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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.


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 | 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.


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.


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.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 143.08K | Year: 2010

DESCRIPTION (provided by applicant): Complete achromatopsia is an inherited retinal disorder characterized by severely reduced visual acuity, nystagmus, severe photophobia, a small central scotoma, eccentric fixation, and complete loss of color discrimination. In 50% of patients with achromatopsia the disease is caused by mutations in the cyclic nucleotide gated channel beta subunit (CNGB3) gene. Preliminary studies indicate that gene therapy using a recombinant adeno-associated virus serotype 5 (rAAV5) vector expressing a human CNGB3 gene can restore cone photoreceptor function in a dog model of achromatopsia caused by mutations in the CNGB3 gene. The objectives of the studies proposed in this application are to confirm and extend these findings using a rAAV5-CNGB3 vector produced using a commercially relevant manufacturing method. This will be accomplished by producing and purifying a rAAV5-hCNGB3 vector and evaluating the safety and efficacy of subretinal administration of a range of vector concentrations (1 x 1010, 1 x 1011, and 1 x 1012 vg/mL) of the rAAV5-CNGB3 vector in a dog model of achromatopsia caused by mutations in the CNGB3 gene. Results of these studies will be important for future advanced development of rAAV-CNGB3 gene therapy for evaluation in patients with CNGB3-related achromatopsia. PUBLIC HEALTH RELEVANCE: Complete achromatopsia is an inherited retinal disease characterized by severely reduced visual acuity and complete loss of color discrimination. In 50% of patients, the disease is caused by mutations in the CNGB3 gene. No treatment for achromatopsia is currently available. This project will evaluate a novel, CNGB3 gene therapy product for treatment of achromatopsia in a dog model.


Patent
Applied Genetic Technologies Corporation | Date: 2010-07-13

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.


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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