Powell Gene Therapy Center

Powell, United States

Powell Gene Therapy Center

Powell, United States
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CAMBRIDGE, Mass.--(BUSINESS WIRE)--Agilis Biotherapeutics, Inc. (Agilis), a biotechnology company advancing innovative DNA therapeutics for rare genetic diseases that affect the central nervous system (CNS), announced today that data from the Company’s gene therapy, AGIL-AADC, for the treatment of Aromatic L-amino acid decarboxylase (AADC) deficiency is being presented at the Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) in Washington, D.C. The poster entitled “A Phase I/II Trial of Gene Therapy for an Inherited Disorder of Monoamine Neurotransmitter Deficiency” will be presented by Dr. Ni-Chung Lee. The study is a 10-patient, open-label clinical trial performed under the direction of Paul Hwu, M.D., Ph.D., Professor of Pediatrics at National Taiwan University Hospital and study principal investigator. The gene therapy treatment candidate, AGIL-AADC, is an adeno-associated virus (AAV) vector containing the human gene for the AADC enzyme. Dr. Hwu and colleagues have treated 18 patients using a single administration of the AGIL-AADC gene therapy. Results to date in the present study reinforce findings Dr. Hwu and colleagues have observed in the first study of 8 patients previously treated with AGIL-AADC. One-year findings in the Phase I/II study reveal that treated patients exhibited gains in motor function and showed de novo dopamine production as visualized by F-DOPA PET imaging and the emergence of dopamine metabolites. In contrast, untreated patients with severe AADC deficiency typically do not gain motor function over time nor achieve critical developmental milestones, as observed in natural history cases. The University of Florida Powell Gene Therapy Center was instrumental in the manufacturing and toxicology work of the initial product. Dr. Hwu stated, “We are pleased to present this important work highlighting the encouraging safety and efficacy observed to date in which AADC deficiency patients treated with the AGIL-AADC gene therapy have exhibited improvements across multiple functional scales, as well as biomarker and imaging measures.” Dr. Kirsten Gruis, Chief Medical Officer of Agilis, commented, “Patients with AADC deficiency continue to face high unmet medical needs and devastating consequences of their disorder in the absence of approved treatment options. We are hopeful that continuing clinical and regulatory efforts with AGIL-AADC may provide an innovative intervention to address the profound symptoms of this rare disorder and enhance the quality of patients’ lives.” “We are encouraged by the progress in advancing the AGIL-AADC gene therapy candidate,” said Mark Pykett, President and CEO of Agilis. “Clinical development of AGIL-AADC to date is rapidly advancing as we strive to position AGIL-AADC for registration and commercialization.” Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic condition resulting in lack of functioning AADC enzyme responsible for the final step in the synthesis of key neurotransmitters dopamine (a precursor of norepinephrine and epinephrine) and serotonin (a precursor of melatonin). AADC deficiency results in developmental failure, global muscular hypotonia, severe, seizure-like episodes known as oculogyric crises, autonomic abnormalities, and the need for life-long care. Given this neurologically devastating illness, patients with severe AADC deficiency have a high risk for death during childhood. Treatment options are limited and there are no approved therapies for patients with AADC deficiency. Agilis is advancing innovative gene therapies designed to provide long-term efficacy for patients with debilitating, often fatal, rare genetic diseases that affect the central nervous system. Agilis’ gene therapies are engineered to impart sustainable clinical benefits by inducing persistent expression of a therapeutic gene through precise targeting and restoration of lost gene function to achieve long-term efficacy. Agilis’ rare disease programs are focused on gene therapy for AADC deficiency, Friedreich’s ataxia, and Angelman syndrome, all rare genetic diseases that include neurological deficits and result in physically debilitating conditions. We invite you to visit our website at www.agilisbio.com. Some of the statements made in this press release are forward-looking statements. These forward-looking statements are based upon our current expectations and projections about future events and generally relate to our plans, objectives and expectations for the development of our business. Although management believes that the plans and objectives reflected in or suggested by these forward-looking statements are reasonable, all forward-looking statements involve risks and uncertainties and actual future results may be materially different from the plans, objectives and expectations expressed in this press release.


