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Metabolic Disorders

January 13, 2014

Adeno-Associated Viral Vector Serotype 5 Poorly Transduces Liver in Rat Models

REGENX Commentary:

The authors demonstrate that AAV5 is not suitable for proof-of-concept studies in rat disease models in which the liver needs to be transduced. Despite its relative efficiency in mouse and non-human primate liver, transduction of rat liver is low. In contrast, AAV8 remains suitable for liver-directed studies in rodents as well as primates.

December 29, 2013

Sustained correction of motoneuron histopathology following intramuscular delivery of AAV in Pompe mice

REGENX Commentary:

This paper describes intralingual delivery of AAV9 in Pompe mice to treat lingual dysfunction. There was robust and persistent transduction of tongue myofibers and motoneurons, and increased body weight over the course of the study.

December 29, 2013

Recombinant AAV as a Platform for Translating the Therapeutic Potential of RNA Interference

REGENX Commentary:

A review of shRNA, miRNA, and miRNA decoys and their use in therapeutic applications when expressed from recombinant AAV vectors (AAV8 and AAV9), which includes preclinical and clinical studies.

August 01, 2012

Long-Term Preservation of Cardiac Structure and Function After Adeno-Associated Virus Serotype 9-Mediated Microdystrophin Gene Transfer in mdx Mice

REGENX Commentary:

AAV9 encoding microdystrophin under the control of a cardiac promoter was injected intravenously into mdx mice, resulting in protection of cardiac morphology and function. This could be developed into a therapeutic for DMD-associated cardiomyopathy.

November 14, 2012

Adeno-Associated Virus Serotype 8 Gene Therapy Leads to Significant Lowering of Plasma Cholesterol Levels in Humanized Mouse Models of Homozygous and Heterozygous Familial Hypercholesterolemia

REGENX Commentary:

A mouse model of familial hypercholesterolemia (LDL receptor-deficiency) was created that has a lipoprotein phenotype that much more closely resembles that of humans than previous mouse models. In this model, gene therapy with AAV8 encoding the human LDL receptor significantly corrected the high plasma cholesterol levels at doses of vector that are able to be developed for human use. In addition, the vector had beneficial effects in treating the more common heterozygous FH phenotype.

October 04, 2013

Biodistribution of AAV8 vectors expressing human LDL receptor in a mouse model of homozygous familial hypercholesterolemia

REGENX Commentary:

This study was performed to support a proposed clinical trial to evaluate AAV8 gene therapy for familial hypercholesterolemia (FH). It describes the biodistribution data following intravenous delivery of AAV8 in the mouse model of FH.

September 25, 2012

Comparison of Adeno-Associated Virus Serotypes and Delivery Methods for Cardiac Gene Transfer

REGENX Commentary:

The authors compare intravenous and intracoronary delivery of AAV5, AAV6, and AAV9. Optimal vector/delivery was determined by quantitating both the percentage of cells positive for GFP expression and GFP intensity. AAV9 was found to be superior in both methods of delivery, with IV delivery resulting in more homogeneous but low-level cardiac expression, and IC delivery resulting in more intense but less homogenous cardiac expression.

March 13, 2012

Impact of age at administration, lysosomal storage, and transgene regulatory elements on AAV2/8-mediated rat liver transduction.

REGENX Commentary:

In a rat model of lysosomal storage disease, the extent of disease did not impact transduction of the liver with AAV8, suggesting that efficiency of gene transfer in humans will not be impacted by age. Inclusion of several additional regulatory elements were deemed to be unnecessary, as they did not improve efficiency nor reduce the immune response to the transgene product

August 06, 2013

Enhancing the Utility of AAV Gene Transfer Through Inducible Tissue-Specific Expression.

REGENX Commentary:

Regulatable promoter systems, such as the rapamycin-inducible ARGENT system, can be incorporated into gene therapy products in order to regulate the timing and level of transgene expression. This paper demonstrates that the ARGENT promoter can be further refined to be tissue-specific. AAV9 was used to deliver the ARGENT system in vivo, demonstrating liver-specific or heart-specific gene expression that was stable, regulatable, and reproducible over multiple cycles of induction.

