluating the company’s ACHMB3 product candidate is enrolling. The company has enrolled three patients in the low dose group. The company plans to enroll two additional patients in the low dose group who will both be treated by a surgeon who treated one of the earlier patients in this group, such that a total of three patients will be treated by a single surgeon. Based on the experience with the ACHMB3 trial, the Company plans to use a single surgeon in the near term to treat patient in the ACHMA3 trial.  Screening is on-going and the company does not expect enrollment to be limited by enrollment of the additional patients in the ACHMB3 trial. For the X-linked retinitis pigmentosa, or XLRP, program, IND-enabling toxicology studies are underway in two relevant disease models. After completion of these studies, the company expects to submit an IND to the FDA in the third quarter of 2017. In January of this year the company entered into a collaboration agreement with Bionic Sight to develop an optogenetic product candidate for patients with advanced retinal disease. Through the AGTC-Bionic Sight collaboration, the companies will seek to develop a new optogenetic therapy that leverages AGTC’s deep experience in gene therapy and ophthalmology and Bionic Sight’s innovative neuro-prosthetic device and algorithm for retinal coding.  The company and Bionic Sight intend to request a pre-IND meeting with the FDA to discuss the IND-enabling studies for this program and the expectation is that an IND will be filed in 2018. Financial Results for the Quarter Ended March 31, 2017 Total revenue for the three months ended March 31, 2017 was $8.4 million compared to $12.0 million generated during the same period in 2016.  Collaboration revenue recorded during the three months ended March 31, 2017 and 2016 resulted primarily from the amortization of upfront fees received under our collaboration agreement with Biogen which began in August 2015. Grant revenue decreased $24 thousand during the three months ended March 31, 2017 compared to the same period in 2016, largely attributable to reduced research and development activities on grant-funded projects. Research and development expense for the three months ended March 31, 2017 decreased by $1.6 million to $6.3 million compared to the same period in 2016. The period-over-period decrease was largely driven by the reduction of licenses and related fees which were lower during the three months ended March 31, 2017 compared to the three months ended March 31, 2016 due to technology access fees that were incurred in 2016 and did not recur in 2017. In addition, outside program costs decreased during the three months ended March 31, 2017 compared to the three months ended March 31, 2016, due largely to temporary delays encountered during the conduct of Phase 1/2 human clinical trials for our XLRS and CNGB3-related ACHM product candidates. The impact of these decreases was partially offset by higher employee-related costs that were driven primarily by hiring additional employees. General and administrative expense for the three months ended March 31, 2017 increased by $0.5 million to $2.9 million compared to the same period in 2016. The increase was primarily driven by higher share-based compensation and employee-related costs which resulted from hiring additional employees to support our continued expansion. Nominal increases in professional fees and other expenses were noted during the three months ended March 31, 2017 compared to the three months ended March 31, 2016. For the three months ended March 31, 2017, the company recorded a net loss after income taxes of $0.8 million, compared to net income after taxes of $2.0 million for the same period of 2016. Financial Results for the Nine Months Ended March 31, 2017 Total revenue for the nine months ended March 31, 2017 was $31.1 million compared to $35.2 million generated during the same period in 2016.  Collaboration revenue recorded during the nine months ended March 31, 2017 and 2016 resulted primarily from the amortization of upfront fees received under our collaboration agreement with Biogen which began in August 2015. Grant revenue decreased $0.4 million during the nine months ended March 31, 2017 compared to same period in 2016, largely attributable to reduced research and development activities on grant-funded projects. Research and development expense for the nine months ended March 31, 2017 decreased by $14.2 million to $17.9 million compared to the same period in 2016.  The decrease was largely driven by the impact of collaboration-related costs and license fees that were incurred in 2016 as a result of our entry into and receipt of fees and payments under the collaboration agreement with Biogen and which did not recur in 2017. Also, licenses and related fees decreased during the nine months ended March 31, 2017 compared to the nine months ended March 31, 2016 due to technology access fees that were incurred in 2016 and did not recur in 2017. In addition, outside program costs decreased in 2017 compared to 2016 due largely to temporary delays encountered during the conduct of Phase 1/2 human clinical trials for our XLRS and CNGB3-related ACHM product candidates.  The impact of these decreases was partially offset by higher employee-related and share-based compensation expenses that were driven primarily by hiring additional employees and the incremental impact of new share-based incentives awarded in 2017, as well as higher laboratory supplies and other costs during 2017, when compared to 2016. General and administrative expense for the nine months ended March 31, 2017 increased by $0.8 million to $8.5 million compared to the same period in 2016.  