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Adeno Associated Virus (AAV)

AAV has been proved as the most excellent gene therapy vector. To date, more than 204 clinical trials have been carried out using AAV vectors for gene delivery [4], and promising gene therapy outcomes have been achieved from Phase 1, Phase 2 and Phase 3 trials for a great number of diseases (Table 1), including lipoprotein lipase deficiency (LPLD) [5], spinal muscular atrophy (SMA) [6], retinal dystrophy [7,8], cystic fibrosis [9,10], Duchenne Muscular Dystrophy [11], Hemophilia [12], congestive heart failure [13], Parkinson's disease [14] and Rheumatoid Arthritis [15,16]. Among them, Luxturna from Spark has been approved by FDA to treat patients with retinal dystrophy, AVXS-101 by AveXis has shown outstanding therapeutic effects in patients with spinal muscular atrophy, while AAVs with micro-dystrophin and coagulation factor IX have displayed great potential in the treatment of Duchenne Muscular Dystrophy and Hemophilia respectively.

a)Luxturna for treatment of retinal dystrophy
The FDA has approved LUXTURNA™ (voretigene neparvovec-rzyl), a one-time gene therapy product designed for the treatment of the LCA ( Leber's congenital amaurosis) patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy in December 2017. LUXTURNA is the first and only pharmacologic treatment for an inherited retinal disease (IRD) and the first AAV vector gene therapy for a genetic disease approved in the U.S. LUXTURNA uses AAV2 to carry out functional copies of the RPE65 gene delivery to the retinal pigment epithelial (RPE) cells to compensate for the RPE65 mutation [17]. With the functional RPE65 gene delivery, retinal pigment epithelial cells begin producing the RPE65 protein [18], letting 11-cis-retinal (a critical visual pigment component) regenerate to restore the visual cycle [4,19]. To date, Phase 1 studies have shown potential benefits of gene replacement in RPE65-mediated inherited retinal dystrophy, and the Phase 3 studies also demonstrate great efficacy and safety of Luxturna gene therapy in participants inherited retinal dystrophy [20].

Table1. Selected clinical trials using AAV vectors.
Indication Gene AAV serotype Route of AAV delivery Phase Sponsor
Lipoprotein lipase deficiency LPL AAV1 Intramuscular II–Ⅲ Amsterdam Molecular Therapeutics
LPL AAV1 Intramuscular I UniQure Biopharma B.V.
Spinal muscular atrophy 1 SMN AAV9 Intravenous I AveXis
SMN AAV9 Intravenous AveXis
SMN AAV9 Intravenous AveXis
Spinal muscular atrophy SMN AAV9 Intravenous I AveXis
SMN AAV9 Intravenous AveXis
SMN AAV9 Intravenous AveXis
Retinal dystrophy RPE65 AAV2 Subretinal I–II University College, London
PDE6B AAV5 Subretinal I–II Horama S.A
Cystic fibrosis CFTR AAV5 Lung, via aerosol I NIDDK
Hemophilia A HLP-FVIII-V3 AAV8 Intravenous I University College, London
Hemophilia B FIX AAV2 Intravenous I Spark Therapeutics
FIX16 AAVrh10 Intravenous I–II Ultragenyx Pharmaceutical Inc
Arthritis TNFR:Fc AAV2 Intraarticular I Targeted Genetics Corporation
TNFR:Fc AAV2 Intraarticular I–II Targeted Genetics Corporation
hIFN-b AAV5 Intraarticular I Arthrogen
hIFN-b AAV5 Intraarticular I Arthrogen
Congestive heart failure SERCA2a AAV1 Intracoronary I–II Celladon Corporation
SERCA2a AAV1 Intracoronary II Celladon Corporation
SERCA2a AAV1 Intracoronary II Imperial College London
SERCA2a AAV1 Intracoronary II Assistance Publique - Hôpitaux de Paris
SERCA2a AAV1 Intracoronary I–II Celladon Corporation
Parkinson's disease GAD AAV2 Surgical infusion I Neurologix, Inc.
GAD AAV2 Intrastriatal I Genzyme, a Sanofi Company
NTN AAV2 Intrastriatal I Genzyme
NTN AAV2 Bilateral Intraputaminal (IPu) II Genzyme
NTN AAV2 Bilateral Intraputaminal and Intranigral I–II Sangamo Therapeutics
Alzheimer's disease NGF AAV5 Bilateral, stereotactic I Ceregene
APOE2 AAVrh.10 Intracisternal I Weill Medical College of Cornell University