CAMBRIDGE, Mass.--(BUSINESS WIRE)--Agilis Biotherapeutics, Inc. (Agilis), a biotechnology company advancing innovative DNA therapeutics for rare genetic diseases that affect the central nervous system (CNS), announced today that data from the Company’s gene therapy, AGIL-AADC, for the treatment of Aromatic L-amino acid decarboxylase (AADC) deficiency are being presented at the Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT) in Washington, D.C. The oral presentation “Gene Therapy for Aromatic L-amino Acid Decarboxylase Deficiency: 5 Years After AAV2-hAADC Transduction” will be presented by Paul Hwu, M.D., Ph.D., Professor of Pediatrics at National Taiwan University Hospital, and study principal investigator. The presentation is at 4:45PM during the session entitled Clinical Trials for Neurologic and Neurosensory Disorders. Dr. Hwu and colleagues have treated 18 patients with severe AADC deficiency in two prospective clinical cohorts using a single administration of the gene therapy, AGIL-AADC, an adeno-associated virus (AAV) vector containing the human gene for the AADC enzyme. The presentation at the ASGCT conference presents, for the first time, multi-year data on the first cohort of treated patients demonstrating sustained motor function improvement and associated biomarker evidence of effect, representing one of the longest-term follow-up periods to date in gene therapy for a rare disease of the central nervous system. Dr. Hwu stated, “We are pleased to have been selected to present our long-term follow-up data at the ASGCT meeting. Over the period of observation, we have seen important treatment benefits as well as a good safety and tolerability profile to date. AADC deficiency patients treated with AGIL-AADC have exhibited improvements across multiple functional scales, developmental milestones, biomarkers and imaging measures.” Data to date indicate that treated subjects have exhibited substantial gains in motor function over multiple years following the gene therapy. Specifically, significant improvements have been observed in two established measures of motor function, the Peabody Development Motor Scale, Second Edition (PDMS-2) and the Alberta Infant Motor Scale (AIMS) and in the achievement of milestones of motor development. Patients have also shown de novo dopamine production as visualized by F-DOPA PET imaging and the emergence of dopamine metabolites. In contrast, untreated subjects typically do not achieve critical developmental milestones, as observed in natural history cases. The University of Florida Powell Gene Therapy Center contributed manufacturing and toxicology work of the initial product. Kirsten Gruis, M.D., Agilis’ Chief Medical Officer, said, “The emerging clinical data indicating motor function improvements over time following a single administration of the AADC gene therapy are encouraging. These data reinforce the premise that gene therapy may be able to provide durable benefits to patients with debilitating disorders that affect the central nervous system.” “We are delighted to have partnered with Dr. Hwu on this pioneering gene therapy effort in this devastating disease,” said Mark Pykett, President and CEO of Agilis. “Ongoing development of AGIL-AADC remains promising, as we strive to position AGIL-AADC for registration and commercialization to potentially bring this important, innovative therapy to patients who currently lack treatment options.” Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic condition resulting in lack of functioning AADC enzyme responsible for the final step in the synthesis of key neurotransmitters dopamine (a precursor of norepinephrine and epinephrine) and serotonin (a precursor of melatonin). AADC deficiency results in developmental failure, global muscular hypotonia, severe, seizure-like episodes known as oculogyric crises, autonomic abnormalities, and the need for life-long care. Given this neurologically devastating illness, patients with severe AADC deficiency have a high risk for death during childhood. Treatment options are limited and there are no approved therapies for patients with AADC deficiency. Agilis is advancing innovative gene therapies designed to provide long-term efficacy for patients with debilitating, often fatal, rare genetic diseases that affect the central nervous system. Agilis’ gene therapies are engineered to impart sustainable clinical benefits by inducing persistent expression of a therapeutic gene through precise targeting and restoration of lost gene function to achieve long-term efficacy. Agilis’ rare disease programs are focused on gene therapy for AADC deficiency, Friedreich’s ataxia, and Angelman syndrome, all rare genetic diseases that include neurological deficits and result in physically debilitating conditions. We invite you to visit our website at www.agilisbio.com Some of the statements made in this press release are forward-looking statements. These forward-looking statements are based upon our current expectations and projections about future events and generally relate to our plans, objectives and expectations for the development of our business. Although management believes that the plans and objectives reflected in or suggested by these forward-looking statements are reasonable, all forward-looking statements involve risks and uncertainties and actual future results may be materially different from the plans, objectives and expectations expressed in this press release.


