- Email: [email protected]
966. Limited Correction of VLCAD Deficiency in Mice with a Native VLCAD Promoter
964. Balloon Occlusion Catheter-Based Delivery of HDAd into the Nonhuman Primate Liver Results in Stable, High Level Transgene Expression with Minimal Toxicity
965. High-Pressure Delivery Via Peripheral Vein Facilitates Transduction of Canine Liver with AAVVectors
Nicola Brunetti-Pierri,' Gary Stapleton.' Mark Law? Donna Palmer; Yu ZUO, l Arthur Beaudet,' Milton Finegold,' Charles Mullins,' Philip Ng.1 'Molecular and Human Genetics, Baylor College a/Medicine. Houston, TX; 2Pediatric Cardiology, Baylor College a/Medicine, Houston, TX; 'Pathology, Baylor College a/Medicine, Houston,
7X
Helper-dependent adenoviral vectors (HDAds) hold tremendous potential for liver-directed gene therapy because they can mediate long-term transgene expression without chronic toxicity. However, due to a nonlinear dose-re sponse, high doses are required to achieve hepatic transduction resulting in dose-dependent acute toxicity. To overcome this important obstacle, we have developed a minimally invasive method to preferentially deliver low dose I-IDAd into the liver of 30 kg baboons to achieve efficient hepatic transduction. Briefly, a single sausage-shaped balloon occlusion catheter was percutaneously positioned in the inferior vena cava (lYC) of baboon I to occlude hepatic venous outflow (Fig. A). Ix I011 vp/kg of a 1,IDAd expressing the baboon a-fetoprotein (bAFP) marker was injected directly into the occluded liver via a percutaneously placed hepatic artery (HA) catheter and left to dwell within the liver for 15 min before balloon deflation. As controls, Ix I011 vp/kg was administered to baboon 2 by peripheral intravenous injection and baboon 3 by HA injection without balloon occlusion. All procedures were uneventful, well tolerated, and following recovery from anesthesia, all three animals returned to their normal, active pre-injection states with no clinical manifestations of toxicity. Mild transaminitis (Grade 1) was observed for all animals , peaking at 24 to 48 h post-vector but quickly returning towards normal the next day. Importantly, a high level of bAFP was achieved in baboon 1 that was -I O-fold great er than baboons 2 and 3 and this high level has been sustained to date (at least 168 days)(Fig. B). To distingui sh between procedure-related versus vector-mediated toxicity, baboon 4 underwent the balloon procedure but was mock injected with saline, not virus and a similar mild transaminitis (Grade I) was observed in this control animal suggesting that this mild hepatotoxicity was related to the procedure, not the vector. To further improve safety, we have recently reduced the occlusion time from 15 min to 7.5 min and this did not affect the level or duration oftransgene expression. These results suggest that the therapeutic index of HDAd can be significantly improved by delivering the vector preferentially into the liver using a minimally invasive balloon occlusion catheter technique and may be a first step towards clinical application of HDAd for liver-directed gene therapy. A.
