Which animal species did regulators accept for approved gene therapies?

“Rat and cynomolgus monkey have been used as the toxicology species for Syn3NODA and cynomolgus monkeys were used for the toxicological assessment of rAd-IFN/Syn3NODA.”

“As a toxicological species, monkeys may be a worst-case model, since systemic toxicity of rAd-IFN will be of very limited relevance to the clinical situation.”

“A toxicology study was also conducted evaluating IV administration of AAVRh74var Padua in nonhuman primates (NHP) at dose levels ranging from 1 x 1012 vg/kg to 5 x 1012 vg/kg.”

“The toxicity of exa-cel has been evaluated in an in vivo combined GLP toxicity and tumorigenicity study with a duration of 20 weeks in NSG mice.”

“No in vivo proof-of-concept studies were conducted as no relevant animal disease model for TDT and SCD exists that could be used for evaluation of exa-cel.”

“The following toxicology studies were conducted to evaluate the safety of ELEVIDYS following administration in WT and mdx mice.”

“The pharmacology studies of ELEVIDYS were conducted in rodent models of DMD including mdx mice and Dmdmdx rats.”

“which investigated the effect of a single intravenous administration of 5.0x1012 to 5.0x1013 vg/kg scAAV9.U1a.SGSH in WT C57Bl/6 mice.”

“Three separate 92-day, single-dose toxicology studies were conducted in healthy adult and juvenile mice.”

“All toxicity studies were performed in wild type mice in accordance with GLP.”

“The use of a single species for toxicity evaluation is in accordance with the guideline for gene therapy medicinal products EMEA/CHMP/GTWP/587488/2007 and the guideline on the non-clinical studies required before first clinical use of gene therapy medicinal products (EMEA/CHMP/GTWP/12459/2006).”

“The toxicology data package of etranacogene dezaparvovec and AMT-060 included single IV dose toxicity studies up to duration of 6 months with 6 months observation period in C57Bl/6 mice and cynomolgus macaques, and a reproduction and developmental toxicity study in mice.”

“From the pharmacokinetic point of view, non-human primates were the most relevant species”

“Exploratory and GLP-compliant repeat dose toxicity studies were conducted in Balb/c mice with up to 12 weekly doses.”

“The expressed human GM-CSF is not bioactive in the mice, thus the findings are likely not related to exposure to this human protein.”

“In vivo toxicology/safety studies conducted in NHPs utilized a single IT administration of OAV101 at 1.2 x 1013 vg/animal, considered equivalent to the proposed starting clinical dose level for ITVISMA of 1.2x1014 vg/patient based on a 10-fold difference in CSF volume between NHP and human.”

“IT administration of scAAV9.CBA.SMN demonstrated a 55-79% transduction efficiency of choline acetyltransferase (ChAT) positive motor neurons in NHP spinal cords.”

“The nonclinical safety program conducted to characterize the toxicity and biodistribution of eladocagene exuparvovec comprised of two studies, a 30-day study, and a 6 month study, both in rats.”

“The applicant also used surrogate Lin- HSPCs transduced with the Chim-CD18-WPRE LV transplanted into recipient mice for their definitive in vivo toxicology and BD studies.”

“CD18HYP and CD18KO mice have deficient CD18 expression and impaired neutrophil migration and inflammatory responses similar to LAD-I patients.”

“The in vivo safety of single IV administration of ARSA LVV-transduced mHSPCs at 1x106 cells/mouse (40-50x106 cells/kg) in irradiated As2-/- mice was evaluated in a pivotal GLP study for up to 12 months post-transplant.”

“The applicant has used the As2-/- mouse as a disease model for MLD in children.”

“Single dose and repeat dose toxicology studies were conducted in normal-sighted dogs, RPE65 mutant dogs, and normal-sighted non-human primates (NHPs).”

“The applicant noted that relative transduction efficiency of AAV2 in RPE cells across species is not known but that, given the sizes of eye in dog and mouse, the studies in Briard dogs are more relevant to human effects than those in mice”

“The following toxicology studies were conducted to evaluate the safety of human HSCs or mBMCs transduced with BB305 LVV following administration in mice.”

“To evaluate the pharmacologic and toxicologic effects of mBMCs transduced with BB305 LVV or mBMCs transduced with HPV569 LVV following IV administration in β-thalassemic mice.”

“Single-dose toxicology studies were conducted in Otof-Q828X hom mice and cynomolgus monkeys.”

“This study provides the most clinically relevant procedural safety data, as it utilized the same RWM surgical approach intended for clinical use and was performed in monkeys with inner ear anatomy similar to humans.”

“The following toxicology study was conducted to evaluate the safety of PRGN-2012 following SC administration in WT mice.”

“The dose level assessed in this non-GLP toxicology study provides a 5-fold safety factor for the clinical dose level with the caveat that the processing and binding sequences in wildtype mice is likely different than the peptides recognized by human T cells .”

“As the clinical schedule foresees one unique injection of BMN 270, all non-clinical studies supporting the safety of BMN 270 are single-dose toxicity studies conducted by the IV route, in male animals, in different animal species (Rag2-/- mice, Rag2-/- x FVIII-/- mice, CD1 mice, monkeys), which is acceptable.”

“All animals used in the nonclinical programme to evaluate BMN 270 were males because > 99% of HA patients are male.”

“pivotal combined in vivo pharmacology, single-dose toxicity, genotoxicity and biodistribution studies in immunodeficient (NSG and NSGS) mice”

“they will be rejected. Therefore immune”

“The use of NSG mouse strain (deficient in mature T/B/NK cells) for the non-clinical biodistribution/single-dose toxicology study after engraftment of CD34+ cells derived from healthy human UCB, transduced with GSK3336223 vector, was endorsed by the CAT/CHMP prior to MAA submission.”

“Subsequently, the results of two bio-distribution studies were submitted using the NSG mouse based on the reports presented that indicate this is a valid model for immunodeficient mice, which can be used as recipient of HSPC transplantation, with longer survival rates and reduced frequency of spontaneous tumours as compared to ADA-/- mice.”

“Toxicology studies evaluating TUDRIQEV and mRP1 were conducted in tumor-bearing immunocompetent mice and healthy rats, respectively.”

“the use of a single species (mice) for the toxicity studies is considered acceptable and in line with the”

“A justification for the choice of mice is not specified, other than the suggestion that this species is historically used in toxicity studies.”

“Two different WAS disease models were used to evaluate in vivo safety of transduced HSPCs: a WAS knockout (WKO) mouse on a C57BL/6 background”

“The impossibility of using autologous human cells in animal models limits the scope of possible nonclinical studies.”

“In the toxicology and biodistribution (BD) study, nonclinical products representative of ZEVASKYN comprised of human acellular dermal matrix and RVV-transduced human keratinocytes (cells alone) were implanted into excisional wounds generated in mice for 4- or 8-weeks.”

“Single-dose toxicology studies were conducted to evaluate the safety of AVXS-101 following a single IV administration in healthy neonatal FVB/n mice.”

“The Applicant has chosen to use the FVB/n strain in the toxicology studies to be able to directly compare safety data from the SMNΔ7 studies.”

“BB305 LVV-transduced cells were evaluated in the β-thalassaemic (Hbbth1/th1) mouse model and in the NSG mice.”

“they are therefore unable to reject the human CD34+ HSCs.”