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Gene Therapy Viral vectors in clinical gene therapies (2) 1st December 2014 Prof. Józef Dulak, PhD, DSc Department of Medical Biotechnology Faculty of Biochemistry, Biophysics and Biotechnology Room 3.025/3.07 Phone 664-63-75 Email: [email protected] Exam 2nd February 2015 (Monday) 13 pm, room D107 Adenoviral vectors Very efficient, transduce many cell types, provide high level of expression Very imunogenic systemic inflammatory response… Adenoviral vectors of the first generation Great: • Very high transduction efficiency • Broad host and cell type ranges • Can be prepared in high titers • Can transduce mitotic and post-mitotic cells • Do not integrate with genome • Can harbor ~ 7 kb of transgene But: • Strong immune response to viral proteins eliminate virally transduced cells within 30 days • Neutralizing antibody response prevents readministration of adenovirus vector of the same serotype Thus: Adenoviral vectors provide the high but transient (<4 weeks) transgene expression 4 Ornithine transcarbamylase deficiency – gene therapy Jesse Gelsinger 1999 Application of adenoviral vectors in gene therapy 1. Gene therapy of inborn errors in metabolism – lack of OCT 2. Gene therapy of monogenic diseases – cystic fibrosis 3. Gene therapy of cardiovascular diseases – transfer of angiogenic genes 4. Gene therapy of cancer – it is possible that toxicity and immongenicity will enhance the therapeutic effectiveness 6 p53 and gene therapy of cancer p53 and cancer development About 50% of cancers have mutated p53 p53-mediated tumor suppressor network Tanazawa et al., Exp Opinion Biol Ther 13 (11): 2013 Adenoviral delivery of p53 gene Adenoviral vector With correct p53 gene TP53 Cancer cell expression of p53 in cancer cell apoptosis First officially registered therapeutic nucleic acid Gendicine (SiBiono GeneTech, Chiny) Adenoviral vector with a correct p53 gene Efficient in patients with head and neck cancers Claimed to be 3 x more efficient than radiotherapy alone Registered on 16. X. 2003, after 5 years of clinical trials ADVEXIN® p53 tumor suppressor therapy ADVEXIN therapy combines the p53 tumor suppressor with a non-replicating, non-integrating adenoviral delivery system we have developed and extensively tested. The p53 gene is one of the most potent members of a group of naturally-occurring tumor suppressors, which act to kill cancer cells, arrest cancer cell growth and protect cells from becoming cancerous. Introgen's clinical trial strategy for ADVEXIN is to test it in a variety of life-threatening cancers for which there are no effective treatments. Introgen is seeking to register ADVEXIN for the treatment of head and neck cancer and Li-Fraumeni Syndrome. Additional late stage clinical trials in breast and lung cancers will enable Introgen to add follow-on indications. FDA designated Fast Track Drug Product Development program FDA and EMEA designated Orphan Drug status for ADVEXIN® in head and neck cancer. ADVEXIN® therapy well tolerated and clinically active. Advexin finally was not registered by FDA… There are doubts on the real effectiveness of Gendicine Leber’s congenital amaurosis – gene therapy 1. Most common cause of congenital blindness in children 2. LCA2 – one of the forms – caused by mutation in the retinal pigment epithelium-specific 65-kD protein gene (RPE65) 3. RPE65 is required to keep light-sensing photoreceptor cells – the rodes and cones of the retina – in operating order 4. The RPE65 gene encodes for the isomerohydrolase that isomerizes bleached all-trans-retinal into photosensitive 11-cis-retinal (Jin et al., 2005; Moiseyev et al., 2005). If no 11-cis-retinal is produced due to loss of or impaired RPE65 function, the chromophore rhodopsin cannot be assembled, and the photoreceptors remain insensitive to light stimuli 5. LCA2 is a rare diseases – in USA only 2000 people – but is untreatable and causes blindness early in life 15 LCA gene therapy - AAV 2 Lancet, October 2009 16 Gene therapy trials for various occular diseases Retinoblastoma – tumor Age-related macular degeneration – AMD – application of PEDF – pigment epithelium derived factor – this is an anti-angiogenic factor Leber’s congenital amaurosis 17 Choroideremia – another type of blindness Choroideremia derives its name from the almost complete loss of the retina, choroid, and retinal pigment epithelium that leads to exposure of the underlying white sclera, which is a unique feature compared with other retinal degenerations. • an incurable X-linked recessive degenerative disease of the retina and choroid • It has a prevalence of about 1:50 000, with northern Finland having the highest • Loss of night vision begins in the first decade of life and progresses with a gradual loss ofperipheral vision and legal blindness by the