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Eduard Ayuso, I Montane Joel,' Anguela M. Xavier,' Callejas David,' Mann Chris, I Garcia Felix," Andaluz Ana, 2 Mingozzi Federico.' High A. Katherin,' Bosch Fatima.' 'Center 0/Animal Biotechnology and Gene Therapy. and Dept. 0/Biochemistry and Molecular Biology. Universitat Autonoma de Barcelona, Bellaterra, Spain: JDept. 0/Animal Medicine and Surgery, Universitat Autonoma de Barcelona, Bellaterra, Spain; 3Dept. 0/ Pediatrics, University 0/ Pennsylvania Medical Center and The Children S Hospital 0/ Philadelphia, Philadelphia. Adeno-associatcd vivurs (AAV) vectors arc desirable vectors for gene therapy because oftheir low immunogenicity, their broad range of target tissue and the wide variety of seroptypes available. The most commonly used seroptypes for liver transduction in dogs are serotypes 2, 6 and 8 whereas in humans it is serotype 2. However, natural neutralizing antibodies (NAs) in humans can limit the effectiveness ofAAY2. Other studies have shown that this response is specific for AAV2 and not for other serotypes. In dogs , virus is commonly delivered via the portal vein and in humans via the hepatic artery, both of which necessitate surgery and are invasive. In several animal models a rapid infusion of volume , and therefore pressure , is one ofthe thechniques most frequently used to improve tranfcr of plasmid DNA into the liver and other tissues, To explore thc ability of pressure to increase liver transduction with AAV-I , a serotype with low liver tropism in mice, we injected 20 ml/kg of AAV-l CMV-G FP solution via the saphenous vein. After 7 days we round a very high transduction or the liver with about 60% of the hepatocytes demon strating GFP expression. In contrast, no expression was detected in the skeletal muscle of the hind limb. Measure ments ofcardiac frequency and arterial diastolic and systolic blood pressure revealed no changes, such as tachycardia, during or after the injection, when the dog was anaesthetised, emphasising the safety ofthe technique. The present work demonstrates that efficient liver transduction in dogs can be achieved with AAV-I using a high pressure method via saphenous vcin. This method may have benefits for human therapy since a less invasive technique is desirable, the effect of pre-existing NAs can be minimised and it could allow the possible readministration in patients treated with other serotypes. Supported by SAF2005-0 1262, Spain and European Community (CLINIGENE, LSHB-CT-2006-0l8933).
966. Limited Correction of VLCAD Deficiency in Mice with a Native VLCAD Promoter David B. Schowalter, I Tien V. Nguyen,' Janice K. Daniels,' 1. Lawrence Merritt.' 'D epartment a/Medical Genetics. Mayo Clinic, Rochester; MN. Deficiency or very long-chain acyl-CoA dehydrogenase (VLCAD) , one of several nuclear encoded mitochondrial enzymes that catalyze the initial step in the beta-oxidation or straight-chain fatty acids, often presents with cardiomyopathy, fasting hypoglycemia, rhabdomyalysis, and/or sudden death. While dietary therapy for VLCAD deficiency has been beneficial to some, many people do not respond. Times of illness with diminished oral intake, exercise, or fasting all increase demand for fatty acid metabolism and can potentially trigger catastrophic events even while on dietary therapy. A murine knockout model of VLCAD deficiency is available and shows a number of features of the human disease. Here we report the development of a recombinant AAV2/8 vector that expresses the human VLCAD gene (AAV8-hVLCAD). In vivo studies with a recombinantAAV2/8 vector utilizing the strong viral CMV promoter have demonstrated an ability to produce hVLCAD protein in liver, heart, and skeletal muscle following tail vein injection . Short-term Molecular Therapy Volume 15.Sup plement I. ~b)" Copyright
© Th e American
~il,:l
y
2007
o f Gene;Th erapy
correction of fasting hypoglycemia and elevated long-chain acylcamitine species has been demonstrated. Over time (75 days) a loss of protein expression is seen with a gradual increase in long-chain serum acylcamitine species to near pre-treatment levels. Studies of hepatic DNA from early- and late-treated mice demonstrate a loss ofAAV genomes as one possible explanation for this. In an effort to develop a more durable expression vector with a more natural distribution oftissuc expression , we prepared several native VLCAD promoter constructs in a luciferase reporter system and compared in vitro promoter activity in 293 cells. Recombinant AAV2/8 vectors were then prepared using the two most promising promoter fragments (p 187. P1154). Following tail vein injection ofVLCADdeficient mice with these recombinant vectors, robust hVLCAD expression is seen in the liver and heart, and serum C 18acylcarnitine levels arc reduced to wild type levels by day II. Altogether, this work demonstrates the ability of the native hVLCAD promoter to produce sufficient hVLCAD protein to correct accumulated CI8 acylcamitine species in murine serum.
967. Non-Viral Gene Transfer into Gunn Rats for Prevention of Drug Toxicity and Investigation of UGT Isoenzyme Function In Vivo Istvan Danko, I Zhen Jia.'
