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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


GAINESVILLE, Fla., and CAMBRIDGE, Mass., Nov. 08, 2016 (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 September 30, 2016. “Over the past quarter, we have remained focused on efficiently enrolling the clinical trials of our lead product candidates for X-linked retinoschisis and achromatopsia caused by mutations in the CNGB3 gene,” said Sue Washer, President and CEO of AGTC. “We recently filed an IND for our product candidate to treat patients with achromatopsia caused by mutations in the CNGA3 gene and we look forward to initiating a Phase 1/2 clinical study for that product candidate in the coming months while continuing to advance our XLRS and achromatopsia B3 programs.” AGTC is currently enrolling patients in a Phase 1/2 clinical trial for its XLRS product candidate, a program on which the company is collaborating with Biogen.  The clinical protocol anticipates enrollment of up to 27 patients.  This trial is currently being conducted at seven clinical sites that specialize in inherited retinal diseases. As of October 2016, the company has enrolled a total of nine patients – six of whom are in the low dose group and three are in the middle dose group, which completes enrollment in those two groups.  As specified in the clinical trial protocol, data from the first nine patients will be reviewed by a Data and Safety Monitoring Committee, or DSMC, before the company enrolls patients in the high dose group. As of October 2016, the company has enrolled three patients in the low dose group for a Phase 1/2 clinical trial for its CNGB3-related ACHM product candidate, which completes enrollment in that group.  As specified in the clinical trial protocol, safety data from the first three patients will be reviewed by a DSMC before the company enrolls patients in the middle dose group. The company's Phase 1/2 ACHM B3 clinical trial is being conducted at four sites that specialize in inherited retinal diseases, with an additional site performing advanced optical testing on every patient. In the company’s X-linked retinitis pigmentosa, or XLRP, program, IND-enabling toxicology studies are underway in two relevant disease models — a naturally occurring dog model and a RPGR knockout mouse model. After completion of these studies, the company expects to submit an IND to the FDA in 2017. As part of its collaboration with Biogen, the company is also developing product candidates for three new indications, two of which are for ophthalmic diseases and one for a non-ophthalmic condition.  Biogen has designated adrenoleukodystrophy, or ALD, as the non-ophthalmic discovery program under this collaboration. ALD is an X-linked genetic disorder that causes damage to the nervous system and adrenal glands, primarily in young boys. In addition to the product candidates being developed under the collaboration with Biogen, the company has other new and solely owned product candidates under development, several of which are part of the company’s new otology initiative. The company is also conducting preclinical research to develop new product candidates for the treatment of age-related macular degeneration, or AMD, by leveraging its experience developing products in orphan ophthalmology and its work with a previous partner on a first-generation product for wet AMD. Financial Results for the Quarter Ended September 30, 2016 Total revenue for the three months ended September 30, 2016 was $11.8 million, up from $11.1 million generated during the same period in 2015.  Revenue recorded during the three months ended September 30, 2016 resulted primarily from the straight-line amortization of upfront fees received under the company’s collaboration with Biogen.  Revenue recorded during the same period in 2015 was primarily comprised of the amortization of these upfront fees amounting to $6.0 million and milestone revenue of $5.0 million that was earned following achievement of a patient enrollment-based milestone under the terms of the collaboration with Biogen. Research and development expense for the three months ended September 30, 2016 decreased by $11.9 million to $5.6 million compared to the same period in 2015.  The year-over-year decrease was largely driven by the impact of $12.0 million of collaboration-related license fees and other costs incurred by the company in 2015 as a result of its entry into and receipt of fees and payments under the collaboration with Biogen.  In addition, outside program costs decreased by $0.8 million to $2.3 million in 2016 compared to the same period in 2015 due largely to temporary delays encountered during the conduct of Phase 1/2 human clinical trials for the company’s XLRS and CNGB3-related ACHM product candidates.  The impact of these decreases was partially offset by higher employee-related and share-based compensation expenses and increased laboratory supply costs driven primarily by the hiring of additional employees and the incremental impact of new share-based incentives awarded in 2016. General and administrative expense for the three months ended September 30, 2016 increased by $59,000 to $2.8 million compared to the same period in 2015.  The year-over-year increase was primarily driven by higher employee-related costs from the hiring of additional employees to support the company’s continued expansion, partially offset by lower legal and professional fees.  The higher legal and professional fees incurred in 2015 were largely attributable to professional consultations associated with the company’s negotiation and entry into its collaboration arrangement with Biogen. For the three months ended September 30, 2016, the company recorded net income of $3.6 million, compared to a net loss of $9.1 million in the same period of 2015. At September 30, 2016, the company's cash, cash equivalents and investments amounted to $166.8 million.  The company believes that 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 for at least the next two years. AGTC will host a conference call and webcast to discuss financial results for the first fiscal quarter ended September 30, 2016 today at 5:00 p.m. (ET).  To access the call, dial 866-565-7742 (US) or 614-999-1914 (outside of the US). The passcode is 4458790. 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 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 six named ophthalmology development programs across five targets (X-linked retinoschisis (XLRS), X-linked retinitis pigmentosa (XLRP), achromatopsia, wet age-related macular degeneration and blue cone monochromacy), two non-ophthalmology programs (alpha-1 antitrypsin deficiency and adrenoleukodystrophy) and AGTC is continuing to develop early research studies in additional indications.  The company is also exploring genetic defects in cells in the inner ear that lead to deafness and expects to advance several product candidates into development within 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, clinical feasibility and commercial potential. 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. 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, including but not limited to if or when the FDA will accept the Company’s IND for its CNGA3-related ACHM product candidate, 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, reliance on third parties over which AGTC may not always have full control; 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: 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.


