Gene Therapy Delivers Intracellular Antibodies To Attack Abnormal Protein in Huntington’s Disease Interview with:
Lee Henderson, Ph.D. CEO Vybion, Inc. Ithaca, NY 14852Lee Henderson, Ph.D.
CEO, Vybion, Inc.
Ithaca, NY 14852 What is the background for this study? What are the main findings?

Response: Huntington’s disease (HD) is a progressive and fatal neurodegenerative disease characterized by loss of both cognitive and motor function as a result of neuron loss primarily within the brain striatum. HD is directly caused by the expansion of CAG repeats in the huntingtin gene resulting in an expanded glutamine region (polyQ) near the N-terminus of the protein. Age of disease onset and the rate of progression is directly correlated to the size of the expansion with pathology observable at 35-70 repeats in adults and greater in juvenile onset. During normal turnover and degradation of the huntingtin protein, the N-terminal polyQ-containing fragments drive pathology and aggregate formation in cells. The direct link to progression has been described by several laboratories using cell-based and animal model studies and confirmed in humans as the binding of these N-terminal fragments to DNA and transcription factors that result in widespread gene dysregulation in neurons. What is the background for this study? What are the main findings?

Response: Vybion has proprietary technology to develop Intrabodies, antibody fragments that are functional inside of cells, unlike normal antibodies which are not functional in the reducing environment of the cell. We deliver the gene encoding these Intrabodies with Adeno-Associated Virus (AAV) to effect Gene Therapy. Our report shows that the INT41 Intrabody, which binds to a proline rich region on the N-terminal fragment of the huntingtin protein, reduces gene dysregulation by inhibiting the binding of the toxic N-terminal fragment of the huntingtin protein to DNA, in part by reducing the ability of this fragment to migrate into the nucleus. We also demonstrate that in an aggressive animal model of Huntington’s disease, INT41 delays both cognitive and motor function loss. INT41 itself does not accumulate in the cell, but is degraded like other cytoplasmic proteins and is not associated with significant alteration of cellular gene expression. Preliminary evidence also suggests that INT41 does not bind to full length huntingtin protein, so is unlikely to affect its normal function. What should readers take away from your report?

Response: Our results not only open a new avenue of therapy for Huntington’s patients. These results also show that there is great potential for Intrabodies as a new class of drug that have the specificity of antibodies and likely lack the off-target effects of small molecule drugs typically used in targeting cellular events. Intrabodies also open up the potential for a wide range of targets including protein-protein interactions that have proven to be extremely challenging with small molecules. What recommendations do you have for future research as a result of this study?

Response: Along with further confirmatory work, the use of nonhuman primates will be employed to:

1. Determine the optimal distribution of AAV6-INT41 and possibly one other serotype of AAV into brain.
2. Conduct a full toxicology investigation to address the safety of INT41.
3. Upon confirmation of safety in non-human primates, we plan on conducting human patient trials. Is there anything else you would like to add?

Response: INT41 may also be therapeutic in several other similar polyQ diseases that have similar features and contain INT41 target regions. These diseases include spinocerebellar ataxia (SCA) types 1, 3 and 7 as well as spinal muscular atrophy (SMA). Validation studies are in the planning stage. Thank you for your contribution to the community.


Journal of Neurodegenerative Diseases
Volume 2016 (2016), Article ID 7120753, 10 pages
Research Article
An Intrabody Drug (rAAV6-INT41) Reduces the Binding of N-Terminal Huntingtin Fragment(s) to DNA to Basal Levels in PC12 Cells and Delays Cognitive Loss in the R6/2 Animal Model
I. Alexandra Amaro and Lee A. Henderson

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on August 26, 2016 by Marie Benz MD FAAD