'Department ofPediatrics, University ofWisconsin-Madison, Madison, IV/. Background: Variation in activ ity of UDP-glucuronosyl transferases (UGTs) in various tissues may be critical determinant of toxicological susceptibility. However overlapping substrate specificities make studying tissue-specific role of various UGTs in vivo very difficult. We have studied the feasibility ofnon-viral transfer of human and rat UGTs (hUGT, rUGT) into UGT deficient Gunn rats to conduct such studies. Methods: Animals: 4-6 week old Gunn and Wistar rats (GR, WR). Plasmid expression vectors for rUGTIAI , rUGTIA5, hUGTIAI were based on pCDNA3hUGTIAI containing CMV promoter (gill ofJ. Ritter). Control: pCI-LacZ (Promega, Madison, WI). Gene transfer: Seven days before Menadione injections groups ofGR received hepatic venous injection of 1/15 of body weight vector solution containing 0.6 mg of plasmid. Menadionc exposure and cvaluation of toxicitv: Serum alanine aminotransfcrase (ALl'; indicator ofhepatoeyte damage; UlL) was measured 24 hours after each ofthree consecutive daily intraperitoneal injections of various doses (5, 10, 15, 25, 50 mg/kg) of Menadione; serum bilirubin (SeBi J.lM/L) was measured before, and 7 and 10 days after gene transfer Gust before the first and one day after the last Menadione injection); Statistics: Data arc expressed as mean ± SO. Differences between the means from two independent samples werc tested with the t test. Results: Toxicitv of Menadione in WR vs. GR: Menadione dose of 10 mg/kg resulted in significantly higher ALl' levels in GR vs. WR (282±18 and 164.5±12 respectively, n""2, p<0.05) without mortality or significant morbidity by 24 hours after the second injection. At earlier time points and with < I0 mg/kg doses the difference was not significant. Mortality in GR was first observed at doses ~25 mglkg. Effect of hepatic expression of various UGTs on Menadione toxicity in GR: Serum ALl' 24 hours after the second Menadione injection of 10 rug/kg in GR expressing hUGTlA I was significantly lower than in GR not expressing hUGTIAI (158±24 vs. 282± 18; n=2 p<0.05). ALl' levels in GR expressing rUGT IA I, rUGTIA5 and lacZ 24 hours after the third injection of 15 rng/kg Menadione were 327.5±16, 433±28 and 416±1O respectively (significantly lower in rUGTIAI group vs. both other groups (n=4, p<0.05». Average SeBi before gene transfer, before first and one day after the third Menadione injection in the respective groups were: 124.8±23, 86.5±20, 93.5±1I; 121.9±21, 119±9.3, 114.5±12 and 120.9±20, 120.6±13, 117.5 ±IO. The decrease in serum bilirubin in GR expressing rUGTIAI vs. GR expressing rUGTIA5 or Molecular Therapy Volume15. Supplement I. ~ "'r 2007 Copyright © The Ameri can Soci ety o r Gene "1l1f:r:lpy
lacZ was statistically significant (n=4, p<0.05) Conclusions: UGT deficiency leads to increased Menadione toxicity. Non-viral expression of both human and rat UGTIAI in Gunn rat liver is protective against Menadione toxicity and leads to significant decrease in serum bilirubin. Selective expression ofUGTs in various tissues by non-viral gene transfer has great potential as a tool for investigating tissue-specific role ofvarious UGT isoenzymes and may provide an innovative gene therapy approach for prevention of the toxicity of various chemotherapy drugs and environmental toxins.
968. Patent Inventorship of Principal Investigators in Phase I Gene Transfer Clinical Trials: An Empirical Analysis Karen L. Durell,' Jonathan Kimmelman.' Josephine Nalbantoglu,' Richard Gold.'