Potter M.,Powell Gene Therapy Center | Lins B.,University of Florida | Mietzsch M.,Institute of Virology | Heilbronn R.,Institute of Virology | And 10 more authors.
Molecular Therapy - Methods and Clinical Development | Year: 2014

We describe a new rapid, low cost, and scalable method for purification of various recombinant adeno-associated viruses (rAAVs) from the lysates of producer cells of either mammalian or insect origin. The method takes advantage of two general biochemical properties of all characterized AAV serotypes: (i) low isoelectric point of a capsid and (ii) relative biological stability of the viral particle in the acidic environment. A simple and rapid clarification of cell lysate toremove the bulk of proteins and DNA is accomplished by utilizing inexpensive off-the-shelf reagents such as sodium citrate and citric acid. After the low-speed centrifugation step, the supernatant is subjected to cation exchange chromatography via sulfopropyl (SP) column. The eluted virus may then be further concentrated by either centrifugal spin devices or tangential flow filtration yielding material of high titer and Good Manufacturing Practice (GMP) grade biochemical purity. The protocol is validated for rAAV serotypes 2, 8, and 9. The described method makes rAAV vector technology readily available for the low budget research laboratories and could be easily adapted for a large scale GMP production format. © 2014 American Society of Gene & Cell Therapy


Ma W.,Powell Gene Therapy Center | Li B.,Powell Gene Therapy Center | Ling C.,Powell Gene Therapy Center | Jayandharan G.R.,Powell Gene Therapy Center | And 7 more authors.
Human Gene Therapy | Year: 2011

We have recently shown that co-administration of conventional single-stranded adeno-associated virus 2 (ssAAV2) vectors with self-complementary (sc) AAV2-protein phosphatase 5 (PP5) vectors leads to a significant increase in the transduction efficiency of ssAAV2 vectors in human cells in vitro as well as in murine hepatocytes in vivo. In the present study, this strategy has been further optimized by generating a mixed population of ssAAV2-EGFP and scAAV2-PP5 vectors at a 10:1 ratio to achieve enhanced green fluorescent protein (EGFP) transgene expression at approximately 5- to 10-fold higher efficiency, both in vitro and in vivo. This simple coproduction method should be adaptable to any ssAAV serotype vector containing transgene cassettes that are too large to be encapsidated in scAAV vectors. © 2011 Mary Ann Liebert, Inc.


Mendell J.R.,Ohio State University | Mendell J.R.,Nationwide Children s Hospital | Rodino-Klapac L.R.,Ohio State University | Rodino-Klapac L.R.,Nationwide Children s Hospital | And 23 more authors.
Annals of Neurology | Year: 2010

