Our Pipeline


We are pioneering a pipeline of proprietary retinal gene therapies,


led by our lead product candidate NSR-REP1, that are designed to substantially modify or halt the progression of inherited retinal diseases that would otherwise progress to blindness and for which there are no currently approved treatments. Nightstar retains worldwide commercial rights to our entire pipeline of retinal gene therapy product candidates, summarized in the table below.

Choroideremia (CHM)

CHM is a rare, degenerative, X-linked genetic retinal disorder primarily affecting males. There are currently no approved or effective treatments for CHM, representing a significant unmet medical need.

CHM is an inherited retinal disease caused by mutations in the CHM gene on the X chromosome that interferes with the production of Rab escort protein-1 (REP-1), a protein that plays a role in intracellular protein trafficking and the elimination of waste products from retinal cells.

We are developing, NSR-REP1, a gene therapy for the treatment of CHM. We have an ongoing Phase 3 registrational clinical trial, known as the STAR trial, of NSR-REP1 for CHM, making it the most clinically advanced candidate for this disease worldwide. We are also conducting a prospective, natural history observational study, known as the NIGHT study, in which patients with CHM have been enrolling at multiple clinical sites in the United States, Europe and Canada since June 2015. The NIGHT study provides important evidence regarding the disease state and rate of disease progression in untreated CHM patients and creates a benchmark for comparison with the effects of NSR-REP1. We are recruiting participants in our STAR Phase 3 registrational trial primarily from the NIGHT study in order to significantly accelerate Phase 3 enrollment from this well-characterized patient population.

NSR-REP1 is comprised of an AAV2 vector containing recombinant human complementary DNA, or cDNA, that is designed to produce REP1 inside the eye. NSR-REP1 is administered surgically by injection into the sub-retinal space, which is between the outer layers of the retina. The introduction of the functional CHM gene is designed to enhance expression of the REP1 protein, thereby reducing the accumulation of waste products in retinal cells and slowing or stopping the decline in vision. In addition, we believe that enhanced REP1 expression may also be able to slow or reverse the early stages of cell death in already damaged retinal cells accounting for the substantial improvements in visual acuity we have observed in certain patients after treatment with NSR-REP1.

Positive results from a Phase 1/2 trial of NSR-REP1 were published in Nature Medicine in 2018, in The New England Journal of Medicine in 2016, and in The Lancet in 2014.

NSR-REP1 Two-Step Surgical Process

NSR-REP1 is administered by injection into the sub-retinal space, which is between the outer layers of the retina, following a standard vitrectomy procedure, in which some of the vitreous, the clear gel that fills the space between the lens and the retina of the eye, is removed to allow for better visualization of the injection site.


Watch the video of the full surgical process:


Our use of this two-step process allows the surgeon to ensure NSR-REP1 is administered directly to the target site. Surgical precision is further enhanced by intra-operative optical coherence tomography, or OCT, providing the surgeon with real-time, cross-sectional imaging of the precise location of NSR-REP1 administration.

Watch the video demonstrating OCT:


CHM presents in childhood as impairment of night vision, or night blindness, followed by progressive constriction of the visual fields, or tunnel vision, which generally leads to severe vision loss in early adulthood and total blindness in mid-late adulthood. Patients generally maintain good visual acuity, or detailed central vision, until the degeneration encroaches into the fovea, or the central part of the retina responsible for detailed vision.

The progressive vision problems in CHM are due to a loss of cells, or atrophy, in the retina and the choroid. This results from a mutation in the CHM gene on the X chromosome that interferes with the production of Rab escort protein-1 (REP-1), a protein that plays a role in intracellular protein trafficking and the elimination of waste products from retinal cells. Absence of functional REP1 leads to death of retinal pigment epithelium (RPE) cells, which provide supportive biological functions for the photoreceptors and the underlying choroid. Without a properly functioning RPE, the photoreceptors and the choroid slowly begin to atrophy, leading to vision loss. For CHM patients, it is often in middle age, when people typically are at or near their peak productive years, that visual impairment begins to limit independent activities of daily living and working productivity, leading to a severe vision loss and, eventually, blindness.