'Faculty ofLaw, McGill University, Montreal, QC. Canada; 2Biomedical Ethics Unit, McGill University, Montreal, QC, Canada; 3 Department ofNeurology and Neurosurgery, McGill University, Montreal, QC, Canada. BACKGROUND: Policies of professional societies , institutions, and journals take widely varying positions on whether patent inventorship represents a potential interest conflict. Whereas institutions like the University of Pennsylvania and journals like JAMA have policies addressing patent inventorship, other universities (e.g. Washington University in St. Louis) and journals (e.g. Journal of Clinical Oncology) do not. Elsewhere, one of us OK) has argued that patent inventorship represents a financial interest that should be managed where human subjects are involved. PURPOSE: We undertook an empirical study to determine the frequency with which principal investigators in phase I gene transfer trials were named as inventors on patents relating to the study agent. METHODS: GEMCRIS entries and Appendix M filings were collected for 200 phase I gene transfer trials submitted to the OBA between 1999 and 2002. U.S. Patent and Trademark Office, and World Intellectual Property Organization Patent, Copyright and Trademark databases were searched using principal investigators in the inventor field. A certified patent agent (KD), in consultation with a gene transfer researcher (IN), determined whether patent elaims corresponded to any aspect ofthc investigational agent. After matches wcrc identified, we recorded the identity of the patent assignee, the identity of matching claims, and checked informed consent documents to determine whether patent interests were disclosed to research subjects. RESULTS: Among the various types of claims that matched protocols were: cells modified with specific genes, vectors, modes of agent administration, methods of expanding modified cells, treatment combinations, treatment steps, methods ofinducing physiological responses , and vector production processes. To date, patent records for 43 principal investigators (of 239 in our sample) have been sought. We found that 18 principal investigators (40%) were named as inventors on patents related to the study; this corresponded to eighteen protocols (45%) . Most patents (61%) were assigned to an institution hosting the clinical trial; the others were assigned to a principal invest igator. Of trials involving an investigator-inventor, 41% consent documents contained generic statements relating to commercialization. These generally took the form of statements about the usc ofdatabanked tissues. Disclosure of specific financial interests like patent invcntorship was observed for 17%. CONCLUSIONS: Our preliminary data indicate that inventorship is common in gene transfer trials. However, disclosure of patent inventorship in informed consent documents is sporadic. These findings, should they hold up after searching remaining protocols, have implications tor ethical review and informed consent practices (funding: Canadian Institutes of Health Research MOP-79288).
S369
965. High-Pressure Delivery Via Peripheral Vein Facilitates Transduction of Canine Liver with AAVVectors
Nicola Brunetti-Pierri,' Gary Stapleton.' Mark Law? Donna Palmer; Yu ZUO, l Arthur Beaudet,' Milton Finegold,' Charles Mullins,' Philip Ng.1 'Molecular and Human Genetics, Baylor College a/Medicine. Houston, TX; 2Pediatric Cardiology, Baylor College a/Medicine, Houston, TX; 'Pathology, Baylor College a/Medicine, Houston,
7X
Helper-dependent adenoviral vectors (HDAds) hold tremendous potential for liver-directed gene therapy because they can mediate long-term transgene expression without chronic toxicity. However, due to a nonlinear dose-re sponse, high doses are required to achieve hepatic transduction resulting in dose-dependent acute toxicity. To overcome this important obstacle, we have developed a minimally invasive method to preferentially deliver low dose I-IDAd into the liver of 30 kg baboons to achieve efficient hepatic transduction. Briefly, a single sausage-shaped balloon occlusion catheter was percutaneously positioned in the inferior vena cava (lYC) of baboon I to occlude hepatic venous outflow (Fig. A). Ix I011 vp/kg of a 1,IDAd expressing the baboon a-fetoprotein (bAFP) marker was injected directly into the occluded liver via a percutaneously placed hepatic artery (HA) catheter and left to dwell within the liver for 15 min before balloon deflation. As controls, Ix I011 vp/kg was administered to baboon 2 by peripheral intravenous injection and baboon 3 by HA injection without balloon occlusion. All procedures were uneventful, well tolerated, and following recovery from anesthesia, all three animals returned to their normal, active pre-injection states with no clinical manifestations of toxicity. Mild transaminitis (Grade 1) was observed for all animals , peaking at 24 to 48 h post-vector but quickly returning towards normal the next day. Importantly, a high level of bAFP was achieved in baboon 1 that was -I O-fold great er than baboons 2 and 3 and this high level has been sustained to date (at least 168 days)(Fig. B). To distingui sh between procedure-related versus vector-mediated toxicity, baboon 4 underwent the balloon procedure but was mock injected with saline, not virus and a similar mild transaminitis (Grade I) was observed in this control animal suggesting that this mild hepatotoxicity was related to the procedure, not the vector. To further improve safety, we have recently reduced the occlusion time from 15 min to 7.5 min and this did not affect the level or duration oftransgene expression. These results suggest that the therapeutic index of HDAd can be significantly improved by delivering the vector preferentially into the liver using a minimally invasive balloon occlusion catheter technique and may be a first step towards clinical application of HDAd for liver-directed gene therapy. A.
