Long-Term Follow-Up After Gene Therapy for Canavan Disease

Leone, Paola; Shera, David; McPhee, Scott; Francis, Jeremy S.; Kolodny, Edwin H.; Bilaniuk, Larissa T.; Wang, Dah Jyuu; Assadi, Mitra; Goldfarb, Olga; Goldman, Howard; Freese, Andrew; Young, Deborah; During, Matthew J.; Samulski, R. Jude; Janson, Christopher G.

doi:10.1126/scitranslmed.3003454

Cited by 242 publications

(198 citation statements)

References 74 publications

Supporting

Mentioning

196

Contrasting

Unclassified

Order By: Relevance

“…Neurometabolic diseases like globoid cell leukodystrophy show favorable outcomes for presymptomatic intervention but not later indicating the existence of a restricted therapeutic time window (Escolar et al 2005). Similar outcomes were seen in preclinical studies (Ahmed et al 2013) and follow-up study on CD clinical trials (Leone et al 2012) indicating that future gene therapy interventions should begin before irreversible neuro-structural changes occur underlining the importance of rodent studies.…”

Section: Perspectives and Future Directionsmentioning

confidence: 49%

“…Moreover, in CD patients, elevated NAA levels appear to cause white matter pathology but rAAV2 was conclusively demonstrated to transduce only neurons (McCown 2005). In a follow-up study on 13 of the 28 patients enrolled in this trial, the long-term safety, dosing parameters, and efficacy of the treatment were evaluated (Leone et al 2012). From the study, it is evident that rAAV-mediated gene therapy is the most promising safe therapeutic modality for CD to date.…”

Section: Gene Therapy Using Gene Replacement Strategymentioning

confidence: 99%

“…Various neurological diseases are subject of several clinical trials using rAAV (Asokan et al 2012) and the available results indicate that the vectors mediate stable gene expression in the human brain (Muramatsu et al 2010;Hwu et al 2012) and are safe (Leone et al 2012). rAAV2 vectors were the first vectors used for CNS gene transfer in animal models as well as in humans, and incidentally Canavan's disease was one of the first CNS diseases to go for clinical trials using rAAV (Leone et al 2000;Janson et al 2002).…”

Section: Gene Therapy Using Gene Replacement Strategymentioning

confidence: 99%

“…The encouraging results suggest that this might be a good therapeutic approach for symptomatic treatment. With seizures being a hallmark of the disease, CD patients have canonically been targeted using anticonvulsive drugs like acetazolamide, clonazepam, and oxcarbazepine (Leone et al 2012). …”

Section: Palliative Measuresmentioning

confidence: 99%

See 3 more Smart Citations

Making the White Matter Matters: Progress in Understanding Canavan’s Disease and Therapeutic Interventions Through Eight Decades

Ahmed

Gao

2014

JIMD Reports

View full text Add to dashboard Cite

Section: Perspectives and Future Directionsmentioning

confidence: 49%

Section: Gene Therapy Using Gene Replacement Strategymentioning

confidence: 99%

Section: Gene Therapy Using Gene Replacement Strategymentioning

confidence: 99%

Section: Palliative Measuresmentioning

confidence: 99%

See 2 more Smart Citations

Making the White Matter Matters: Progress in Understanding Canavan’s Disease and Therapeutic Interventions Through Eight Decades

Ahmed

Gao

2014

JIMD Reports

View full text Add to dashboard Cite

“…This approach has seen a degree of success in improving the major disease symptoms; however, progress is still to be made. The use of liposome encapsulated plasmids and adeno-associated viruses as vectors to insert the ASPA gene into CD mice, tremor mice and human CD subjects has resulted in enhanced ASPA production and activity and, in some cases, reduced CNS NAA levels and improved spongiform degeneration (Ahmed et al, 2013;Klugmann et al, 2005;Leone et al, 2000;Leone et al, 2012;McPhee et al, 2005). However, it must be noted that in some cases the observed decrease in NAA and spongiform pathology is transient , while in others the effects are limited within a confined area surrounding the region of intracerebral injection (Leone et al, 2000;.…”

Section: Therapeutic Approaches To CDmentioning

confidence: 99%

Non-genetic therapeutic approaches to Canavan disease

Roscoe

Elliott

Ζάρρος

et al. 2016

Journal of the Neurological Sciences

View full text Add to dashboard Cite

show abstract

Concepts in Fetal Gene Therapy

Mattar

Biswas

Choolani

et al. 2013

Encyclopedia of Life Sciences

View full text Add to dashboard Cite

Many congenital anomalies have a genetic basis. With the evolution of fetal therapy over the past half‐century since the first intrauterine transfusion was performed, novel treatments including genetic correction of such diseases may be possible. Using a variety of therapeutic vector constructs, proof of concept for fetal gene therapy (FGT) has been achieved in several single‐gene disorders including thalassaemia and haemophilia B. The current challenge is to determine the long‐term safety and efficacy of FGT, as well as important maternal bystander effects, in clinically relevant large‐animal models, and to individualise FGT strategies according to the disease of interest, with respect to target organ and vector construct. Key Concepts: Fetal gene therapy research has been directed towards monogenic diseases, but there is scope for this target to be expanded to include chromosomal and structural anomalies in the near future. The fetus, weighing several log‐fold less than an infant or child, allows gene therapy to be economised, facilitating a widespread effect with a smaller amount of vector, and an easier task in adjusting vector dose to achieve the desired outcome. The goal of fetal gene therapy is to achieve phenotypic rescue of a lethal or severely morbid monogenic disease. If cure is not achievable, correction of the disorder to the point of downgrading its severity is the other worthy goal. In addition to genetic correction, treatment initiated in early gestation may encourage tolerance to the gene therapy vector and transgenic protein, events critical to facilitating sustained transgene expression. Gene therapy may be achieved in vivo , through the direct introduction of the transgene enveloped in a vector, or ex vivo with the use of genetically manipulated stem cells to achieve the desired effect. Proof of this concept has been demonstrated using viral vectors in small genetic knockout models of diseases, including haemophilia B and inborn errors of metabolism disease. Evidence of safety and efficacy has been demonstrated in sheep and nonhuman primates which, being physiologically more representative of human pregnancies, are considered robust preclinical models. The success of this intervention depends on the efficacy of cellular transduction, accessibility of the target organ, the type of vector used, immune maturity and route of vector administration. Fetal gene therapy must be optimised to each condition of interest, in terms of appropriate gestation at intervention, efficacy of vector and principal objectives of therapy (gestation at which peak transgene expression is desired, importance of immune maturity and desired duration of transgene expression). Several ethical issues raised by fetal gene therapy have to be considered in anticipation of eventual clinical translation. These include reliance on data from preclinical large animal models that are not genetic knockouts, the consequences of partial correction, the possibility of germ‐line transmission and the long‐term risk of oncogenesis.

show abstract

Long-Term Follow-Up After Gene Therapy for Canavan Disease

Cited by 242 publications

References 74 publications

Making the White Matter Matters: Progress in Understanding Canavan’s Disease and Therapeutic Interventions Through Eight Decades

Making the White Matter Matters: Progress in Understanding Canavan’s Disease and Therapeutic Interventions Through Eight Decades

Non-genetic therapeutic approaches to Canavan disease

Concepts in Fetal Gene Therapy

Contact Info

Product

Resources

About