December 09, 2011

AAV8-mediated Hepatic Gene Transfer in Infant Rhesus Monkeys

REGENX Commentary:

In order to understand how to treat genetic diseases that affect newborns, it is critical to understand hepatic gene transfer in neonates. This study demonstrates that heptic gene transfer with AAV8 in newborn rhesus monkeys is extremely efficient, but transgene expression is less stable than in adolescent monkeys.

December 09, 2011

Sustained correction of OTC deficiency in spf( ash) mice using optimized self-complementary AAV2/8 vectors.

REGENX Commentary:

A gene therapy for OTC deficiency is being developed using AAV8 for gene replacement. This paper delineates vector optimization that further increased gene expression to improve efficacy and lower the dose of vector required for therapeutic effect.

May 30, 2013

Intranasal Antibody Gene Transfer in Mice and Ferrets Elicits Broad Protection Against Pandemic Influenza

REGENX Commentary:

The authors used AAV9 to deliver a broadly neutralizing anti-influenza monoclonal antibody to influenza’s portal of entry, namely, the nose. They demonstrated complete protection of mice and ferrets from several different isolates of influenza that have been associated with human pandemics. This strategy has the potential to be rapidly deployed to protect against emerging pandemics as well as seasonal influenza.

December 09, 2011

Hepatorenal Correction in Murine Glycogen Storage Disease Type I With dsAAV9

REGENX Commentary:

GSD-Ia mice were injected intravenously with either AAV2, AAV7, AAV8, or AAV9 encoding a normal copy of the deficient enzyme, glucose-6-phosphatase (G6Pase). While AAV7, AAV8, and AAV9 all correced the hepatic phenotype of G6Pase deficiency, treatment with AAV9 also reduced the renal complications of the disease.

August 15, 2011

AAV8-Mediated Long-Term Expression of Human LCAT Significantly Improves Lipid Profiles in hCETP;Ldlr(+/-) Mice.

REGENX Commentary:

AAV8 was used to deliver a cDNA encoding the cholesterol metabolic pathway enzyme LCAT to mouse liver; expression was stable for at least 32 weeks.  The gene was delivered to a mouse strain that was genetically modified to have a more human-like metabolic pathway, to determine that LCAT improved lipid profiles.

November 30, 2011

Antibody-based protection against HIV infection by vectored immunoprophylaxis

REGENX Commentary:

Dr. David Baltimore at California Institute of Technology and his colleagues reported that NAV rAAV8 vectors encoding genes for anti-HIV neutralizing antibodies, when injected into the muscle of mice, can direct the synthesis and secretion of therapeutic levels of those antibodies into the circulation. They further demonstrated that the antibodies are capable of protecting the experimental animals from HIV challenge.  This approach is designated “passive immunization”, in which an individual is given high levels of an antibody that has already been demonstrated to be capable of neutralizing HIV to prevent infection.  To avoid repetitive delivery of purified antibodies over a lifetime, researchers adopted gene delivery with NAV rAAV8 vectors involving a one-time injection of the vector, which directs cells to synthesize and secrete the antibody long-term.

July 21, 2011

Cardiac AAV9-S100A1 Gene Therapy Rescues Post-Ischemic Heart Failure in a Preclinical Large Animal Model

REGENX Commentary:

AAV9 was shown to efficiently deliver a therapeutic gene to a large animal heart.  Heart failure in the pig was rescued with AAV9-mediated delivery of S100A1, which regulates calcium-controlled myocardial contractility.

May 16, 2011

Induction and Prevention of Severe Hyperammonemia in the spf(ash) Mouse Model of Ornithine Transcarbamylase Deficiency Using shRNA and rAAV-mediated Gene Delivery

REGENX Commentary:

The mouse model of OTC deficiency was made to more closely resemble the human disease by rAAV8-mediated delivery of an shRNA to knockdown residual endogenous OTC mRNA, causing the mice to develop hyperammonemia.  Furthermore, co-administration of rAAV8 encoding a “rescue” OTC cDNA determined the doses required to control the manifestations of OTC deficiency.

May 16, 2011

Efficacy of a Combined Intracerebral and Systemic Gene Delivery Approach for the Treatment of a Severe Lysosomal Storage Disorder

REGENX Commentary:

The mouse model of multiple sulfatase deficiency (MSD) was treated with rAAV9 delivered both systemically and into the CNS.  This demonstrates that delivery of a single therapeutic by two routes could be used for treating severe whole-body disorders.