The prevalence of CHM is estimated to be one in 50,000 people, suggesting a total population of approximately 13,000 patients in the United States and major European markets.

*images provided by the Choroideremia Research Foundation



Select list of publications relevant to our choroideremia program, which can be accessed online at PubMed.

  1. Seabra, MC, Brown, MS, et al. (1993). “Retinal degeneration in choroideremia: deficiency of rab geranylgeranyl transferase.” Science 259(5093): 377-381.
  2. Seabra MC, Ho YK, Anant JS. Deficient geranylgeranylation of Ram/Rab27 in choroideremia. J Biol Chem 1995 270:24420-7.
  3. van den Hurk JA, Schwartz M, van Bokhoven H, van de Pol TJ, Bogerd L, Pinckers AJ, Bleeker-Wagemakers EM, Pawlowitzki IH, Rüther K, Ropers HH, Cremers FP. Molecular basis of choroideremia (CHM): Mutations involving the Rab Escort Protein-1 (REP-1) gene. Hum Mutat. 1997; 9(2): 110-117.
  4. Tolmachova, T, Anders, R, et al. (2006). “Independent degeneration of photoreceptors and retinal pigment epithelium in conditional knockout mouse models of choroideremia.” J Clin Invest 116(2): 386-394.
  5. Jacobson SG, Cideciyan AV, Sumaroka A, Aleman TS, Schwartz SB, Windsor EA, Roman AJ, Stone EM, MacDonald IM. Remodeling of the human retina in choroideremia: rab escort protein 1 (REP1) mutations. IOVS 2006 47:4113-20.
  6. MacLaren, RE (2009). “An analysis of retinal gene therapy clinical trials.” Curr Opin Mol Ther 11(5): 540-546.
  7. MacDonald IM, Smaoui N, Seabra MC. Choroideremia. 2003 Feb 21 [Updated 2010 Jun 3]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1337/.
  8. Coussa RG, Traboulsi EI. Choroideremia: a review of general findings and pathogenesis. Ophthalmic Genetics. 2012;33(2):57–65.
  9. Tolmachova, T, Tolmachov, OE, et al. (2013). “Functional expression of Rab escort protein 1 following AAV2-mediated gene delivery in the retina of choroideremia mice and human cells ex vivo.” J Mol Med (Berl) 91(7): 825-837.
  10. MacLaren, RE, Groppe, M, et al. (2014). “Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial.” Lancet 383(9923): 1129-1137.
  11. Edwards TL, Jolly JK, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Black GC, Webster AR, Lotery AJ, Holder GE, Xue K, Downes SM, Simunovic MP, Seabra MC, MacLaren RE.”Visual acuity after retinal gene therapy for choroideremia.” New England Journal of Medicine. N Engl J Med. 2016;374(20):1996-8.
  12. Patricio MI, Barnard AR, Orlans HO, McClements ME, MacLaren RE. Inclusion of the Woodchuck Hepatitis Virus Posttranscriptional Regulatory Element Enhances AAV1-Drivien Transduction of Mouse and Human Retina. Molecular Therapy: Nucleic Acids 2017; 6: 198-208.


X-linked Retinitis Pigmentosa (XLRP)

XLRP, a form of retinitis pigmentosa, is a rare inherited X-linked recessive genetic retinal disorder primarily affecting males. The disease is characterized by mutations in the RPGR gene leading to a lack of protein transport and a loss of photoreceptors, resulting in rapid disease progression and severe retinal dysfunction. XLRP is incurable and there are currently no treatments available. 

NSR-RPGR is being evaluated in a dose-ranging Phase 1/2 clinical trial for the treatment of XLRP in patients with the RPGR mutation, known as the XIRIUS trial. The XIRIUS trial is a multicenter trial consisting of a dose escalation study and an expansion study that will be enrolling patients in both the United States and the United Kingdom. Enrollment of the dose escalation study in the XIRIUS trial was completed in August 2018. On September 22, 2018, we announced positive preliminary safety and efficacy data from the XIRIUS trial for the first five cohorts (combined n=15) of the dose escalation study at the EURETINA medical meeting. We have also initiated a prospective, natural history observational study across multiple clinical sites, which we refer to as the XOLARIS study, to better understand the progression of untreated XLRP.