B.
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Eduard Ayuso, I Montane Joel,' Anguela M. Xavier,' Callejas David,' Mann Chris, I Garcia Felix," Andaluz Ana, 2 Mingozzi Federico.' High A. Katherin,' Bosch Fatima.' 'Center 0/Animal Biotechnology and Gene Therapy. and Dept. 0/Biochemistry and Molecular Biology. Universitat Autonoma de Barcelona, Bellaterra, Spain: JDept. 0/Animal Medicine and Surgery, Universitat Autonoma de Barcelona, Bellaterra, Spain; 3Dept. 0/ Pediatrics, University 0/ Pennsylvania Medical Center and The Children S Hospital 0/ Philadelphia, Philadelphia. Adeno-associatcd vivurs (AAV) vectors arc desirable vectors for gene therapy because oftheir low immunogenicity, their broad range of target tissue and the wide variety of seroptypes available. The most commonly used seroptypes for liver transduction in dogs are serotypes 2, 6 and 8 whereas in humans it is serotype 2. However, natural neutralizing antibodies (NAs) in humans can limit the effectiveness ofAAY2. Other studies have shown that this response is specific for AAV2 and not for other serotypes. In dogs , virus is commonly delivered via the portal vein and in humans via the hepatic artery, both of which necessitate surgery and are invasive. In several animal models a rapid infusion of volume , and therefore pressure , is one ofthe thechniques most frequently used to improve tranfcr of plasmid DNA into the liver and other tissues, To explore thc ability of pressure to increase liver transduction with AAV-I , a serotype with low liver tropism in mice, we injected 20 ml/kg of AAV-l CMV-G FP solution via the saphenous vein. After 7 days we round a very high transduction or the liver with about 60% of the hepatocytes demon strating GFP expression. In contrast, no expression was detected in the skeletal muscle of the hind limb. Measure ments ofcardiac frequency and arterial diastolic and systolic blood pressure revealed no changes, such as tachycardia, during or after the injection, when the dog was anaesthetised, emphasising the safety ofthe technique. The present work demonstrates that efficient liver transduction in dogs can be achieved with AAV-I using a high pressure method via saphenous vcin. This method may have benefits for human therapy since a less invasive technique is desirable, the effect of pre-existing NAs can be minimised and it could allow the possible readministration in patients treated with other serotypes. Supported by SAF2005-0 1262, Spain and European Community (CLINIGENE, LSHB-CT-2006-0l8933).