May 16, 2011

Phenotypic Correction of a Mouse Model for Primary Hyperoxaluria With Adeno-associated Virus Gene Transfer

REGENX Commentary:

The mouse model of primary hyperoxaluria type I (PH1) was treated with rAAV8 or rAAV5 delivered systemically.  Both were able to normalize metabolism, with AAV8 showing higher levels of transgene expression in the liver.

April 12, 2011

Recombinant Adeno-Associated Virus-Mediated Gene Transfer for the Potential Therapy of Adenosine Deaminase-Deficient Severe Combined Immune Deficiency

REGENX Commentary:

This form of severe combined immunodeficiency (SCID) has previously been treated using enzyme replacement therapy or using virally-transduced T cells.  In this paper, AAV1 delivered IM is compared to rAAV9 delivered IV, and shows enzyme replacement and immune reconstitution of ADA-deficient mice using AAV9.

April 08, 2011

Apolipoprotein B Knockdown by AAV-delivered shRNA Lowers Plasma Cholesterol in Mice

REGENX Commentary:

rAAV8 was used to deliver shRNA to ApoB to mouse liver, showing significant reduction in circulating LDL levels.

April 08, 2011

Efficient Serotype-Dependent Release of Functional Vector into the Culture Medium During Adeno-Associated Virus Manufacturing

REGENX Commentary:

NAV Technology-based AAV vectors were shown to be efficiently released into the medium during manufacturing, increasing vector yields and simplifying production.

See also accompanying article, Rapid, Simple, and Versatile Manufacturing of Recombinant Adeno-Associated Viral Vectors at Scale.  Hum. Gene Ther. 2010 21:1259-1271

April 08, 2011

Correction of Neurological Disease of Mucopolysaccharidosis IIIB in Adult Mice by rAAV9 Trans-Blood-Brain Barrier Gene Delivery

REGENX Commentary:

rAAV9 delivered IV to MPS IIIB mice corrects lysosomal storage defects and provides neurological benefit and survival benefit.

Hematologic Disorders

May 24, 2012

Transient B cell depletion or improved transgene expression by codon optimization promote tolerance to factor VIII in gene therapy

REGENX Commentary:

Treatment of hemophilia A (Factor VIII deficiency) is complicated by the development of antibodies to Factor VIII. AAV8 was used to deliver a copy of the Factor VIII gene to hemophilia A mice. The optimal approach of using a codon-optimized Factor VIII transgene coupled to a liver-specific promoter resulted in sustained therapeutic expression, and tolerance to Factor VIII without additional manipulations.

May 29, 2013

Adeno-associated virus serotype 9 efficiently targets ischemic skeletal muscle following systemic delivery

REGENX Commentary:

This paper and "Cardiac-selective expression of extracellular superoxide dismutase after systemic injection of adeno-associated virus 9 protects the heart against post-myocardial infarction left ventricular remodeling" demonstrate that AAV9 is efficient in targeting ischemic skeletal muscle, and in transducing heart. Furthermore, expression of extracellular superoxide dismutase (EcSOD) under control of a heart-specific promoter protects against acute myocardial infarction and subsequent left ventricular remodeling.

May 09, 2013

Kinetics of Adeno-Associated Virus Serotype 2 (AAV2) and AAV8 Capsid Antigen Presentation In Vivo Are Identical

REGENX Commentary:

Using engineered AAV capsids with an ovalbumin immunodominant peptide, this study demonstrates that AAV2 capsid stimulates a T-cell response in mice, but that AAV8 does not. This is despite equivalent levels and kinetics of capsid antigen presentation. These data do not support a previously proposed hypothesis from a hemophilia B clinical trial that CTLs to AAV capsid clear transduced cells.

December 14, 2011

Merry Christmas for Patients with Hemophilia B.

REGENX Commentary:

This editorial accompanied the article on the Phase I clinical trial of AAV8 for Hemophilia B. It describes the history of Hemophilia B (also known as Christmas disease), and why the current clinical trial is a landmark study.

December 13, 2011

Clinicial progress in gene therapy: Sustained partial correction of the bleeding disorder in patients suffering from severe hemophilia B.

REGENX Commentary:

This commentary in Human Gene Therapy describes the NEJM article on the Phase 1 clinical trial of AAV8 in Hemophilia B patients and highlights the potential of AAV8 and the other novel AAV serotypes in clinical gene therapy.

