N Engl J Med

N Engl J Med. that at month 12, the difference between study eye minus fellow eye improvement in Group II patients of 0.53 logMAR was greater than that observed in our prior acute natural history patients of 0.21 logMAR (p=0.053). At month 18, the difference between study eye minus fellow eye improvement in our acute Group II gene therapy patients of 0.96 was greater than that observed in our prior acute natural history patients (0.17 logMAR) p 0.001. Two patients developed asymptomatic uveitis that resolved without treatment. OCT of treated eyes had an average temporal RNFL thickness of 54 m prior to injection and 55 m at month 12. For fellow eyes prior to injection it was 56 m dropping to 50 m at month 12, p = 0.013. GEE suggested that PERG amplitudes worsened more in treated eyes than in fellow eyes by about 0.05 uV (p exchangeable = 0.009). No difference between eyes in outcomes of other visual function measures was evident. CONCLUSIONS Allotopic gene therapy for LHON at low and medium doses appears safe and does not damage the temporal RNFL opening the door for testing of the high dose next. Introduction Leber Hereditary Optic Neuropathy (LHON) was first associated with a G to A transition at nt-11778 in the ND4 subunit gene of complex I of mtDNA that changes an arginine to histidine at amino acid 340.1 Visual loss is usually severe and bilateral. Unilateral visual loss is typically followed by fellow eye involvement within months, but intervals greater than a year2 and even as long as 18 years3 have been described. A prospective study of the natural history of visual acuity found that spontaneous recovery of visual acuity of 3 lines or Sesamolin more occurs in ~18% of patients.4 Two other primary mutations G3460A and T14484C have also been identified in LHON patients mtDNA that are each associated with a higher rate of spontaneous recovery.5;6 Here, we recoded the ND4 subunit of complex I in the universal genetic code and imported into the mitochondrion from the cytoplasm by adding a targeting sequence derived from the P1 isoform of subunit c of ATP synthase (ATPc).7 We refer to the Rabbit polyclonal to ERK1-2.ERK1 p42 MAP kinase plays a critical role in the regulation of cell growth and differentiation.Activated by a wide variety of extracellular signals including growth and neurotrophic factors, cytokines, hormones and neurotransmitters. nuclear encoded ND4 with the appended ATPc targeting sequences as It Sesamolin was inserted into a self-complementary adenoassociated vector scAAV2(Y444,500,730F). We first determined its safety and tolerability in preclinical studies of rodents and nonhuman primates,8 before testing in our first 5 LHON patients.9 Here we describe our findings with longer-term follow-up of Sesamolin these patients in addition to 9 more patients enrolled since that publication for a total of 14 participants. Participants and Methods Study Entry and Dosing The study is approved by the University of Miami Institutional Review Board, FDA, RAC of the NIH and monitored by a DSMC constituted by the NEI. .After obtaining informed consent, 14 LHON participants with the G11778A mutation were entered into the study (Table 1).Ten participants were men and four participants were women. All patients were Caucasian except for one who was of partial American Indian heritage. Each received a single intravitreal injection of scAAV2(Y444,500,730F)-in one eye. Six participants had chronic bilateral visual loss longer than 1 year (Group I). The first three received the low dose (5xe9 vg) and the next 3 received the medium dose (2.46xe10vg). Six additional participants had acute bilateral visual loss less than 1 year (Group II). The first three received the low dose study drug and the next 3 received the medium dose. Two participants with unilateral visual loss received the low dose into the eye with good vision before it lost central vision. As of November 2016, these participants have returned for 5 or more post injection visits (3 to 18 months) and nine patients had at least 12.