in one aspect , the invention provides a method for recovering or improving visual function in a mammalian subject , which comprises : a ) providing a recombinant adeno - associated viral ( aav ) vector carrying an expression cassette which contains a nucleic acid molecule encoding oa1 or a protein substantially homologous to oa1 , wherein said nucleic acid molecule is operably linked to regulatory control elements that direct the transcription and translation thereof ; b ) transducing retinal pigment epithelial cells with said recombinant aav vector , whereby said nucleic acid molecule is expressed by the retinal pigment epithelial cells at a level sufficient to recover or improve visual function in said mammalian subject . as a result of this treatment , the number of melanosomes in retinal pigment epithelial cells is increased and the dark adaptation of the treated subject is improved . in a particularly preferred embodiment of the invention , the above method is applied to human subjects who have been positively diagnosed for the nettleship - falls disease ( ocular albinism type i ). recombinant adeno - associated viral ( aav ) vectors are known to be safe and efficient vehicles for gene transfer . several serotypes of aav have so far been isolated and vectors based on them have been constructed and used for gene - therapy protocols in animal models . various aav serotypes may be used according to the invention , depending e . g . on their level of transgene expression and on the presence of pre - existing serotype - specific antibodies in the patient to be treated , which may limit the efficiency of infection . aav vectors of serotype 1 , 2 , 4 or 6 are preferred . the oa1 gene ( genbank acc . no . : nm000273 ), also known as gpr143 , is located in xp22 . 3 and encodes an orphan g - protein coupled receptor , which crosses the melanosomal membrane . oa1 is expressed exclusively in the retinal pigment epithelium ( rpe ) and skin melanocytes , and its transcript is detectable in murine embryonic rpe from early stages of development . for the purpose of this invention , the coding sequence of oa1 ( human and murine sequences deposited at genbank nm — 00027 and nm — 010951 , respectively ), or a sequence substantially homologous thereto , is functionally linked to a promoter able to regulate the expression of the transgene in a eukaryotic cell , preferably in a mammalian retinal cell , more preferably in a retinal pigment epithelium cell . suitable promoters that can be used according to the invention include the rpe65 , the oa1 and the ubiquitous cytomegalovirus ( cmv ) promoters , as well as inducible promoters . in a particularly preferred embodiment of the invention , the expression cassette contains the human or mouse oa1 coding sequence ( seq id no : 1 and seq id no : 2 , respectively ) functionally linked to a promoter sequence which is selected from the group consisting of the cmv promoter ( seq id no : 3 ), the human oa1 promoter ( seq id no : 4 ; − 668 bp from the atg of oa1 coding sequence , genbank ac003047 ) and the human rpe65 - specific promoter fragment ( seq id no : 5 ; 806 bp , genbank nm_000329 ). the construction of an aav vector can be carried out following procedures and using techniques which are known to any person skilled in the art . the theory and practice for adeno - associated viral vector construction and use in therapy are illustrated in several scientific and patent publications ( the following bibliography is herein incorporated by reference : flotte t r . adeno - associated virus - based gene therapy for inherited disorders . pediatr res . 2005 december ; 58 ( 6 ): 1143 - 7 ; goncalves m a . adeno - associated virus : from defective virus to effective vector , virol j . 2005 may 6 ; 2 : 43 ; surace e m , auricchio a . adeno - associated viral vectors for retinal gene transfer . prog retin eye res . 2003 november ; 22 ( 6 ): 705 - 19 ; mandel r j , manfredsson f p , foust k d , rising a , reimsnider s , nash k , burger c . recombinant adeno - associated viral vectors as therapeutic agents to treat neurological disorders . mol ther . 