fi fth decade. • Choroideremia is caused by mutations in the CHM gene, which was one of the first genes identified by use of positional cloning • Subsequently, prenylation deficiency due to absence of Rab escort protein-1 (REP1) encoded by CHM was identified as the cause of retinal degeneration in choroideremia • Nearly all reported cases of choroideremia so far have been attributed to functionally null mutations • that, combined with the slow rate of degeneration and small size of the CHM protein coding sequence (1.9 kb), make gene therapy with AAV vectors an appealing treatment strategy. RE MaclLaren et al., Lancet 2014; 383: 1129–37 Gene therapy of choroideremia • In The Lancet , Robert MacLaren and colleagues present data for six patients treated with subretinal delivery of an AAV vector encoding CHM , the gene disrupted in choroideremia, in a phase 1 trial. • All patients recovered to baseline visual acuity despite detachment of the fovea as part of the surgical procedure. • The authors did not notice any obvious detrimental effects resulting from detachment and treatment of the fovea, which is paramount since the ultimate goal of such an intervention is to prevent central visual loss. • Two of the patients gained signifi cant visual acuity. HPN Scholl & JA Sahel, Lancet January 16, 2014 Haemophilia Nature, 27th November Outlook on Haemophilia Haemophilia – basic facts Haemophilia – basic facts • treatment: several times a week with infusions of concentrated factor • Problems: necessity of repeating, continuous (life-time) injections - risk of infections (HIF, HCV) - cost Haemophilia – royal family history Inheritance pattern of haemophilia Treatment of haemophilia Hemofilia A and B and gene therapy 1. Factor VIII production is not regulated in response to bleeding; 2. Even low levels of the protein can be beneficial 3. The broad therapeutic index of factor VIII minimises the risk of overdoses; 4. Delivery of factor VIII into the bloodstream does not require expression of the gene by specific organ; Size of the coding sequences of factor VIII and factor IX mRNA - factor VIII - 8,8 kb factor IX - 1,8 kb 26 Clinical gene therapy for haemophilia A Ex vivo – plasmid gene therapy Roth DA et al., NEJM 2001; 344: 1735 27 Clinical gene therapy for haemophilia A Roth DA et al., NEJM 2001; 344: 173528 Effect of ex vivo haemophilia A gene therapy Roth DA et al., NEJM 2001; 344: 1735 29 AAV8-mediated gene therapy of haemophilia A McIntosh et al., Blood 2013 Ex vivo gene therapy of haemophilia A – lentiviral delivery of factor VIII - Dogs - HSC transduced with lentiviral vector - Factor VIII released from platelets: a hybrid FVIII molecule fused to the von Willebrand factor propeptide-D2 domain that traffics FVIII into α-granules - Prevention of severe bleedings for at least 2.5 years after gene therapy Du et al., Nature Commun 2013; J Gould, Nature 27 November 2014 „Christmas” disease NEJM, December 2011 32 Gene therapy of heamophilia B – AAV2 AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B – Manno CS et al., Blood 2003; Despite strong evidence for gene transfer and expression, circulating levels of F.IX were in all cases less than 2% and most were less than 1% Gene therapy of heamophilia B – AAV2 - Liver delivery – sustained expression, - Muscle injection – no effects 34 Gene therapy of haemophilia B – AAV8 35 Gene therapy of haemophilia B – AAV8 1. Self-complementary AAV vector 2. AAV8-pseudotyped 3. Targeting to liver 4. Limitations of immune response (lower prevalence of anti-AAV8 antibodies) Nathwani et al., NEJM December 2011 36 The higher the dose of a AAV-Factor IX vector, the highest the level of FIX But higher doses of AAV8 may elicit inflammatory response Nathawani et al., NEJM, December 2011 37 Current status of gene therapy for hemophilia K.A. High, Blood 2013 38 Clinical trials for gene therapy in haemophilia – summary MI Cancio et al., Appl Clin Genetics, 6: 91-101; 2013 Potential complications of AAV-FIX gene therapy for hemophilia K.A. High, Blood 20123 40 (Gene) therapy of haemophilia – problems • About 40% of patients with haemophilia B produce antibodies against AAV – they will be excluded from this type of gene therapy • Haemophilia A – is more difficult to target by gene therapy (longer gene of factor VIII) • Shortened version of factor VIII is produced • Still, the strong immune response against AAV8 limits the effectiveness of the therapy - injections of AAV8 cannot be repeated • The problem may be potentially overcome by ex vivo HSC therapy with lentiviral vector harboring the factor VIII gene • Potential of gene editing in therapy of haemophilia • Recombinant-clotting factors – was associated with tens of thousands of haemophiliacs infected with HIV and HCV • About 75% of
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