The increase was primarily driven by higher employee-related and share-based compensation costs which resulted from hiring additional employees to support our continued expansion, partially offset by lower legal and professional fees and other expenses. The higher legal and professional fees incurred in 2016 were largely attributable to professional consultations associated with the negotiation and entry into our collaboration with Biogen. For the nine months ended March 31, 2017, the company recorded net income after income taxes of $4.9 million, compared to a net loss after income taxes of $4.1 million in the same period of 2016. As of March 31, 2017, the company’s cash, cash equivalents, and investments amounted to $148.7 million.  The company believes these cash, cash equivalents, and investments will be sufficient to enable it to advance planned preclinical studies and clinical trials for its lead product candidates and currently planned discovery programs for at least the next two years. AGTC will host a conference call and webcast to discuss financial results for the third fiscal quarter ended March 31, 2017 today at 4:30pm ET.  To access the call, dial 866-565-7742 (US) or 614-999-1914 (outside of the US). The passcode is 14485210. A live webcast will be available in the Events and Presentations section of AGTC’s Investor Relations site at http://ir.agtc.com/events.cfm. Please log in approximately 10 minutes prior to the scheduled start time. The archived webcast will be available in the Events and Presentations section of the company’s website. AGTC is a clinical-stage biotechnology company that uses its proprietary gene therapy platform to develop treatments designed to transform the lives of patients with severe diseases, with an initial focus in ophthalmology. AGTC's product pipeline includes ophthalmology programs in X-linked retinoschisis (XLRS), X-linked retinitis pigmentosa (XLRP), both partnered with Biogen, achromatopsia caused by mutations in the CNGB3 and CNGA3 genes, wet age-related macular degeneration, and our collaborative optogenetics program with Bionic Sight. AGTC’s non-ophthalmology programs include its adrenoleukodystrophy program, also partnered with Biogen, and its otology research program. The otology programs are in pre-clinical development and the company expects to advance several otology product candidates into clinical development in the next few years. AGTC employs a highly-targeted approach to selecting and designing its product candidates, choosing to develop therapies for indications having high unmet medical need that it believes are clinically feasible and present commercial opportunities. AGTC has a significant intellectual property portfolio and extensive expertise in the design of gene therapy products including capsids, promoters and expression cassettes, as well as, expertise in the formulation, manufacture and physical delivery of gene therapy treatments. XLRS is an inherited retinal disease caused by mutations in the RS1 gene, which encodes the retinoschisin protein. It is characterized by abnormal splitting of the layers of the retina, resulting in poor visual acuity in young boys, which can progress to legal blindness in adult men. Achromatopsia is an inherited retinal disease, which is present from birth and is characterized by the lack of cone photoreceptor function. The condition results in markedly reduced visual acuity, extreme light sensitivity causing day blindness, and complete loss of color discrimination. Best-corrected visual acuity in persons affected by achromatopsia, even under subdued light conditions, is usually about 20/200, a level at which people are considered legally blind. XLRP is an inherited condition that causes boys to develop night blindness by the time they are ten and progresses to legal blindness by their early forties. This release contains forward-looking statements that reflect AGTC's plans, estimates, assumptions and beliefs. Forward-looking statements include information concerning possible or assumed future results of operations, business strategies and operations, preclinical and clinical product development and regulatory progress, potential growth opportunities, potential market opportunities and the effects of competition. Forward-looking statements include all statements that are not historical facts and can be identified by terms such as "anticipates," "believes," "could," "seeks," "estimates," "expects," "intends," "may," "plans," "potential," "predicts," "projects," "should," "will," "would" or similar expressions and the negatives of those terms. Actual results could differ materially from those discussed in the forward-looking statements, due to a number of important factors. Risks and uncertainties that may cause actual results to differ materially include, among others:  no gene therapy products have been approved in the United States and only two such products have been approved in Europe; AGTC cannot predict when or if it will obtain regulatory approval to commercialize a product candidate; uncertainty inherent in the regulatory review process; risks and uncertainties associated with drug development and commercialization; factors that could cause actual results to differ materially from those described in the forward-looking statements are set forth under the heading "Risk Factors" in the company's Annual Report on Form 10-K for the fiscal year ended June 30, 2016, as amended and filed with the SEC. Given these uncertainties, you should not place undue reliance on these forward-looking statements. Also, forward-looking statements represent management's plans, estimates, assumptions and beliefs only as of the date of this release. Except as required by law, we assume no obligation to update these forward-looking statements publicly or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, even if new information becomes available in the future.