966. Limited Correction of VLCAD Deficiency in Mice with a Native VLCAD Promoter David B. Schowalter, I Tien V. Nguyen,' Janice K. Daniels,' 1. Lawrence Merritt.' 'D epartment a/Medical Genetics. Mayo Clinic, Rochester; MN. Deficiency or very long-chain acyl-CoA dehydrogenase (VLCAD) , one of several nuclear encoded mitochondrial enzymes that catalyze the initial step in the beta-oxidation or straight-chain fatty acids, often presents with cardiomyopathy, fasting hypoglycemia, rhabdomyalysis, and/or sudden death. While dietary therapy for VLCAD deficiency has been beneficial to some, many people do not respond. Times of illness with diminished oral intake, exercise, or fasting all increase demand for fatty acid metabolism and can potentially trigger catastrophic events even while on dietary therapy. A murine knockout model of VLCAD deficiency is available and shows a number of features of the human disease. Here we report the development of a recombinant AAV2/8 vector that expresses the human VLCAD gene (AAV8-hVLCAD). In vivo studies with a recombinantAAV2/8 vector utilizing the strong viral CMV promoter have demonstrated an ability to produce hVLCAD protein in liver, heart, and skeletal muscle following tail vein injection . Short-term Molecular Therapy Volume 15.Sup plement I. ~b)" Copyright
© Th e American
~il,:l
y
2007
o f Gene;Th erapy
correction of fasting hypoglycemia and elevated long-chain acylcamitine species has been demonstrated. Over time (75 days) a loss of protein expression is seen with a gradual increase in long-chain serum acylcamitine species to near pre-treatment levels. Studies of hepatic DNA from early- and late-treated mice demonstrate a loss ofAAV genomes as one possible explanation for this. In an effort to develop a more durable expression vector with a more natural distribution oftissuc expression , we prepared several native VLCAD promoter constructs in a luciferase reporter system and compared in vitro promoter activity in 293 cells. Recombinant AAV2/8 vectors were then prepared using the two most promising promoter fragments (p 187. P1154). Following tail vein injection ofVLCADdeficient mice with these recombinant vectors, robust hVLCAD expression is seen in the liver and heart, and serum C 18acylcarnitine levels arc reduced to wild type levels by day II. Altogether, this work demonstrates the ability of the native hVLCAD promoter to produce sufficient hVLCAD protein to correct accumulated CI8 acylcamitine species in murine serum.
967. Non-Viral Gene Transfer into Gunn Rats for Prevention of Drug Toxicity and Investigation of UGT Isoenzyme Function In Vivo Istvan Danko, I Zhen Jia.'
'Department ofPediatrics, University ofWisconsin-Madison, Madison, IV/. Background: Variation in activ ity of UDP-glucuronosyl transferases (UGTs) in various tissues may be critical determinant of toxicological susceptibility. However overlapping substrate specificities make studying tissue-specific role of various UGTs in vivo very difficult. We have studied the feasibility ofnon-viral transfer of human and rat UGTs (hUGT, rUGT) into UGT deficient Gunn rats to conduct such studies. Methods: Animals: 4-6 week old Gunn and Wistar rats (GR, WR). Plasmid expression vectors for rUGTIAI , rUGTIA5, hUGTIAI were based on pCDNA3hUGTIAI containing CMV promoter (gill ofJ. Ritter). Control: pCI-LacZ (Promega, Madison, WI). Gene transfer: Seven days before Menadione injections groups ofGR received hepatic venous injection of 1/15 of body weight vector solution containing 0.6 mg of plasmid. Menadionc exposure and cvaluation of toxicitv: Serum alanine aminotransfcrase (ALl'; indicator ofhepatoeyte damage; UlL) was measured 24 hours after each ofthree consecutive daily intraperitoneal injections of various doses (5, 10, 15, 25, 50 mg/kg) of Menadione; serum bilirubin (SeBi J.lM/L) was measured before, and 7 and 10 days after gene transfer Gust before the first and one day after the last Menadione injection); Statistics: Data arc expressed as mean ± SO. Differences between the means from two independent samples werc tested with the t test. Results: Toxicitv of Menadione in WR vs. GR: Menadione dose of 10 mg/kg resulted in significantly higher ALl' levels in GR vs. WR (282±18 and 164.5±12 respectively, n""2, p<0.05) without mortality or significant morbidity by 24 hours after the second injection. At earlier time points and with < I0 mg/kg doses the difference was not significant. Mortality in GR was first observed at doses ~25 mglkg. Effect of hepatic expression of various UGTs on Menadione toxicity in GR: Serum ALl' 24 hours after the second Menadione injection of 