Our NSR-RPGR gene therapy consists of a standard AAV8 vector, including the codon-optimized human RPGR DNA. We have developed a codon-optimized gene for the production of RPGR that features higher protein expression levels than with a wild-type RPGR coding sequence. In addition, codon optimization provides greater sequence stability, which results in the consistent production of an identical protein product. NSR-RPGR is designed to produce RPGR-ORF15, the form of RPGR preferentially expressed in the retina.

Based on preclinical findings indicating the potential for safety and efficacy with a significant rescue of photoreceptors, we believe NSR-RPGR has the ability to slow or stop retinal degeneration of photoreceptors and to restore or maintain vision in patients affected by these mutations. In two mouse models of XLRP in which the mice lacked RPGR-ORF15 expression in the retina, treatment with NSR-RPGR resulted in a statistically significant rescue of photoreceptor cells in the treated eyes, but not in the untreated eyes. A single treatment in both eyes of wild-type mice with NSR-RPGR indicated a favorable safety profile, without inducing any toxic effects.

The onset, progression, severity and clinical manifestations of XLRP vary among patients. Typically, a male patient first experiences increasing symptoms of night blindness during childhood, followed by a narrowing of his peripheral vision and progressive loss of central vision over the course of his 20s and 30s. Legal or total blindness commonly occurs by the time a patient reaches his 40s.

Approximately 70 percent of XLRP cases are due to variants in the genes responsible for the production of retinitis pigmentosa GTPase regulator protein, or RPGR, which is involved in the transport of proteins necessary for the maintenance of photoreceptor cells. Loss of RPGR function in the retinal cells causes the progressive loss of rod and cone photoreceptors, leading to a loss of vision in patients.

The estimated worldwide prevalence of XLRP due to RPGR variants is approximately one in 40,000 people, which represents approximately 17,000 patients in the United States and the five major European markets.


Select list of publications relevant to our XLRP program, which can be accessed online at PubMed.

  1. Kirschner R, Rosenberg T, Schultz-Heienbrok R, et al. RPGR transcription studies in mouse and human tissues reveal a retina-specific isoform that is disrupted in apatient with X-linked retinitis pigmentosa. Hum Mol Genet. 1999;8:1571-1578.
  2. Vervoort R, Lennon A, Bird AC, et al. Mutational hot spot within a new RPGR exon in X-linked retinitis pigmentosa. Nat Genet. 2000;25:462-466.
  3. Hong DH, Li T. Complex expression pattern of RPGR reveals a role for purine-rich exonic splicing enhancers. Invest Ophthalmol Vis Sci. 2002;43:3373-3382.
  4. Schmid F, Glaus E, Cremers FP, et al. Mutation- and tissue-specific alterations of RPGR transcripts. Invest Ophthalmol Vis Sci. 2010;51:1628-1635.
  5. Ferrari S, Di Iorio E, Barbaro V, et al. Retinitis pigmentosa: genes and disease mechanisms. Curr Genomics. 2011;12(4):238-249. doi: 10.2174/138920211795860107.
  6. Deng WT, Dyka FM, Dinculescu A. Stability and safety of an AAV vector for treating RPGR-ORF15 X-linked retinitis pigmentosa. Hum Gene Ther. 2015;26(9):593-602. doi:10.1089/hum.2015.035. Epub 2015 Jul 29.
  7. Wu Z, Hiriyanna S, Qian H, et al. A long-term efficacy study of gene replacement therapy for RPGR-associated retinal degeneration. Hum Mol Genet. 2015;24(14):3956-3970. doi: 10.1093/hmg/ddv134. Epub 2015 Apr 15.
  8. Pawlyk BS, Bulgakov OV, Sun X, et al. Photoreceptor rescue by an abbreviated human RPGR gene in a murine model of X-linked retinitis pigmentosa. Gene Ther. 2016;23(2):196-204. doi:10.1038/gt.2015.93. Epub 2015 Sep 8.
  9. Tee JJ, Smith AJ, Hardcastle AJ, et al. RPGR-associated retinopathy: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol. 2016 Feb 3. pii: bjophthalmol-2015-307698. doi: 10.1136/bjophthalmol-2015-307698. [Epub ahead of print]
  10. Fischer MD, McClements ME, Martinez-Fernandez de la Camara C, Bellingrath JS, Dauletbekov D, Ramsden SC, Hickey DG, Barnard AR, MacLaren RE. Codon-Optimized RPGR Improves Stability and Efficacy of AAV8 Gene Therapy in Two Mouse Models of X-Linked Retinitis Pigmentosa. Mol Ther. 2017 Aug 2;25(8):1854-1865.