2006 march ; 13 ( 3 ): 463 - 83 .). in a further aspect , the invention relates to a pharmaceutical composition containing an aav vector expressing the oa1 coding sequence , in a form suitable for ocular administration . suitable administration forms include , but are not limited to , injectable solutions or suspensions , eye lotions and ophthalmic ointment . in a preferred embodiment , the aav vector is administered by subretinal injection , e . g . by injection in the vitreous , in the anterior chamber or in the retrobulbar space . preferably the viral vectors are delivered via a transcleral transchorodial approach ( as described in liang , f . q . et al ., intraocular delivery of recombinant virus . methods mol . med . 47 : 125 - 139 ). the doses of virus for use in therapy shall be determined on a case by case basis , depending on the administration route , the severity of the disease , the general conditions of the patients , and other clinical parameters . in general , suitable dosages will vary from 10 9 to 10 12 vg ( vector genomes )/ ml . a mouse knock - out ( ko ) model has been generated which shows some of the oa1 landmarks [ 13 ]. the oa1 −/ y male or −/− female mice ( herein referred to as oa1 −/− mice ) are viable and fertile . ophthalmologic examination shows hypopigmentation of the ocular fundus in mutant animals compared with wild - type [ 13 ]. microscopic examination of the rpe shows the presence of macromelanosomes already detectable at birth ( p1 ) and comparable with those described in oa1 patients [ 13 ]. in addition , oa1 −/− mice ( similarly to the oa1 patients ) show abnormal crossing of the optic fibers at the chiasm which occurs between embryonic days 12 and 18 in mice [ 13 - 15 ]. foveal hypoplasia can not be evaluated in rodents who lack this structure . the oa1 mouse ko represents a unique model for the elucidation of the oa pathophysiology and for testing potential therapies for an otherwise untreatable ocular disorder . to test whether oa1 gene knock - out results in abnormal retinal function , extensive electophysiological analysis was performed in oa1 −/− and wild type , age - matched c57 / bl6 mice . ganzfeld flash electroretinograms ( erg ) were measured after 3 hour dark adaptation in oa1 −/− and wild - type mice ( 8 - 9 months old , fig1 ). the amplitude of erg a —( fig1 b , c ) and b —( fig1 b , d ) waves is significantly decreased in oa1 −/− mice when compared to wild type c57 / bl6 mice , suggesting abnormal photoreceptor function as a result of absence of the oa1 gene . compared to the scotopic responses , photopic erg was affected to a lesser extent ( statistical significance among the oa1 −/− and wild type animals was not reached using the anova test described in material and methods ) suggesting that absence of oa1 impairs mainly the rod pathway . a similar shift towards lower intensities has been recently observed in other albino mice [ 24 , 25 , 27 ]. these combined results suggest that the rpe defect in albinism , whether due to absence of melanin or to abnormal melanosomal biogenesis , impacts on photoreceptor function as assessed by flash erg analysis . the ability of the oa1 −/− mouse retina to recover from a photoreceptor desensitizing light stimulus ( dark adapt ), which has been reported to be delayed in rodents affected by different types of albinism [ 25 - 27 ], was then analyzed . the mice were exposed to an intense bleaching condition ( 600 cd * m - 2 for 3 min ) before monitoring the recovery of b - wave using a flash of 1 cd * m - 2 sec - 1 . recovery of b - wave amplitude was measured over time ; the amplitude of the b - wave relative to that prior to photoreceptor desensitization is represented in fig1 e while absolute values are depicted in table 1 . a significant delay in recovery from photoreceptor desensitization was observed in oa1 −/− mice when compared to wild type mice . the oa1 −/− mice b - wave eventually recovers 100 ′- 120 ′ after bleaching conditions suggesting that prolonged functional uncoupling between the rpe and the photoreceptors may result as a consequence of the absence of oa1 . an aav2 / 1 vector expressing the murine oa1 coding sequence under the control of the ubiquitous cytomegalovirus ( cmv ) promoter ( aav2 / 1 - cmv - moa1 ) was produced and injected subretinally in 1 month - old oa1 −/− mice . four weeks later oa1 expression was