News Article | December 5, 2016
Site: globenewswire.com

GAINESVILLE, Fla., and CAMBRIDGE, Mass., Dec. 05, 2016 (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 its participation in upcoming conferences. 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 six named ophthalmology development programs across five targets (X-linked retinoschisis (XLRS), X-linked retinitis pigmentosa (XLRP), achromatopsia, wet age-related macular degeneration and blue cone monochromacy), two non-ophthalmology programs (alpha-1 antitrypsin deficiency and adrenoleukodystrophy) and AGTC is continuing to develop early research studies in additional indications. The company is also exploring genetic defects in cells in the inner ear that lead to deafness and expects to advance several product candidates into development within 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, clinical feasibility and commercial potential. 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.


GAINESVILLE, Fla. and CAMBRIDGE, Mass., Oct. 27, 2016 (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 that it will report financial results for the quarter ended September 30, 2016 after the market closes on Tuesday, November 8, 2016. AGTC management will host a conference call beginning at 5:00 pm Eastern Time that day to review results and provide a corporate update. To access the call, dial 866-565-7742 (US) or 614-999-1914 (outside of the US). The passcode is 4458790. A live webcast will be available in the Events and Presentations section of the Investor Relations page 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 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 six named ophthalmology development programs across five targets (X-linked retinoschisis (XLRS), X-linked retinitis pigmentosa (XLRP), achromatopsia, wet age-related macular degeneration and blue cone monochromacy), two non-ophthalmology programs (alpha-1 antitrypsin deficiency and adrenoleukodystrophy) and AGTC is continuing to develop early research studies in additional indications.  The company is also exploring genetic defects in cells in the inner ear that lead to deafness and expects to advance several product candidates into development within 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, clinical feasibility and commercial potential. 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.


News Article | November 3, 2016
Site: globenewswire.com

GAINESVILLE, Fla. and CAMBRIDGE, Mass., Nov. 03, 2016 (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 that Sue Washer, President and Chief Executive Officer, will present at the Stifel 2016 Healthcare Conference on Tuesday, November 15, 2016 at 3:45pm ET in New York. A live audio webcast of the presentation can be accessible by visiting ir.agtc.com/events.cfm. A replay will be available on the company’s website following the event. 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 six named ophthalmology development programs across five targets (X-linked retinoschisis (XLRS), X-linked retinitis pigmentosa (XLRP), achromatopsia, wet age-related macular degeneration and blue cone monochromacy), two non-ophthalmology programs (alpha-1 antitrypsin deficiency and adrenoleukodystrophy) and AGTC is continuing to develop early research studies in additional indications.  The company is also exploring genetic defects in cells in the inner ear that lead to deafness and expects to advance several product candidates into development within 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, clinical feasibility and commercial potential. 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.

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