Results from a phase I safety trial of
            <i>hAADC</i>
            gene therapy for Parkinson disease

Eberling, Jamie L.; Jagust, William J.; Christine, Chadwick W.; Starr, Phillip A.; Larson, Paul; Bankiewicz, Krystof S.; Aminoff, Michael J.

doi:10.1212/01.wnl.0000312381.29287.ff

Cited by 328 publications

(230 citation statements)

References 6 publications

Supporting

Mentioning

220

Contrasting

Unclassified

Order By: Relevance

“…Clinically, AAV2 has been regarded as the vector of choice for CNS gene delivery for several reasons, including its relatively widespread use in neurological gene therapy in Parkinson's disease (Kaplitt et al, 2007;Eberling et al, 2008;Marks et al, 2008;Christine et al, 2009), its tropism for neurons (Bartlett et al, 1998), and long-term CNS expression after delivery Daadi et al, 2006). Consistent with previous observations, we have also demonstrated high efficiency and cellular tropism of AAV2 for neurons after CED, with no astrogliosis (Fig.…”

Section: Aguilar Salegio Et Alsupporting

confidence: 90%

Magnetic Resonance Imaging-Guided Delivery of Adeno-Associated Virus Type 2 to the Primate Brain for the Treatment of Lysosomal Storage Disorders

et al. 2010

View full text Add to dashboard Cite

Gene replacement therapy for the neurological deficits caused by lysosomal storage disorders, such as in Niemann-Pick disease type A, will require widespread expression of efficacious levels of acid sphingomyelinase (ASM) in the infant human brain. At present there is no treatment available for this devastating pediatric condition. This is partly because of inherent constraints associated with the efficient delivery of therapeutic agents into the CNS of higher order models. In this study we used an adeno-associated virus type 2 (AAV2) vector encoding human acid sphingomyelinase tagged with a viral hemagglutinin epitope (AAV2-hASM-HA) to transduce highly interconnected CNS regions such as the brainstem and thalamus. On the basis of our data showing global cortical expression of a secreted reporter after thalamic delivery in nonhuman primates (NHPs), we set out to investigate whether such widespread expression could be enhanced after brainstem infusion. To maximize delivery of the therapeutic transgene throughout the CNS, we combined a single brainstem infusion with bilateral thalamic infusions in naive NHPs. We found that enzymatic augmentation in brainstem, thalamic, cortical, as well subcortical areas provided convincing evidence that much of the large NHP brain can be transduced with as few as three injection sites.

show abstract

Section: Aguilar Salegio Et Alsupporting

confidence: 90%

Magnetic Resonance Imaging-Guided Delivery of Adeno-Associated Virus Type 2 to the Primate Brain for the Treatment of Lysosomal Storage Disorders

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Studies have aimed at two main anatomical targets, the STN, in which an AAV vector has been used to deliver the enzyme glutamic acid decarboxylase (GAD) with the hope of transforming some glutamatergic STN neurons into GABAreleasing cells (Kaplitt et al, 2007;Lewitt et al, 2011), and the striatum, in which AAV or lentiviral vectors are used to generate striatal neurons that produce dopamine either by themselves or from dietary tyrosine or LD administered as a drug (Eberling et al, 2008;Christine et al, 2009;Jarraya et al, 2009). Ongoing trials are in progress to assess the efficacy of these approaches in advanced PD patients.…”

Section: Gene Therapy For Pdmentioning

confidence: 99%

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

Smith

Wichmann

Factor

et al. 2011

Neuropsychopharmacol

188

134

View full text Add to dashboard Cite

The demonstration that dopamine loss is the key pathological feature of Parkinson's disease (PD), and the subsequent introduction of levodopa have revolutionalized the field of PD therapeutics. This review will discuss the significant progress that has been made in the development of new pharmacological and surgical tools to treat PD motor symptoms since this major breakthrough in the 1960s. However, we will also highlight some of the challenges the field of PD therapeutics has been struggling with during the past decades. The lack of neuroprotective therapies and the limited treatment strategies for the nonmotor symptoms of the disease (ie, cognitive impairments, autonomic dysfunctions, psychiatric disorders, etc.) are among the most pressing issues to be addressed in the years to come. It appears that the combination of early PD nonmotor symptoms with imaging of the nigrostriatal dopaminergic system offers a promising path toward the identification of PD biomarkers, which, once characterized, will set the stage for efficient use of neuroprotective agents that could slow down and alter the course of the disease.

show abstract

“…(Also, the retina lies adjacent to a confined fluid-filled space, presenting similarity to the DRG-directed IT gene therapy considered in this review.) The CNS disorders addressed in these trials were Canavan disease, 49 Parkinson's disease, 35,36,50 and Batten disease. 37 The retina-directed trials were for Leber's congenital amaurosis (LCA).…”

Section: Cns Clinical Trialsmentioning

confidence: 99%

AAV for pain: steps towards clinical translation

Beutler

Reinhardt

2009

Gene Ther

View full text Add to dashboard Cite

Recombinant adeno-associated virus (rAAV) vectors consisting of self-complementary genomes and packaged in certain capsids can target primary sensory neurons efficiently and can control neuropathic pain long term by expressing opioid or non-opioid analgesic genes. This review examines the therapeutic potential of the approach in five sections: Pain control in oncology (including a discussion of cancer centers as translational pain research environment); vector biology; safety considerations and immunological lessons learned from rAAV clinical trials of other disorders; development of intrathecal rAAV therapy in rodent models of pain; and preclinical steps towards clinical translation of rAAV for pain. In the field of analgesic drug development, clinical validation of new approaches identified in rodents is currently a critical limiting step. Small-molecule therapeutics suitable as conventional drugs to probe novel targets in clinical trials are often unavailable. In this context, gene therapy could fill an important gap in the drug development process facilitating first-into-human trials of untested targeted treatments, each instantiated as a therapeutic gene.

show abstract

Results from a phase I safety trial of hAADC gene therapy for Parkinson disease

Cited by 328 publications

References 6 publications

Magnetic Resonance Imaging-Guided Delivery of Adeno-Associated Virus Type 2 to the Primate Brain for the Treatment of Lysosomal Storage Disorders

Magnetic Resonance Imaging-Guided Delivery of Adeno-Associated Virus Type 2 to the Primate Brain for the Treatment of Lysosomal Storage Disorders

Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa

AAV for pain: steps towards clinical translation

Contact Info

Product

Resources

About