analyzed in retinal sections by immunofluorescence : a strong signal was detected in both rpe and photoreceptors . to test whether the oa1 − mouse photoreceptor dysfunction is reversible , oa1 −/− mice ( 8 months old ) were subretinally injected in one eye with 2 - 3 × 10 9 genome copies ( gc ) of a 1 : 1 mixture of aav2 / 1 - cmv - moa1 + aav2 / 1 - cmv - egfp ( expressing the enhanced green fluorescence protein , egfp ) and in the contralateral with the same dose of aav2 / 1 - cmv - egfp alone as control . four weeks after vector administration , indirect ophthalmoscopic evaluation was performed to assess egfp expression [ 21 ] followed by flash erg analysis ( fig2 ). b - wave amplitude elicited in photopic conditions was higher ( albeit not statistically significant ) in oa1 - treated than untreated mice suggesting a partial rescue of cone function . in addition , both a - and b - waves amplitude in scotopic conditions were significantly higher ( albeit not normal ) at the highest light intensities in the retinae injected with both the oa1 and egfp vectors than in the contralateral injected with the vector expressing egfp alone ( fig2 ). these data suggest that a partial rescue of both rod and cone function occurred in the retinae expressing recombinant oa1 . although aav - mediated oa1 expression was detected in both rpe and photoreceptors , the recovery of photoreceptors activity in the oa1 −/− mouse is likely due to robust transduction of the rpe which is the only oa1 physiological site of expression in the retina ( and therefore affected in the ko animal ). to verify whether the delayed recovery from photoreceptor desensitization present in the oa1 −/− mice was reversible and whether this could be dependent on the age of the animals treated , 2 cohorts of oa1 −/− mice of different ages ( 1 and 8 months old ) were subretinally injected similarly to those treated in fig2 and four weeks later their ability to dark adapt tested ( fig3 ). independently of the age of treatment , the retinae that received the oa1 vector completely recovered from the delay in dark adaptation in 75 ′ similarly to wild type retinae . the contralateral egfp - treated retinae do not recover after 90 ′, the latest time point of the analysis in some animals . this suggests that oa1 gene delivery , applied at different time points to the adult retina , can rescue the delayed dark adaptation present in the mouse model . to test whether the modification in electrophysiological activity following gene transfer to the oa1 −/− mouse retina could be related to changes occurring in the oa1 −−/− rpe melanosomes , which are of lower number ( marigo et al , unpublished results ) and increased size since birth [ 13 ], eyes from some of the animals used for the experiment depicted in fig3 a were enucleated and the transduced , egfp - positive areas from eyes injected either with the aav2 / 1 - cmv - moa1 + aav2 / 1 - cmv - egfp mixture or with the aav2 / 1 - cmv - egfp vector alone were dissected under a fluorescent microscope . egfp - positive , transduced areas accounted for 40 - 50 % of the whole retina with minor inter - animal variation . two different regions of the eye were analyzed , one centrally located in the proximity of the optic nerve and the remaining peripheral region , representing the vast majority of the retina . the rpe from these regions was isolated and analyzed by electron microscopy to assess melanosome number and size . a representative picture from oa1 - or egfp - injected eyes is shown in fig4 . in two independent electron microscopy measurements , the melanosome density ( melanosome / μm 2 ) in the peripheral rpe injected with the oa1 - expressing vector was higher than that measured in the same area of the contra - lateral eyes injected with the egfp vector alone ( fig5 a ). in one eye , both the transduced peripheral and central retinae were analyzed , confirming that treatment with the oa1 vector increases melanosome density independently of the area of transduction ( fig5 b ). the number of normal sized melanosomes in the peripheral rpe is increased in the 2 retinae treated with the oa1 vector when compared to the contralateral treated with the egfp vector alone , while the number of giant size melanosomes (& gt ; 1 . 