Phase 1/2 trial in patients with achromatopsia due to CNGB3 mutations is currently enrolling patients; Phase 1/2 trial in patients with CNGA3-related achromatopsia is scheduling patients for enrollment WASHINGTON, May 11, 2017 (GLOBE NEWSWIRE) -- Applied Genetic Technologies Corporation (NASDAQ:AGTC), a biotechnology company conducting human clinical trials of adeno-associated virus (AAV)-based gene therapies for the treatment of rare diseases, today announced the presentation of new data from studies in animal models of achromatopsia (ACHM) and X-linked retinitis pigmentosa (XLRP) that support the company’s clinical development programs in these indications. The data were presented at the American Society of Gene and Cell Therapy 20th Annual Meeting, taking place in Washington, D.C., May 10-13. ACHM and XLRP are rare inherited retinal diseases. ACHM results from mutations in either of the CNGB3 or CNGA3 genes. Mutations in these genes account for approximately 75 percent of the total achromatopsia patient population. Individuals with achromatopsia have markedly reduced visual acuity, extreme light sensitivity, and complete loss of color discrimination. AGTC is currently enrolling patients in a clinical trial for its CNGB3 gene-related ACHM treatment candidate, and is currently scheduling patients to be enrolled in a clinical trial for its CNGA3 gene-related ACHM treatment candidate. Patients and caregivers interested in participating in or learning more about these trials may find more information at www.agtc.com/patients-and-caregivers or by contacting advocacy@agtc.com. XLRP affects boys, causing night blindness by the time they are ten, and progresses to legal blindness by their early forties. AGTC is developing a gene-based therapy for XLRP in collaboration with Biogen and expects to file an Investigational New Drug (IND) Application with the U.S. Food and Drug Administration for this product candidate this year. Lisa R. Keyes, Ph.D., Research Scientist at AGTC, will present the ACHM data in an abstract titled, “Evaluating Safety and Efficacy of the AAV2tYF-PR1.7-CNGA3 Vector in CNGA3-Deficient Sheep” (Abstract #299) today in an oral session from 4:15 p.m. to 4:30 p.m. EDT. These data are from a study that assessed toxicity, CNGA3 expression and efficacy of two subretinally administered vectors [AAV2tYF-PR1.7-hCNGA3 and AAV5-PR2.1-hCNGA3 (a vector previously shown to rescue cone photoreceptor responses)] in an animal model of ACHM, over a 12-week evaluation period. No systemic toxicity was associated with treatment and no consistent test article-related effects were observed. Two out of five animals treated with the higher dose of AAV2tYF-PR1.7-CNGA3 had microscopic findings of outer retinal atrophy, with or without inflammatory cells in the retina and choroid that were considered procedural- and/or test article-related. All vector-treated eyes demonstrated CNGA3 expression, and developed cone-mediated electroretinogram (ERG) responses with no change in rod-mediated ERG responses. Improvements in maze navigation times and obstacle collisions were observed in all vector-treated eyes compared with control eyes and with pre-dose results in the treated eyes. The researchers conclude that these results support the use of AAV2tYF-PR1.7-hCNGA3 in clinical studies in patients with achromatopsia caused by mutations in CNGA3. “The improvements in maze navigation times, obstacle collisions and ERG responses observed with the product candidate in this study suggest that AAV-based gene therapy has important potential in the treatment of ACHM resulting from mutations in the CNGA3 gene,” said Sue Washer, President and CEO of AGTC. “The favorable tolerability profile observed in this study also supports the use of this vector construct in human clinical trials. These study findings provided the basis for the design of the Phase 1/2 clinical trial of our gene-based therapy for ACHM resulting from CNGA3 mutations, which is currently scheduling patients for enrollment.” Jilin Liu, Associate Scientist at AGTC, will present the XLRP data in an abstract titled, “Evaluation of AAV2tYF-GRK1-RPGR Vectors in a Canine Model of RPGR-XLRP” (Abstract #692) in a poster session May 12, from 5:45 p.m. to 7:45 p.m. EDT. The poster will include results from a study evaluating the efficacy of two vectors (AAV2tYF-GRK1-RPGRco and AAV2tYF-GRK1-RPGRstb) containing the AAV2tYF capsid, human GRK1 promoter and a codon-optimized or stabilized version of the human RPGR gene administered subretinally in an animal model of mid-stage XLRP resulting from mutations in the RPGR gene. In this model, mid-stage disease occurs when animals are approximately 12 weeks of age and is associated with an approximate 40% loss of photoreceptors. Two animals per group received RPGRco in the right eye and RPGRstb in the left eye at each of three dose levels. Rescue of