Preclinical Studies for Leber Congenital Amaurosis

Transcription

1 Preclinical Studies for Leber Congenital Amaurosis Consortium: UPenn U. Fl, Gainesville Cornell Iowa Washington ASGT Stakeholders Meeting April 7, 2005 Jean Bennett, M.D., Ph.D.

2 Rando Allikmets Anonymous Karl Csaky Richard Hurwitz Albert Maguire Phillipe Moullier Eric Pierce Steve Rose Paul Sieving Richard Snyder Edwin Stone Santa Tumminia Jean Bennett Disclosure I am listed as one of the 6 co-inventors on the patent: Gene Therapy for Leber Congenital Amaurosis However: I have waived all potential financial interests (as have Albert Maguire and Samuel Jacobson) Acknowledgements

3 #1: Orphan Disease Issues (academia vs industry): Profit Intellectual property/personal investment Regulatory/bureaucratic issues Vector biases Trial design Patient selection Expectations/Goals

4 Issues common with other diseases Regulatory Environment The challenge: Increasingly more difficult and expensive to get research from bench to bedside Gene therapy has extra layers of scrutiny The solution:? CBER IRB DSMB COI GMP OBA HAL CROPre-IND USDA GLPCLIA GCMC FSJUTA OBA RAC IND IBC

5 Regulatory Environment/Funding Consider: Only 2 ocular gene therapy clinical trials over past 6 years Ad.PEDF (AMD): Rasmussen et al 2001 Hum Gene Ther 12: Ad.TK (retinoblastoma) Hurwitz et al 1999 Science 284:2066 One biotech start-up went from idea to ocular clinical trial in 11 months (involving RNAi for AMD -but not gene rx) no long-term safety/efficacy data Efficacy data challenged

6 Limited Resources Plus: Fragmentation of Resources At least 2 different groups are planning a gene therapy human clinical trial for LCA- RPE65. Plans for each clinical trial are shrouded in secrecy There is no exchange of information between the groups Solution??????

7 Problem: Patient Selection Need for a national database with comprehensive clinical and genetic data and: HIPAA compliance Lack of redundancy Searchable interactive data base Maintenance of follow-up with patient 20/20 Optimal timing of Rx Visual acuity Clinically Blind {Modified from slide of E. Stone} Age

8 Problem: How to recruit the prerequisite number of individuals for a clinical trial? 10,000 individuals in USA have LCA 90% are not screened 450 individuals are available through databases 10% have RPE65 mutations 45 individuals 50% most likely have null mutations ( stop mutations) 22 individuals 50% advanced age/disease or other exclusion issues 11 individuals

9 Solution: How to gain 1 log unit 10,000 individuals in USA have LCA 90% are not screened 450 individuals are available through databases 10% have RPE65 mutations 1,000 individuals 50% most likely have null mutations ( stop mutations) 500 individuals 50% advanced age/disease or other exclusion issues 250 individuals

10 Problem: Patient Selection based on Genotype/Phenotype Data Situation at present: CLIA-Certified Molecular Diagnostic Testing at: Carver Laboratory for Molecular Diagnosis/University of Iowa (Ed Stone, Kellogg Eye Center/University of Michigan ( X-Linked Juvenile Retinoschisis» GeneDx, Inc; Gaithersburg ( NIH Ocular Genetics Laboratory ( Many other labs perform Research Genotyping

11 Solution: Patient Selection based on Genotype/Phenotype Data Not yet solved, but National Ophthalmic Genotyping Diagnostic and Research Network (NEI): CLIA laboratories that can deliver genotype + phenotype information to a secure database >12 groups responded Data is to be maintained at NEI/NIH Investigators will be designated to screen for specific gene defects Challenges»$$$$»Ability to tap into experience/expertise already existent»avoid conflicts of interest

12 Issues common with other diseases Trial Design: Age of the subjects/stage of disease Dejneka & Bennett, 2001 Bioessays 23:662 The challenges: Retinal photoreceptors die as disease progresses For LCA, there is decreasing plasticity with age with respect to retinal/cns connections (amblyopia)

13 Why not start with children? Informed consent issues Ethical concerns? One ethicist recommended working with children potential therapeutic effect PI does not have extensive experience with pediatric evaluation affiliation with pediatric facility

14 Trial Design Issue: Should children be the subjects? A solution: Phase I/II will involve adults with advanced disease Outcome measures will identify toxicity and therapeutic effect Mutant of month Nat Gen Feb 2002

15 Issues common with other diseases Predictive nature of animal models Mouse = dog = monkey = human

16 Issues Unique to Ocular Disease Preclinical Toxicity Studies Presence of a macula in primates Lack of macula in animal models

17 Issues unique to the eye Should treatment be delivered to macula or to peripheral retina? Macular delivery: highest likelihood of therapeutic effect perceptible to the patient Risk is proportional to pre-existing macular vision

18 Issues common with other diseases The Problem: Risk of Heightened Expectations Rescue may not be as dramatic as has been shown in dogs: Untreated 3 mos post bilateral treatment

19 The problem of hype Outcome could be extraordinary but. the extent of therapeutic efficacy will depend on the disease, stage at which it is treated Consider the cases of: Mike May

20 Michael May Blinded by chemical explosion at age 3 Age 46, received stem cells/ corneal transplant The operation fully restored May's visual capabilities, meaning he can "see." But his brain's ability to interpret and understand those signals remains far from normal. He can catch a ball, but he can't recognize his wife's face. He can only tell a cube is a cube if it's moving. He recognizes colors perfectly but he can't tell shadows from trees. Rob Stein, Washington Post, Aug. 25, 2003

21 Retinal/CNS Connectivity issues are unique to LCA These are irrelevant to the majority of other retinal/macular degenerative diseases

22 Summary: How can industry help? Funding for orphan disease studies Help with regulatory/bureaucratic issues Help with preclinical toxicity studies Advice regarding trial design Children as subjects? Patient genotyping? Help educate the public regarding realistic expectations Use this trial to encourage development of other trials for blinding disease

23 Problem: Availability of Unique Animal Models Some models are available to any scientist through vendors or academic investigators Restricted access Some unique strains areonly made available through collaboration (i.e. co-authorship; restrictions on use/breeding) Disproportionate charges to purchase some unique strains (e.g. ~ $40,000/mouse breeding pair) Some important animal models are made unavailable regardless of cost or collaboration

24 Solution: Animal Model Resource Centers Jackson Labs Other facilities???? Large animals????