5 μm ) remained similar ( fig5 c ). this suggests that in the period following gene transfer ( 4 weeks ) biogenesis of melanosomes of normal size occurs in the oa1 −/− rpe treated with the therapeutic vector rather than modification of the pre - existing abnormal organelles . the results show that gene transfer to the adult retina can rescue the electrophysiological abnormalities , as well as the altered melanosome density observed in oa1 −/− mice . the non - progressive nature of the disease and the possibility to ameliorate visual function with treatment to the adult retina open novel therapeutic perspectives for albino patients . table 1 . values of mean b - wave amplitudes — including standard deviation and error — at different time points before (− 4 ′) and after photoreceptor desensitization . fig1 . electrophysiological abnormalities in oa1 mice . ergs recorded after dark adaptation . a ) typical erg produced by a flash ( 10 cd * m - 2 ) in a dark adapted wild type c57 / bl6 mouse : a - and b - waves are indicated in an expanded scale ( horizontal bar = 20 msec , vertical bar = 150 μv ). dotted lines refer to a - and b - wave amplitudes . b ) erg produced by a flash ( 1 cd * m − 2 ) in a wild type c57 / bl6 ( upper waveform ) and oa1 −/− ( lower waveform ) mouse ; horizontal bar = 100 msec , vertical bar = 200 μv . erg components in scotopic and photopic conditions : a - ( c ) and b - waves ( d ) in oa1 −/− and c57 / bl6 wild type mice . the amplitudes ( mean ± s . e . m .) evoked by increasing light intensities in scotopic conditions in oa1 −/− mice ( empty triangles , n = 10 eyes ) and age matched controls ( black circles , n = 10 eyes ) are shown . the amplitude of a - and b - wave elicited in photopic conditions is indicated by an arrow . e ) recovery of b - wave amplitude after bleaching condition ( 600 cd * m − 2 for 3 min ) in oa1 −/− ( empty triangles , n = 12 eyes ) and wild type c57 / bl6 mice ( black circles , n = 12 eyes ). the amplitude of b - wave after bleaching condition was measured for flash of 1 cd * m − 2 sec − 1 and expressed as relative mean value compared to the amplitude of b - wave measured before bleaching condition . asterisks depict statistical significance ( p & lt ; 0 . 05 ). fig2 . partial recovery of the rod function following subretinal delivery of aav2 / 1 - cmv - oa1 to oa1 −/− mice . amplitude of a - ( a ) and b - waves ( b ) in scotopic and photopic ( depicted by the arrows ) conditions ( mean ± s . e . m ) from aav2 / 1 - cmv - oa1 ( empty triangles , n = 5 ) and aav2 / 1 - cmv - egfp ( black circles , n = 3 ) treated eyes recorded 1 month after vector delivery . asterisks depict statistical significance ( p & lt ; 0 . 05 ). fig3 . rescue from delayed recovery from photoreceptor desensitization in oa1 −/− mice treated with aav . progressive recovery over time of the b - wave amplitude following bleaching conditions in 2 -( a ) and 9 - month ( b ) old oa1 −/− animals injected subretinally either with aav2 / 1 - cmv - oa1 ( black circles , n = 6 eyes in both a and b ) or aav2 / 1 - cmv - egfp ( empty triangles , n = 6 eyes in a and 9 in b ). asterisks depict statistical significance ( p & lt ; 0 . 05 ). fig4 . increased density of normal sized stage iv melanosomes in the oa1 retinae transduced with aav . representative electron micrographs of peripheral rpe in 2 - months old treated and control oa1 −/− retinae . left panel shows the low melanosome density and macromelanosome presence typical of the oa1 − rpe transduced with aav2 / 1 - cmv - egfp . middle and right panels show different areas of the same rpe cell in a retina transduced with aav2 / 1 - cmv - oa1 . note the increased number of normal sized melanosomes ( middle panel ) with persistence of macromelanosomes ( right panel ). size bar 1 . 