Methods in enzymology
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Methods in enzymology · Jan 2012
Clinical TrialLentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy.
X-linked adrenoleukodystrophy (X-ALD) is a severe genetic demyelinating disease caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. When performed at an early stage of the disease, allogeneic hematopoietic stem cell transplantation (HCT) can arrest the progression of cerebral demyelinating lesions. To overcome the limitations of allogeneic HCT, hematopoietic stem cell (HSC) gene therapy strategy aiming to perform autologous transplantation of lentivirally corrected cells was developed. ⋯ There was no evidence of clonal dominance or skewing based on the retrieval of lentiviral insertion repertoire in different hematopoietic lineages by deep sequencing. Cerebral demyelination was arrested 14 and 16months, respectively, in the two treated patients, without further progression up to the last follow-up, a clinical outcome that is comparable to that observed after allogeneic HCT. Longer follow-up of these two treated patients and HSC gene therapy performed in additional ALD patients are however needed to evaluate the safety and efficacy of lentiviral HSC gene therapy in cerebral forms of X-ALD.
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Methods in enzymology · Jan 2012
Regulatory structures for gene therapy medicinal products in the European Union.
Taking into account the complexity and technical specificity of advanced therapy medicinal products: (gene and cell therapy medicinal products and tissue engineered products), a dedicated European regulatory framework was needed. Regulation (EC) No. 1394/2007, the "ATMP Regulation" provides tailored regulatory principles for the evaluation and authorization of these innovative medicines. The majority of gene or cell therapy product development is carried out by academia, hospitals, and small- and medium-sized enterprises (SMEs). ⋯ Two such organizations are represented in the CAT. Research networks play another important role in the development of gene therapy medicinal products. The European Commission is funding such networks through the EU Sixth Framework Program.
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Methods in enzymology · Jan 2012
Generation of dual-variable-domain immunoglobulin molecules for dual-specific targeting.
Bispecific antibodies may be used to improve clinical efficacy by targeting two disease mechanisms for the treatment of complex human diseases in a single agent. Bispecific antibodies also hold promise for certain therapeutic applications difficult to achieve by single-targeting monospecific antibodies, such as immune (T cell or NK) cell retargeting, site-specific targeting, enabling therapeutics to cross the blood-brain barrier, and unique receptor modulation. Although the history of bispecific antibody research is almost as long as hybridoma technology, it is not until recent that bispecific antibodies have made substantial breakthrough, thanks to promising clinical trial results of a few bispecific antibodies and the development of new formats which largely ease manufacturing and physicochemical property challenges encountered by early bispecific antibody formats. ⋯ An optimized DVD-Ig™ molecule has many desirable properties of a mAb, such as good expression in mammalian cells, easy purification to homogeneity using standard approaches, displaying good drug-like biophysical and pharmacokinetic properties, and amenability to large-scale manufacturing. Several DVD-Ig molecules have demonstrated favorable pharmacokinetic properties and efficacy in preclinical animal models. Here, we provide an example of construction and preliminary characterization of a DVD-Ig™ molecule and discuss the general approach used in optimization.