Figure 6.

rAAV vectors and VHH engineering for A-MAD. Summary of potential modifications for A-MAD. Engineering the rAAV capsid and transgene cassette can maximize BBB crossing, NAbs evasion and spatially restrict VHH expression to the desired cell-type. More efficient production systems will lower production costs. The outstanding versatility of VHH allows easy engineering to generate multivalent drugs, or drive proteosomal degradation of toxic protein conformations via construction of Proteolysis targeting chimeras (PROTACs). Additionally, incorporation of secretion signals into the VHH will allow targeting of extracellular aggregates, preventing prion-type transmission. Together, the impact of improved rAAV vector technology and VHH engineering will produce more efficient A-MAD-based therapeutics, with concomitant reductions in undesired side-effects and lower treatment costs.