Objective: The aim of this study was to attain long-lasting alpha-sarcoglycan gene expression in limb-girdle muscular dystrophy, type 2D (LGMD2D) subjects mediated by adeno-associated virus (AAV) gene transfer under control of a muscle specific promoter (tMCK). Methods: rAAV1.tMCK.hSGCA (3.25 - 10 11 vector genomes) was delivered to the extensor digitorum brevis muscle of 3 subjects with documented SGCA mutations via a double-blind, randomized, placebo controlled trial. Control sides received saline. The blind was not broken until the study was completed at 6 months and all results were reported to the oversight committee. Results: Persistent alpha-sarcoglycan gene expression was achieved for 6 months in 2 of 3 LGMD2D subjects. Markers for muscle fiber transduction other than alpha-sarcoglycan included expression of major histocompatibility complex I, increase in muscle fiber size, and restoration of the full sarcoglycan complex. Mononuclear inflammatory cells recruited to the site of gene transfer appeared to undergo programmed cell death, demonstrated by terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling and caspase-3 staining. A patient failing gene transfer demonstrated an early rise in neutralizing antibody titers and T-cell immunity to AAV, validated by enzyme-linked immunospot on the second day after gene injection. This was in clear distinction to other participants with satisfactory gene expression. Interpretation: The findings of this gene replacement study in LGMD2D subjects have important implications not previously demonstrated in muscular dystrophy. Long-term, sustainable gene expression of alpha-sarcoglycan was observed following gene transfer mediated by AAV. The merit of a muscle-specific tMCK promoter, not previously used in a clinical trial, was evident, and the potential for reversal of disease was displayed. ANN NEUROL 2010;68:629-638 © 2010 American Neurological Association.


Ling C.,Powell Gene Therapy Center | Ling C.,Genetics Institute | Agbandje-McKenna M.,Powell Gene Therapy Center | Agbandje-McKenna M.,Genetics Institute | And 6 more authors.
Human Gene Therapy Methods | Year: 2015

The ubiquitin-proteasome pathway plays a critical role in the intracellular trafficking of recombinant adeno-associated virus 2 (AAV2) vectors, which negatively impacts the transduction efficiency of these vectors. Because ubiquitination occurs on lysine (K) residues, we performed site-directed mutagenesis where we replaced each of 10 surface-exposed K residues (K258, K490, K507, K527, K532, K544, K549, K556, K665, and K706) with glutamic acid (E) because of similarity of size and lack of recognition by modifying enzymes. The transduction efficiency of K490E, K544E, K549E, and K556E scAAV2 vectors increased in HeLa cells in vitro up to 5-fold compared with wild-type (WT) AAV2 vectors, with the K556E mutant being the most efficient. Intravenous delivery of WT and K-mutant ssAAV2 vectors further corroborated these results in murine hepatocytes in vivo. Because AAV8 vectors transduce murine hepatocytes exceedingly well, and because some of the surface-exposed K residues are conserved between these serotypes, we generated and tested two single mutants (K547E and K569E), and one double-mutant (K547 + 569E) AAV8 vector. However, no significant increase in the transduction efficiency of any of these mutant AAV8 vectors was observed in murine hepatocytes in vivo. These studies suggest that although targeting the surface-exposed K residues is yet another strategy to improve the transduction efficiency of AAV vectors, phenotypic outcome is serotype specific. © Copyright 2015 Mary Ann Liebert, Inc.


PubMed | Institute of Virology, University of Florida and Powell Gene Therapy Center
Type: | Journal: Molecular therapy. Methods & clinical development | Year: 2015

We describe a new rapid, low cost, and scalable method for purification of various recombinant adeno-associated viruses (rAAVs) from the lysates of producer cells of either mammalian or insect origin. The method takes advantage of two general biochemical properties of all characterized AAV serotypes: (i) low isoelectric point of a capsid and (ii) relative biological stability of the viral particle in the acidic environment. A simple and rapid clarification of cell lysate toremove the bulk of proteins and DNA is accomplished by utilizing inexpensive off-the-shelf reagents such as sodium citrate and citric acid. After the low-speed centrifugation step, the supernatant is subjected to cation exchange chromatography via sulfopropyl (SP) column. The eluted virus may then be further concentrated by either centrifugal spin devices or tangential flow filtration yielding material of high titer and Good Manufacturing Practice (GMP) grade biochemical purity. The protocol is validated for rAAV serotypes 2, 8, and 9. The described method makes rAAV vector technology readily available for the low budget research laboratories and could be easily adapted for a large scale GMP production format.

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