photoreceptor structure was assessed by clinical examination and histology and/or immunohistochemistry on retinal cryosections eight weeks post injection. No abnormal ophthalmic findings were noted in any eyes at the middle- or low-dose levels. Fundoscopic examination at 8 weeks post-dosage showed signs of retinal detachment and inflammation in the eyes injected with the high dose of either RPGRco or RPGRstb. Dose-dependent RPGR transgene expression was observed with both vectors, with greater RPGR expression noted in eyes injected with RPGRco compared with contralateral eyes injected with RPGRstb at the same dose levels. Correction of rod opsin and middle/long wavelength cone opsin mislocalization was demonstrated in all AAV-RPGR treated eyes. Researchers conclude that the results demonstrate greater RPGR expression with RPGRco compared with RPGRstb, and that the middle doses of both vectors resulted in optimal correction at mid-stage disease with limited inflammation in this animal model of XLRP. Data from both the ACHM and XLRP studies were also presented earlier in the week at ARVO 2017, the Association for Research in Vision and Ophthalmology Annual Meeting, which took place in Baltimore from May 7-11. AGTC is a clinical-stage biotechnology company that uses its proprietary gene therapy platform to develop products designed to transform the lives of patients with severe diseases, with an initial focus in ophthalmology. AGTC's lead product candidates are designed to treat inherited orphan diseases of the eye, caused by mutations in single genes that significantly affect visual function and currently lack effective medical treatments. AGTC's product pipeline includes ophthalmology programs in X-linked retinoschisis (XLRS), X-linked retinitis pigmentosa (XLRP), achromatopsia, wet age-related macular degeneration, and our optogenetics program with Bionic Sight. AGTC's non-ophthalmology programs include its adrenoleukodystrophy program and its otology program, which is in pre-clinical development, and the company expects to advance several otology product candidates into clinical development in the next few years. Each of AGTC's XLRS, XLRP and adrenoleukodystrophy programs is partnered with Biogen. AGTC employs a highly-targeted approach to selecting and designing its product candidates, choosing to develop therapies for indications having high unmet medical need that it believes are clinically feasible and present commercial opportunities. AGTC has a significant intellectual property portfolio and extensive expertise in the design of gene therapy products including capsids, promoters and expression cassettes, as well as, expertise in the formulation, manufacture and physical delivery of gene therapy products. This release contains forward-looking statements that reflect AGTC's plans, estimates, assumptions and beliefs. Forward-looking statements include information concerning possible or assumed future results of operations, business strategies and operations, preclinical and clinical product development and regulatory progress, potential growth opportunities, potential market opportunities and the effects of competition. Forward-looking statements include all statements that are not historical facts and can be identified by terms such as "anticipates," "believes," "could," "seeks," "estimates," "expects," "intends," "may," "plans," "potential," "predicts," "projects," "should," "will," "would" or similar expressions and the negatives of those terms. Actual results could differ materially from those discussed in the forward-looking statements, due to a number of important factors. Risks and uncertainties that may cause actual results to differ materially include, among others: no gene therapy products have been approved in the United States and only two such products have been approved in Europe; AGTC cannot predict when or if it will obtain regulatory approval to commercialize a product candidate; uncertainty inherent in the regulatory review process; risks and uncertainties associated with drug development and commercialization; factors that could cause actual results to differ materially from those described in the forward-looking statements are set forth under the heading "Risk Factors" in the Company's Annual Report on Form 10-K for the fiscal year ended June 30, 2016, as filed with the SEC. Given these uncertainties, you should not place undue reliance on these forward-looking statements. Also, forward-looking statements represent management's plans, estimates, assumptions and beliefs only as of the date of this release. Except as required by law, we assume no obligation to update these forward-looking statements publicly or to update the reasons actual results could differ materially from those anticipated in these forward-looking statements, even if new information becomes available in the future.