May 16, 2011

Long-term Safety and Efficacy Following Systemic Administration of a Self-complementary AAV Vector Encoding Human FIX Pseudotyped With Serotype 5 and 8 Capsid Proteins.

REGENX Commentary:

This study examined long-term safety of intravenous administration of rAAV8 encoding the human Factor IX cDNA in non-human primates, demonstrating >5 years of transgene expression.

December 14, 2011

Adenovirus-Associated Virus Vector-Mediated Gene Transfer in Hemophilia B

REGENX Commentary:

Researchers report on a combined Phase 1/2 clinical trial involving NAV rAAV8-mediated gene transfer in patients with hemophilia B. In this trial, six hemophilia B patients received a single intravenous injection of NAV rAAV8 vectors encoding a normal copy of the defective gene, Factor IX.  All patients are expressing enough Factor IX to convert their phenotypes from severe to mild-moderate. Four out of six patients have been able to discontinue use of prophylactic, recombinant Factor IX and have not experienced spontaneous bleeding since receiving the therapy. The other two patients have been able to extend the time between prophylactic treatments. Most importantly, the therapeutic was well-tolerated.

Muscle Diseases

February 05, 2014

Gene Therapy Prolongs Survival and Restores Function in Murine and Canine Models of Myotubular Myopathy

REGENX Commentary:

X-linked myotobular myopathy is a fatal pediatric disease of skeletal muscle, for which there is no effective treatment. This paper demonstrates that intravascular administration of AAV8 encoding myotubularin prolonged survival in both mouse and dog models of the disease, providing proof of concept to support future clinical trials.

Ocular Diseases

August 16, 2011

Long-Term Preservation of Cones and Improvement in Visual Function Following Gene Therapy in a Mouse Model of Leber Congenital Amaurosis Caused by Guanylate Cyclase-1 Deficiency

REGENX Commentary:

AAV8 transduced rods and cones in a mouse model of LCA1, improving visual funct6ion.  AAV8 was shown to be more effective than lentivirus or AAV5, which have been used in previous publications.

October 04, 2013

Combined rod and cone transduction by AAV2/8

REGENX Commentary:

This study demonstrates that AAV8 transduces the cones of the pig retina as well as AAV9. Efficacy was dependent on the promoter selected. Subsequently, AAV8 was shown to restore cone function in the mouse model of Leber congenital amaurosis type 1 (LCA1), confirming the utility of AAV8 in gene therapy of diseases affecting both rods and cones.

July 08, 2011

AAV-mediated photoreceptor transduction of the pig cone-enriched retina

REGENX Commentary:

This publication demonstrates that AAV8 is more efficient than AAV5 in transducing photoreceptors in a large animal, including both rods and cones.  Along with the recent published data in non-human primates (below), this demonstrates the utility of AAV8 in treating a wide variety of retinal degenerative diseases such as retinitis pigmentosa.

March 27, 2013

AAV9 targets cone photoreceptors in the nonhuman primate retina

REGENX Commentary:

This study in non-human primates demonstrates the abilities of AAV8 and AAV9 to transduce cones as well as rods in the retina. Because the NHP retina is the most similar to humans, it suggests that different AAV serotypes could be used for different retinal degenerations in humans, depending on which cells of the retina need to be most efficiently transduced.

July 08, 2011

Dosage Thresholds for AAV2 and AAV8 Photoreceptor Gene Therapy in Monkey

REGENX Commentary:

This publication is the first study to analyze the retinal cell types transduced by rAAV8 in non-human primates, which have a retinal structure closest to that of humans.  AAV8 was shown to be approximately 10-fold more efficient in transducing both the RPE and photoreceptors, which are targets for gene therapy of most forms of retinitis pigmentosa and other inherited retinal degenerative diseases.

More detailed commentary: http://regenxbio.com/index.php/science/publications/

September 30, 2011

REGENX’s NAV Vector rAAV8 demonstrates potential for safer and more efficient gene delivery

REGENX Commentary:

This publication details the unique properties of REGENX’s NAV rAAV8 that enable it to provide a therapeutic platform for treatment of many retinal degenerative diseases.
 