5 μm . fig5 . melanosomal modifications in the oa1 −/− rpe following delivery of aav2 / 1 - cmv - oa1 ( black bar ) or aav2 / 1 - cmv - egfp ( white bar ). a ) mature ( stage iv ) melanosome density in the peripheral rpe ( mean ± s . e . m . ; n = 2 eyes / group , 2 sections / eye ). b ) mature ( stage iv ) melanosomal density in the peripheral and central rpe area of aav - treated and wild type c57 / bl6 ( grey bar ) retinae ( n = 1 eye / group , mean of 2 sections / area ). c ) density of different size melanosomes in the peripheral rpe transduced with aav ( mean ± s . e . m . ; n = 2 eyes / group , 2 sections / eye ). melan , melanosome size . fig6 . recovery of retinal function following subretinal delivery of aav2 / 1 vectors encoding human or mouse oa1 gene under the transcriptional control of cmv , oa1 , and rpe65 promoters . max b - wave amplitude ( mean ± sem ) produced by a flash ( 10 cd m - 2 ) in dark adapted wt , oa1 and treated animals . treated animals were injected with aav2 / 1 viruses encoding human or mouse oa1 under different promoters . asterisks depict statistical significance ( p & lt ; 0 . 05 ): gray is significance vs oa1 not treated mice ; black is significance vs oa1 mice injected with aav2 / 1 cmv egfp as control . moa1 , mouse oa1 coding sequence ; hoa1 , human oa1 coding sequence ; promhoa1 , human oa1 promoter fragment ; prpe65 , human rpe65 promoter fragment . generation of the paav2 . 1 - cmv - oa1 construct , aav vector production , and purification . the murine oa1 coding sequence in pbs - sk plasmid was mutagenized via pcr using the advantage cdna pcr kit ( clontech , palo alto , calif ., usa ) in order to eliminate the hindiii restriction site , and to insert a not and a hindiii sites at the 5 ′ and 3 ′ end respectively with the following primers : oa1 - noti - f : aagcggccgcatggcctccccgcgcctgggaattttctgctgcc ctacgtgggacgcagccacacagctggtgctaagutccaac ( seq id no : 6 ); oa1 - hindiii - r : ttgactccatttcccaagcccagggggaactctgaaagcttaa ( seq id no : 7 ). the pcr product was then digested noti , hindiii and cloned in paav2 . 1 - cmv - egfp [ 28 ] by removing the egfp coding sequence ( noti - hindiii ). aav2 / 1 - cmv - oa1 and aav2 / 1 - cmv - egfp vectors were produced by triple transfection , purified by cscl2 ultracentrifugation and titered using a real - time pcr - based assay as previously described [ 21 , 28 ]. aav vectors were produced by the aav tigem vector core . subretinal vector administration . all procedures on mice ( including their euthanasia ) were performed in accordance with institutional guidelines for animal research . oa1 ( kept in a c57 / bl6 ) and wild type c57 / bl6 mice were used ( charles river italia , lecco , italy ). for subretinal vector administration , mice were anesthetized with an intraperitoneal injection of avertin at 2 ml / 100 g body weight ( 1 . 25 % ( w / v ) 2 , 2 , 2 - tribromoethanol and 2 . 5 % ( v / v ) 2 - methyl - 2 - butanol ; aldrich , st . louis , mo ., usa ) and viral vectors were delivered via a transscleral transchoroidal approach as described [ 29 ]. immunofluorescence . one month after injection treated and control eyes were collected , fixed overnight in 4 % paraformaldehyde , incubated in 30 % sucrose for 2 hours and then frozen in oct compound ( kaltech , padova , italy ). serial cryosections ( 12 μm thick ) were obtained . to detect oa1 by immunofluorescence , cryosections were fixed in 4 % paraformaldehyde for 20 ′. to detect oa1 by immunofluorescence , cryosections were fixed in 4 % paraformaldehyde for 20 ′, washed and incubated at room temperature in 30 mm nh 4 cl for 30 ′. sections were then permeabilized and blocked against non - specific binding in a buffer containing 10 % fbs ( gibco , invitrogen life technology , carlsbad , calif . ), 0 . 1 % saponin in pbs over night at 4 ° c . samples were then washed with pbs and incubated with rabbit anti - mouse - oa1 primary antibody ( 1 : 50 diluted in 0 . 01 % saponin ) for two hours at room temperature . after extensive washing in 0 . 01 % saponin , sections were incubated with secondary cy2 - labeled anti - rabbit antibody ( jackson immunoresearch , cambridgeshire , uk , 1 : 100 diluted in 0 . 01 % saponin ) for 1 hour at room temperature , washed with pbs and mounted with vectashield mounting media ( vector laboratories , burlingame , calif .). treated slides were then analyzed under the axioplan 2 imaging fluorescent microscope ( carl zeiss , milano , italy ). electrophysiological recordings . flash erg was evoked by 10 msec flashes of light generated through a ganzfeld stimulator ( lace , pisa , italy ). the electrophysiological signals were recorded through gold plate electrodes inserted under the lower eyelids in contact with the cornea previously anaesthetized with ossibuprocaine ( novesine , novartis pharma , switzerland ). electrode in each eye was referred to a needle electrode inserted subcutaneously at the level of corresponding frontal region . the different electrodes were connected to a two channels &# 39 ; amplifier . after 180 min . of dark adaptation , mice were anaesthetized by an intraperitoneal injection of avertin ( 1 . 