Stargardt Disease

The form of Stargardt disease we are targeting is an autosomal recessive disease that is linked to mutations in the ABCA4 gene that are inherited from both parents of an affected individual. The progressive central vision loss associated with Stargardt disease is caused by the degeneration of photoreceptor cells in the central portion of the retina called the macula. Stargardt disease typically develops during childhood and adolescence, and can lead to blindness in patients by their twenties.

Our retinal gene therapy product candidate, NSR-ABCA4, is in preclinical development for the treatment of Stargardt disease in patients with mutations in the gene encoding ATP-binding cassette, sub-family A member 4, or ABCA4. Due to the large size of the ABCA4 cDNA, we have developed a dual vector approach to address the size limitations associated with the AAV packaging capacity based on optimizing the length of DNA overlap between the two vectors.

In mouse models of Stargardt disease, NSR-ABCA4 has shown expression of full length ABCA4 protein in photoreceptor outer segments, leading to significant reductions in toxic metabolic byproducts associated with Stargardt disease.

In Stargardt disease, mutations in the ABCA4 gene lead to a lack of functional ABCA4 protein in retinal cells.

Stargardt disease is the most common form of inherited juvenile macular dystrophy with a prevalence of approximately one in 10,000 which represents approximately 65,000 patients in the United States and the five major European markets. There is currently no treatment for patients with Stargardt disease.

Other Programs Under Evaluation

We also have product candidates in preclinical development for a number of inherited retinal diseases for which there are no approved treatments such Best vitelliform macular dystrophy, or Best disease and Retinitis Pigmentosa. We are evaluating other in-licensing opportunities to broaden our pipeline and drive future growth.

Gene Therapy – Ideally Suited for Retinal Diseases

Gene therapy is used to overcome the effects of a defective, disease-causing gene by using engineered viruses, or viral vectors, to deliver a functional version of the gene into cells. Once delivered into a patient, the delivered gene utilizes available cellular mechanisms to produce a functional protein that leads to a therapeutic effect.

Our retinal gene therapy candidates utilize vectors based on adeno-associated virus (AAV), which are believed to be especially well suited for treating retinal diseases because AAV is a small, replication-deficient virus that is non-pathogenic and has a well-documented safety profile. Over 250 genes that play a role in inherited retinal diseases have been identified, although fewer than 10 of these targets are currently in clinical development.

The eye is an excellent target organ for gene therapy due to its accessibility, small size, compartmentalization and relative immune privileged status. The vectors can be directly injected into the diseased tissue and non-invasively observed for efficacy and safety. The blood-ocular barrier in the eye prevents the widespread dissemination of locally administered vectors throughout the body. Given the small volume of the eye, the amount of vector needed to achieve a therapeutic effect is low, reducing the amount of vector required to be administered to the patient and reducing potential systemic side effects.

Our Clinical Trials

We are developing a pipeline of novel and potentially curative, one-time retinal gene therapies for patients suffering from rare inherited retinal diseases that would otherwise progress to blindness, and for which there are no currently approved treatments. For more information about our ongoing clinical trials, please visit www.clinicaltrials.gov and search for Nightstar Therapeutics.