Retinal degenerative diseases such as retinitis pigmentosa lead to impaired vision and blindness, and are typically difficult to treat.  Gene therapy has been showing promise in treating retinal disease, as demonstrated recently in early-stage clinical trials treating Leber congenital amaurosis (LCA), an inherited form of blindness for which there is no treatment. However, it is critical to be able to target the appropriate cells within the retina as efficiently as possible, and to develop a platform technology that can be used across multiple retinal degenerative diseases. 
 
Studying gene delivery in the retina in preclinical experiments can be difficult, since the retinal architecture in small animals is quite different from that of humans. The non-human primate is the species whose retina is most similar to the human retina, especially as it is the only species other than humans that has a macula. The current study describes a comparison between rAAV2 and rAAV8 in the non-human primate retina, and demonstrates that rAAV8 is capable of transferring genes into cells in the retina at a ten-fold (10x) higher rate of efficiency than rAAV2. This is especially important in volume-limited sites of delivery, such as the retina. Furthermore, for many inherited retinal diseases, target cells are not the retinal pigment epithelium (RPE), as required for treating LCA, but instead are the photoreceptor cells, including rods and clones. Subretinal injection of rAAV8 was ten-fold (10x) more efficient in targeting these photoreceptor cells, especially the rods, and also was capable of transducing the cone cells which are responsible for visual acuity and color perception, albeit at a lower efficiency than rods. This is the first direct demonstration of the ability to transduce cones in the non-human primate eye with an AAV vector, and indicates that rAAV8 can be used in diseases where the RPE, rods and/or cone photoreceptors need to be treated.
 
These data demonstrate that REGENX’s NAV rAAV8 is the next generation of improved AAV vectors, as it can be used at lower doses than AAV2, and would be expected to have a wider window of efficacy. REGENX’s NAV rAAV8 has the potential to become a platform for therapeutics that will be useful across a range of retinal diseases.

Neurodegenerative Disorders

July 31, 2012

Extended Normal Life After AAVrh10-mediated Gene Therapy in the Mouse Model of Krabbe Disease

REGENX Commentary:

AAVrh10 was used to deliver a therapeutic transgene to treat mice with Krabbe disease (globoid cell leukodystrophy). A combination of intracerebroventricular, intracerebellar, and intravenous injection in newborn mice resulted in nearly normal phenotype for up to 8 months.

November 08, 2011

Systemic Gene Delivery in Large Species for Targeting Spinal Cord, Brain, and Peripheral Tissues for Pediatric Disorders.

REGENX Commentary:

A variety of inherited diseases require treatment of young children; rAAV9, the serotype preferred for IV-based gene transfer to the CNS, was studied in young non-human primates. At all ages studied, from birth through 3 years, AAV9 was efficient at crossing the blood-brain barrier. Cerebrospinal fluid (CSF) injections were performed, which efficiently targeted motor neurons, and restricted gene expression to the CNS.

September 11, 2013

Therapeutic AAV9-mediated Suppression of Mutant SOD1 Slows Disease Progression and Extends Survival in Models of Inherited ALS

REGENX Commentary:

The mouse model of amyotrophic lateral sclerosis (ALS), like the human disease, has proven very difficult to treat. In this study, AAV9 was used to deliver an shRNA to reduce superoxide dismutase 1 (SOD1) gene expression in the mutant SOD1G93A mouse. This not only increased survival when delivered at birth, it also significantly slowed disease progression after disease onset in the mouse model. This suggests that the therapeutic may be beneficial in the familial forms of ALS that are caused by SOD1 mutations, and may also be beneficial in some patients with sporadic disease.

June 06, 2011

Several rAAV Vectors Efficiently Cross the Blood–brain Barrier and Transduce Neurons and Astrocytes in the Neonatal Mouse Central Nervous System.

REGENX Commentary:

A total of 10 different AAV serotypes were tested, and rAAVrh.10, as well as rAAV9, were shown to efficiently cross the BBB of neonatal mice.  Transgene expression was carefully documented within regions of the brain and spinal cord.