b)AVXS-101 for treatment of spinal muscular atrophy (SMA)
AVXS-101 is being developed by AveXis (Owned by Novartis) to carry out gene delivery of a functional copy of the SMN1 gene by using AAV9 vector to motor neuron cells in SMA patients [21]. The SMN1 transgene in AVXS-101 contains double-stranded DNA, meaning it consists of the genetic instructions and takes the same form as natural genes, so that it can be activated more quickly to produce continuous and sustainable SMN protein, resulting in more efficient gene therapy in vivo. The safety, tolerability and impressive improvements in motor function of AVXS-101 in all patients with SMA Type 1 has been guaranteed during Phase 1 clinical trials [51]. Based on the preliminary top-line results, the FDA has granted AVXS-101 Orphan Drug Designation for the treatment of all types of SMA and Breakthrough Therapy Designation, as well as Fast Track Designation, for the treatment of SMA Type 1. Likewise, the European Medicines Agency (EMA) also granted AveXis access into its PRIority Medicines (PRIME) program for AVXS-101 for the treatment of SMA Type 1 in January 2017. Then in December 2017, AveXis also announced the start of an open-label, dose-comparison, multi-center Phase 1 trial, also known as STRONG, to evaluate the safety, optimal dosing and proof of concept for efficacy of AVXS-101 gene therapy in two distinct age groups of patients with SMA Type II. Nowadays, AveXis is running a Phase 3 trial, called STR1VE (NCT03306277) in infants with SMA type 1 to further understanding of both the safety of AVXS-101 gene therapy, and how well AVXS-101 may work in SMA patients, which may bring new hope for pediatric and adult patients with other types of motor neuron diseases.

c)AAV with micro-dystrophin for treatment of Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD), resulting from dystrophin gene mutation, is a severe genetic disease resulting in body-wide muscle degeneration and necrosis in boys and young men [22]. In gene therapy theory, replacing or correcting the mutated dystrophin gene with a functional one would cure this disease [23]. However, the enormous size of dystrophin cDNA and the distribution of muscle throughout the body presented great challenges to this arduous task. To address these obstacles, researchers have developed the highly abbreviated micro-dystrophin gene and designed systemic gene delivery with AAV2.5, which was a translational optimized AAV variant, inducing stronger transduction in skeletal muscles than AAV2 and displaying lower crossreactivity to AAV2 neutralizing antibodies [11]. To date, preclinical data suggests that intravascular AAV micro-dystrophin delivery can significantly ameliorate muscle pathology, enhance muscle force, and attenuate dystrophic cardiomyopathy in animals, such as mice and canines [24,25]. Phase 1 clinical trials of AAV2.5 in DMD patients have shown that rationally designed AAV vector (AAV2.5) was safe and well-tolerated, setting the foundation of customizing AAV vectors best suiting the clinical objectives [11]. Meanwhile, more clinical trials are required to estimate the clinical efficacy of AAV2.5 with micro-dystrophin gene, and the findings display great prospects of body-wide DMD therapy with a synthetic micro-dystrophin AAV vector [26].

d)AAV with coagulation factor IX for treatment of Hemophilia B
Hemophilia B (HB) is an X-linked disease, caused by a deficiency in functional coagulation factor IX protein (FIX) [27]. Currently, preclinical data suggests AAV vector-mediated gene transfer of coagulation factor IX to the skeletal muscle or liver have shown sustained correction of hemophilia B in mice and dogs [28,29]. The two initial phase I/II clinical trials with FIX cDNA gene delivery by AAV vectors for treatment of hemophilia B displayed no serious adverse effects, but demonstrated contrary results, no therapeutic level of FIX in muscle trial while some therapeutic effects closely with that of hemophilic dogs [30]. To date, gene therapy for Hemophilia B via systemic administration of AAV vectors containing an optimized coagulation factor IX construct has achieved considerable progress, ameliorating the bleeding phenotype numerous patients [31]. However, challenges remain for sustained gene therapy in patients, and efforts are still required to improve long term expression of factor IX, via optimizations to the AAV vector, transgene cassette and correction strategy.


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