Patent
Applied Genetic Technologies Corporation, Johns Hopkins University and Foundation University | Date: 2015-10-02

The present invention includes methods and compositions for the production of high titer recombinant Adeno-Associated Virus (rAAV) in a variety of mammalian cells. The disclosed rAAV are useful in gene therapy applications. Disclosed methods based on co-infection of cells with two or more replication-defective recombinant herpes virus (rHSV) vectors are suitable for high-titer, large-scale production of infectious rAAV.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: STTR | Phase: Phase I | Award Amount: 657.70K | Year: 2013

DESCRIPTION provided by applicant Complete achromatopsia is an autosomal recessive inherited congenital disorder of retinal cone photoreceptors Patients with complete achromatopsia experience extreme light sensitivity and daytime blindness and best visual acuity under non bright light conditions is usually or worse and generally stable over time In addition to poor acuity hypersensitivity to light is an extremely troubling symptom No specific therapy is currently available Previous studies in a dog model of achromatopsia caused by mutations in the CNGB gene showed that subretinal injection of a recombinant adeno associated virus rAAV vector expressing human CNGB rescued cone photoreceptor function but at high doses was associated with findings consistent with immune mediated toxicity that may be due to the low amino acid identity between human and canine CNGB The objectives of the studies proposed in this Fast Track Phase I II STTR application are to confirm and extend these findings by comparing rAAV vectors expressing human or canine CNGB This will be accomplished by constructing an AAV proviral plasmid or rHSV helper virus containing canine CNGB cDNA driven by a cone specific promoter and using the construct to produce rAAV vectors expressing canine or human CNGB that will be tested for safety and efficacy in the dog model of CNGB related achromatopsia Previous attempts to clone a stable full length dog CNGB dCNGB coding region into a plasmid to generate an AAV expression cassette that could be used to packaging a rAAV CNGB vector have been uniformly unsuccessful To overcome this problem we will use two innovative approaches In one approach we will modify the codons of the dCNGB cDNA in a way that they favor gene expression in humans but are rarely utilized in E coli To overcome toxicity related to a presumed cryptic promoter we will also introduce a mutation at codon from methionine to leucine and additional silent mutations i e using synonymous codons upstream of codon in order to suppress possible internal promoter functions In a second approach we will directly introduce a synthesized dCNGB expression cassette into a recombinant herpes simplex virus HSV helper virus that can be used for rAAV production using AGTCandapos s HSV based rAAV production system thereby bypassing the potential of toxicity in E coli meditated by plasmids containing a dCNGB expression cassette These studies will also support development of several assays critical to support of human clinical studies of a product to treat Achromatopsia A better understanding of the effects of rAAV CNGB vectors in animals especially with respect to toxicity seen at higher doses will help to guide future development of rAAV CNGB gene therapy for human patients PUBLIC HEALTH RELEVANCE Complete achromatopsia is an inherited retinal disorder characterized by severely reduced visual acuity daytime blindness and complete loss of color discrimination It can be caused by mutations in any one of four different genes Gene therapy using a modified virus containing a normal copy of one of these genes can improve vision and correct daytime blindness in animal models of achromatopsia The current research project will provide information on how to evaluate the safety of gene therapy vectors in an animal model of the disease


Patent
Applied Genetic Technologies Corporation | Date: 2015-04-15

This invention relates generally to a codon optimized nucleic acid encoding a retinitis pigmentosa GTPase regulator (RPGR) protein. The nucleic acid has enhanced stability during plasmid production relative to a wildtype cDNA encoding the RPGR protein. The invention also relates to expression cassettes, vectors, and host cells comprising the codon optimized nucleic acid. Methods for preparing a recombinant adeno-associated (rAAV) expression vector comprising the codon optimized nucleic acid sequence are also provided. The nucleic acids, expression cassettes, vectors, and host cells provided may be useful in the large scale production of rAAV expression vectors for gene therapy applications.


Patent
Applied Genetic Technologies Corporation | Date: 2012-11-21

The invention generally provides methods for producing recombinant AAV viral particles using cells grown in suspension. The invention provides recombinant AAV particles for use in methods for delivering genes encoding therapeutic proteins, and methods for using the recombinant AAV particles in gene therapy.

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