2 % tribromoethanol and 2 . 4 % amylene hydrate in distilled water ; 2 ml / 100 g body weight ) and loosely mounted in a stereotaxic apparatus under dim red light with the body temperature maintained at 37 . 5 . for recordings in dark adapted conditions we adopted the following protocol : after dark adaptation erg was recorded in response to flash of different light intensities , ranging from 1 × 10 − 4 to 20 cd * m - 2 sec - 1 . the time interval between each stimulus was 4 - 5 min . amplitudes of a - and b - waves were plotted as function of increasing light intensities . after completion of responses obtained in dark - adapted conditions the recording session continued with the aim to dissect the cone pathway mediating the light response . to this aim the erg in response to light of 20 cd * m - 2 sec - 1 was recorded in the presence of constant light background set at 20 cd * m - 2 . in a different group of mice scotopic erg was recorded in response to light of 1 cd * m - 2 sec - 1 . for screening purpose 10 different responses were averaged with an interstimulus interval of 2 - 4 sec . mice were then exposed to a constant light whose intensity was set at 600 cd / m 2 for 3 minutes ( pre - adapting light , bleaching condition ). recovery of b - wave was monitored at fixed intervals after pre - adapting light ( 0 , 5 , 15 , 30 , 45 , 60 , 75 min ). the amplitude of b - wave in response to a flash of 1 cd * m - 2 sec - 1 after the pre - adapting light was measured and expressed as relative value respect to that measured before the pre - adapting light . data were statistically analyzed using the statistica ( statsoft , usa : two - way anova using least significance difference test for pair - wise comparisons ). ultrastructural analysis of the oa1 −/− retinal pigment epithelium . oa1 −/− eyes injected with avv2 / 1 - cmv - oa1 + avv2 / 1 - egfp ( right eyes ) and avv2 / 1 - egfp ( left eyes ) were removed and fixed in 2 . 5 % glutaraldehyde ( polyscience inc ., eppelheim , germany ) in cacodylate buffer 0 . 1m ( sigma - aldrich , st . louis , mo .). the injected portion of the retina was identified with a dissecting microscope equipped with epifluorescence illumination . the egfp positive region was dissected and processed for electron microscopy analysis , as described [ 30 ]. briefly , the dissected tissue was fixed 2 hrs in 2 . 5 % glutaraldehyde in cacodylate buffer 0 . 1m , post - fixed 2 hrs in 1 % osmium tetroxide ( electron microscopy science , hatfield , pa .) in cacodylate buffer 0 . 1m , and en bloc stained 2 hr with 1 % uranyl acetate ( electron microscopy science , hatfield , pa . ), at room temperature . samples were then dehydrated through graded ethanol series and propylene oxide ( taab laboratories equipment ltd , aldermaston , england ), and embedded in poly - bed ( polyscience inc ., eppelheim , germany ) epoxy resin . ultrathin sections were obtained from two different areas of the rpe ( peripheral and central retina ) in each sample . for each area two series of sections at 60 μm distance from each other were collected . samples were analyzed with a fei tecnai 12 - g2 tem and fei analysys software ( fei company , eindhoven , the netherlands ). we analyzed the rpe of 2 - months old mice . the analysis was performed on a total of ˜ 800 μm 2 for each series of sections , calculated with the “ closed polygon ” option of the software . we determined the density of total stage iv melanosomes ( number of melanosome / μm 2 ), and the diameter of stage iv melanosomes , calculated along the major axis of the organelle . we measured the diameter of melanosomes completely enclosed in each micrograph . 1 . king , r . a ., hearing , v . j ., creel , d . j ., and oetting , w . s . 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