10 rug/kg in GR expressing hUGTlA I was significantly lower than in GR not expressing hUGTIAI (158±24 vs. 282± 18; n=2 p<0.05). ALl' levels in GR expressing rUGT IA I, rUGTIA5 and lacZ 24 hours after the third injection of 15 rng/kg Menadione were 327.5±16, 433±28 and 416±1O respectively (significantly lower in rUGTIAI group vs. both other groups (n=4, p<0.05». Average SeBi before gene transfer, before first and one day after the third Menadione injection in the respective groups were: 124.8±23, 86.5±20, 93.5±1I; 121.9±21, 119±9.3, 114.5±12 and 120.9±20, 120.6±13, 117.5 ±IO. The decrease in serum bilirubin in GR expressing rUGTIAI vs. GR expressing rUGTIA5 or Molecular Therapy Volume15. Supplement I. ~ "'r 2007 Copyright © The Ameri can Soci ety o r Gene "1l1f:r:lpy
lacZ was statistically significant (n=4, p<0.05) Conclusions: UGT deficiency leads to increased Menadione toxicity. Non-viral expression of both human and rat UGTIAI in Gunn rat liver is protective against Menadione toxicity and leads to significant decrease in serum bilirubin. Selective expression ofUGTs in various tissues by non-viral gene transfer has great potential as a tool for investigating tissue-specific role ofvarious UGT isoenzymes and may provide an innovative gene therapy approach for prevention of the toxicity of various chemotherapy drugs and environmental toxins.
968. Patent Inventorship of Principal Investigators in Phase I Gene Transfer Clinical Trials: An Empirical Analysis Karen L. Durell,' Jonathan Kimmelman.' Josephine Nalbantoglu,' Richard Gold.'
'Faculty ofLaw, McGill University, Montreal, QC. Canada; 2Biomedical Ethics Unit, McGill University, Montreal, QC, Canada; 3 Department ofNeurology and Neurosurgery, McGill University, Montreal, QC, Canada. BACKGROUND: Policies of professional societies , institutions, and journals take widely varying positions on whether patent inventorship represents a potential interest conflict. Whereas institutions like the University of Pennsylvania and journals like JAMA have policies addressing patent inventorship, other universities (e.g. Washington University in St. Louis) and journals (e.g. Journal of Clinical Oncology) do not. Elsewhere, one of us OK) has argued that patent inventorship represents a financial interest that should be managed where human subjects are involved. PURPOSE: We undertook an empirical study to determine the frequency with which principal investigators in phase I gene transfer trials were named as inventors on patents relating to the study agent. METHODS: GEMCRIS entries and Appendix M filings were collected for 200 phase I gene transfer trials submitted to the OBA between 1999 and 2002. U.S. Patent and Trademark Office, and World Intellectual Property Organization Patent, Copyright and Trademark databases were searched using principal investigators in the inventor field. A certified patent agent (KD), in consultation with a gene transfer researcher (IN), determined whether patent elaims corresponded to any aspect ofthc investigational agent. After matches wcrc identified, we recorded the identity of the patent assignee, the identity of matching claims, and checked informed consent documents to determine whether patent interests were disclosed to research subjects. RESULTS: Among the various types of claims that matched protocols were: cells modified with specific genes, vectors, modes of agent administration, methods of expanding modified cells, treatment combinations, treatment steps, methods ofinducing physiological responses , and vector production processes. To date, patent records for 43 principal investigators (of 239 in our sample) have been sought. We found that 18 principal investigators (40%) were named as inventors on patents related to the study; this corresponded to eighteen protocols (45%) . Most patents (61%) were assigned to an institution hosting the clinical trial; the others were assigned to a principal invest igator. Of trials involving an investigator-inventor, 41% consent documents contained generic statements relating to commercialization. These generally took the form of statements about the usc ofdatabanked tissues. Disclosure of specific financial interests like patent invcntorship was observed for 17%. CONCLUSIONS: Our preliminary data indicate that inventorship is common in gene transfer trials. However, disclosure of patent inventorship in informed consent documents is sporadic. These findings, should they hold up after searching remaining protocols, have implications tor ethical review and informed consent practices (funding: Canadian Institutes of Health Research MOP-79288).
S369