September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Assessment of Neutralizing Antibodies Against Adeno-associated virus (AAV)2 Capsids in Serum and Ocular Fluid Samples of Leber’ Hereditary Optic Neuropathy (LHON) Gene Therapy Clinical Trial Patients
Author Affiliations & Notes
  • Rajeshwari D Koilkonda
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
  • William J Feuer
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
  • Joyce C Schiffman
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
  • Janet L Davis
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
  • Vittorio Porciatti
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
  • Phillip Gonzalez
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
  • Byron L Lam
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
  • John Guy
    Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida, United States
  • Footnotes
    Commercial Relationships   Rajeshwari Koilkonda, None; William Feuer, None; Joyce Schiffman, None; Janet Davis, None; Vittorio Porciatti, None; Phillip Gonzalez, None; Byron Lam, None; John Guy, None
  • Footnotes
    Support  1U10EY023558-01A1 (Guy), 1U10EY024247-01 (Feuer) and P30EY014801 (Porciatti).
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 5083. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Rajeshwari D Koilkonda, William J Feuer, Joyce C Schiffman, Janet L Davis, Vittorio Porciatti, Phillip Gonzalez, Byron L Lam, John Guy; Assessment of Neutralizing Antibodies Against Adeno-associated virus (AAV)2 Capsids in Serum and Ocular Fluid Samples of Leber’ Hereditary Optic Neuropathy (LHON) Gene Therapy Clinical Trial Patients. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5083.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose : Neutralizing antibodies (NAb) against AAV, could interfere with the recombinant AAV vector-mediated gene transfer, thus decreasing the efficiency of the vector administered. We evaluated NAb titers against tyrosine-mutant AAV2 in LHON patients before and after gene therapy injections.

Methods : Self-complementary AAV2 (Y444, 500, 730F)-P1ND4v2 was intravitreally injected into the eyes of 9 LHON G11778A participants. The eye with worse acuity was treated. Six of them received low dose vector (5x109vg) and three medium dose (2.46x1010vg). NAbs were assessed in serum and anterior chamber fluid (ACF) samples. The NAb titer was reported as the highest serum or ACF dilution that inhibited scAAV2-smCBA-mCherry transduction by >50%, compared with no serum control. NAb levels were categorized as low (<80), moderate (<5120) or high (>20,480).

Results : Serum Results. Strong inhibition to mCherry expression due to high NAbs against AAV2 (>20,480) were found in serum samples of 4/9 (44%) LHON subjects at baseline, 1d, 7d, 3m, 6m and (or) 1yr postinjection (pi). 3 patients showed absent or low NAbs at baseline (33.3%). One of these patients with NAb=5 at baseline and received a low dose vector showed a transient rise of NAb to 20 at 7dpi, however NAbs decreased to baseline at 3 mpi. Another patient with NAb=80 at baseline, who received a medium dose showed a moderate increase at 1dpi to 320 and a further rise to higher levels at 7dpi (>20,480). At 2mpi this patient developed uveitis in the injected eye that subsided at 3m, however the serum NAb titer remained unaltered. In the third patient, the NAb titer was low to absent (=5) at baseline and did not change postinjection. One of the 4 patients who had high NAbs and received low dose vector also showed uveitis 2mpi. Two other subjects (22.2%) had moderate NAb levels (>5120 and >320) at baseline, 1d, 7d and 3mpi. ACF Results. NAbs in all the baseline ACF samples were absent or mild.

Conclusions : Despite the presence of high NAbs to AAV2 in baseline serum samples of LHON participants, the NAb levels detected from ACF were lower, suggestive of high serum NAb levels may not be a barrier to successful ocular gene therapy. Transient uveitis developed in the treated eyes of two patients, might be due to immunopathogenic response to the P1ND4v2 AAV2.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×