May 29, 2013

A highly secreted sulphamidase engineered to cross the blood-brain barrier corrects brain lesions of mice with mucopolysaccharidoses type IIIA

REGENX Commentary:

To treat MPS IIIA (Sanfilippo A), the authors engineered the deficient sulphamidase gene with a signal sequence that allows more efficient secretion, and an LDL receptor-binding domain. Expression of this protein using a liver-targeted AAV8 resulted in high levels of sulphamidase in both liver and in the brain, due to transcytosis across the blood-brain barrier via the LDL receptor. This demonstrated correction of both peripheral tissues and the brain with a single injection of AAV8

August 22, 2013

Systemic Delivery of MeCP2 Rescues Behavioral and Cellular Deficits in Female Mouse Models of Rett Syndrome

REGENX Commentary:

This article demonstrates the utility of AAV9 in treating the female mouse model of Rett syndrome. Previous publications had used male mice; however, this neurologic disease primarily affects females. Gene replacement by systemic administration of AAV9-MeCP2 in affected female mice stabilized or reversed symptoms.

October 18, 2011

Liver Production of Sulfamidase Reverses Peripheral and Ameliorates CNS Pathology in Mucopolysaccharidosis IIIA Mice.

REGENX Commentary:

rAAV8-mediatedgene transfer to the liver of MPS IIIA mice resulted in high and sustained levels of circulating active sulfamidase, and completely corrected lysosomal GAG accumulation in most somatic tissues. Surprisingly, high sustained circulating sulfamidase levels also resulted a 50% reduction of GAG accumulation in the brain of male mice, which were expressing 4x normal levels of enzyme, and these mice had an increased lifespan.

March 27, 2013

Strong Cortical and Spinal Cord Transtuction After AAV7 And AAV9 Delivery Into the CSF of NHP

REGENX Commentary:

Treatment of neurologic diseases with novel AAV serotypes has been gaining momentum, as these vectors have been shown to transduce much of the CNS with less invasive routes of administration. This study demonstrates that Intrathecal delivery of AAV9 as well as AAV7  in non-human primates gives widespread gene expression in the CNS and the peripheral nervous system.

January 15, 2013

Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates

REGENX Commentary:

The authors show that AAV9 delivery to the CNS by injection into the CSF (including intrathecal injections) is not inhibited by the presence of serum neutralizing antibodies (NAbs) to AAV9, up to titers of at least 1:128. This suggests that for diseases that might be treated through this route of administration, the vast majority of patients would be eligible for treatment, given the low frequency of high titer NAbs to AAV9.

July 10, 2013

Capsid Serotype and Timing of Injection Determines AAV Transduction in the Neonatal Mice Brain

REGENX Commentary:

Six different serotypes of AAV were injected intracerebroventricularly (ICV) into neonatal mice, on postnatal days P0, P2, and P3. Of the serotypes tested, AAV8 and AAV9 showed the most widespread transduction.

June 06, 2011

rAAV9 is featured in 4 research articles and a commentary in the June 2011 issue of Molecular Therapy

REGENX Commentary:

Commentary:

AAV9: Over the Fence and Into the Woods . . .

Research Articles:

  • Correction of Neurological Disease of Mucopolysaccharidosis IIIB in Adult Mice by rAAV9 Trans-Blood–Brain Barrier Gene Delivery
  • Preclinical Differences of Intravascular AAV9 Delivery to Neurons and Glia: A Comparative Study of Adult Mice and Nonhuman Primates
  • Engineering Liver-detargeted AAV9 Vectors for Cardiac and Musculoskeletal Gene Transfer
  • A Potential Role of Distinctively Delayed Blood Clearance of Recombinant Adeno-associated Virus Serotype 9 in Robust Cardiac Transduction
July 10, 2013

Transduction of the Central Nervous System Following Intra-cerebroventricular Injection of Adeno-associated Viral Vectors in Neonatal and Juvenile Mice

REGENX Commentary:

This paper shows AAV9 distribution throughout the brain after ICV injection into slightly older mice (5 and 21 days of age). There was widespread transduction throughout the brain, but with different patterns of cell-specific gene expression, depending on the time of injection and the promoter used.

August 28, 2012

Correction of Brain Oligodendrocytes by AAVrh.10 Intracerebral Gene Therapy in Metachromatic Leukodystrophy Mice

REGENX Commentary:

The authors demonstrated the superiority of AAVrh.10 as compared to AAV5 for the treatment of metachromatic leukodystrophy in the mouse model. The efficacy shown supports a proposed clinical trial, which is expected to begin dosing patients shortly. In this month's issue of Human Gene Therapy researchers discuss the signficance of this study.