Does Patisiran Reduce Ocular Transthyretin Synthesis? A Pilot Study of Two Cases

Background: Variant transthyretin-mediated amyloidosis (ATTR-v) is a well-characterized disease affecting the neurologic and cardiovascular systems. Patisiran has been approved for neurologic involvement as it reduces hepatic synthesis of transthyretin (TTR). Eye involvement is a late-onset feature increasing the risk of glaucoma and cataracts in patients. The aim of this case series was to assess whether patisiran can effectively reduce TTR synthesis in such a barrier-protected organ as the eye. Methods: Two patisiran-treated ATTR-v patients underwent serum and aqueous humor sampling to measure TTR levels detected by SDS-PAGE and immunoblotting. Serum samples were compared to a healthy control (HC), whereas aqueous humor samples were compared to non-amyloidotic subjects affected by cataracts and glaucoma. Results: Serum TTR levels representative of hepatic synthesis were sharply lower in treated patients if compared to the HC (-87.5% and -93.75% respectively). Aqueous humor TTR levels showed mild-to- no reduction in treated patients compared to non-amyloidotic subjects with cataracts (-34.9% and +8.1% respectively) and glaucoma (-41.1% and -2.1%). Conclusions: Patisiran does not seem to be so effective in inhibiting ocular TTR synthesis as it is in inhibiting hepatic synthesis. Re-engineering the envelope could allow the drug to target RPE cells thus avoiding any ocular involvement.