RNAi-mediated rheostat for dynamic control of AAV-delivered transgenes

Megha Subramanian, James McIninch, Ivan Zlatev, Mark K. Schlegel, Charalambos Kaittanis, Tuyen Nguyen, Saket Agarwal, Timothy Racie, Martha Arbaiza Alvarado, Kelly Wassarman, Thomas S. Collins, Tyler Chickering, Christopher R. Brown, Karyn Schmidt, Adam B. Castoreno, Svetlana Shulga-Morskaya, Elena Stamenova, Kira Buckowing, Daniel Berman, Joseph D. Barry, Anna Bisbe, Martin A. Maier, Kevin Fitzgerald and Vasant Jadhav ()
Additional contact information
Megha Subramanian: Alnylam Pharmaceuticals
James McIninch: Alnylam Pharmaceuticals
Ivan Zlatev: Alnylam Pharmaceuticals
Mark K. Schlegel: Alnylam Pharmaceuticals
Charalambos Kaittanis: Alnylam Pharmaceuticals
Tuyen Nguyen: Alnylam Pharmaceuticals
Saket Agarwal: Alnylam Pharmaceuticals
Timothy Racie: Alnylam Pharmaceuticals
Martha Arbaiza Alvarado: Alnylam Pharmaceuticals
Kelly Wassarman: Alnylam Pharmaceuticals
Thomas S. Collins: Alnylam Pharmaceuticals
Tyler Chickering: Alnylam Pharmaceuticals
Christopher R. Brown: Alnylam Pharmaceuticals
Karyn Schmidt: Alnylam Pharmaceuticals
Adam B. Castoreno: Alnylam Pharmaceuticals
Svetlana Shulga-Morskaya: Alnylam Pharmaceuticals
Elena Stamenova: Alnylam Pharmaceuticals
Kira Buckowing: Alnylam Pharmaceuticals
Daniel Berman: Alnylam Pharmaceuticals
Joseph D. Barry: Alnylam Pharmaceuticals
Anna Bisbe: Alnylam Pharmaceuticals
Martin A. Maier: Alnylam Pharmaceuticals
Kevin Fitzgerald: Alnylam Pharmaceuticals
Vasant Jadhav: Alnylam Pharmaceuticals

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Adeno-associated virus (AAV)-based gene therapy could be facilitated by the development of molecular switches to control the magnitude and timing of expression of therapeutic transgenes. RNA interference (RNAi)-based approaches hold unique potential as a clinically proven modality to pharmacologically regulate AAV gene dosage in a sequence-specific manner. We present a generalizable RNAi-based rheostat wherein hepatocyte-directed AAV transgene expression is silenced using the clinically validated modality of chemically modified small interfering RNA (siRNA) conjugates or vectorized co-expression of short hairpin RNA (shRNA). For transgene induction, we employ REVERSIR technology, a synthetic high-affinity oligonucleotide complementary to the siRNA or shRNA guide strand to reverse RNAi activity and rapidly recover transgene expression. For potential clinical development, we report potent and specific siRNA sequences that may allow selective regulation of transgenes while minimizing unintended off-target effects. Our results establish a conceptual framework for RNAi-based regulatory switches with potential for infrequent dosing in clinical settings to dynamically modulate expression of virally-delivered gene therapies.

Date: 2023
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DOI: 10.1038/s41467-023-37774-5

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