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Natural History content

Natural history studies track the course of a disease over a period of time. These studies are an important source of information for scientists, clinicians, industry, regulators and people affected by the conditions such as retinal degenerations.

They are particularly significant in rare diseases, which are often not well documented and poorly understood due to low numbers of people affected and the complexity of some conditions. Registries play a major role in facilitating such vital studies such as the Target 5000 registry or other platforms such as the Foundation Fighting Blindness MyRetinaTracker.

By collecting this valuable information from a population we can achieve the following:

  • A better understanding of a condition and how it is likely to progress over time.
  • Provide demographic, genetic, environmental and other factors that may have an effect on disease progression.
  • Assess the likely effectiveness of any intervention.
  • Identify and aid in the selection of suitable participants in clinical trials.
  • Identify the best outcome measures to investigate in a clinical trial.
  • Provide information about the most appropriate time to treat a disease.

Natural history studies also enable people affected to better understand their condition and what to expect as the disease progresses. This is important so that people can prepare and plan for the future.

Natural history studies have been carried out for a number of sight loss conditions including Stargardt disease, Usher syndrome, X-linked retinoschisis, ChoroideremiaRetinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Bardet-Biedl Syndrome (BBS),  Age-related macular degeneration (AMD), Glaucoma, CNGB3 achromatopsia, dry eye and Diabetic retinopathy. Details of some of these studies are provided below. For further information, please contact research@fightingblindness.ie.

 

Stargardt Disease

ProgSTAR – A natural history of the progression of Stargardt disease

This study, coordinated by Foundation Fighting Blindness Clinical Research Institute, began in October 2013 and completed in 2017. The primary objective was to describe the genetic characteristics and to determine geographic differences based on the allele frequency in Stargardt disease (STGD1).

345 participants with a clinical diagnosis of STGD1 and harbouring at least one disease-causing ABCA4 variant were enrolled from 9 centres in the USA and Europe. Outcomes from this study demonstrated a large spectrum of ABCA4 sequence variants, including the identification of 50 novel disease-causing variants. Additionally, significant differences in allele frequencies between nations were observed.

ProgStar 4 – The natural history of the progression of atrophy secondary to Stargardt disease Type 4

A very rare form of Stargardt disease called Stargardt type 4 is caused by a mutation in the prominin-1 gene (PROM1) gene. Very little clinical data exists to date about this condition. This study was a prospective natural history study being led by John Hopkins University in the US and completed in 2018.

Fifteen participants aged 6 years and older, harboring disease-causing variants in the PROM1 gene and with specified ocular lesions were enrolled. Data on disease progression in PROM1-related retinopathy from this study will contribute to the characterisation of the natural history of disease and help establish patient cohorts worldwide for future clinical trials.

NEI – natural history of eye diseases related to ABCA4 Mutations

The National Eye Institute (NEI) in the US is conducting a natural history study of Stargardt disease and other ABCA4-related diseases (ClinicalTrials.gov Identifier: NCT01736293). The study is following 45 individuals with ABCA4 mutations for five years. The main goals are to better understand the natural course of the disease, to make contact with people who may be interested in future clinical trials, and to collect blood, skin, and DNA samples from those people. These samples can be studied in the lab to explore the mechanisms of Stargardt disease.

Usher Syndrome

NEI – natural history and genetic studies of Usher syndrome

This is a prospective natural history study led by the National Eye Institute in the US (ClinicalTrials.gov Identifier: NCT00106743). The study will explore the clinical and genetic aspects of Usher syndrome.

The study commenced in 2005 and is currently on-going but not recruiting participants. In total, 237 individuals have been enrolled and include participants affected with all three clinical types of Usher syndrome. Unaffected family members, primary parents and siblings were also enrolled to assist in providing crucial information for linkage analysis.

FFB – rate of progression in USH2A related retinal degeneration (RUSH2A)

This is a prospective, longitudinal natural history study of individuals diagnosed with Usher Syndrome and also for individuals diagnosed with non-syndromic retinitis pigmentosa (RP39) (who have at least two, pathogenic mutations in the USH2A gene).

This study commenced in 2017 and is expected to complete by the end of 2021. The study investigators hope to include approximately 120 individuals in this research (ClinicalTrials.gov Identifier: NCT03146078).

Fondazione Telethon – natural history study in subjects with Usher syndrome

This is a prospective natural history study of people living with the Type 1B form of Usher Syndrome (ClinicalTrials.gov Identifier: NCT03814499). This study is supported by Fondazione Telethon and is being conducted in sites in the Netherlands, Italy and Spain. It is hoped that 50 individuals will be recruited to the study, which is due to complete in December 2021.

LIGHT4DEAF Study – natural history of Usher syndrome

This is an observational study being conducted in France, where patients will be followed for 5 years. This study is expected to complete in 2027. For more information visit the European Reference Networks website.

FFB – natural history with Usher syndrome Type 1 Owing to MYO7A Mutation

Mutations in the MYO7A gene are the most common causes of Usher syndrome, type 1. This retrospective natural history case series was led by Moorfields Eye Hosptial, NHS Foundation Trust and Foundation Fighting Blindness (FFB).

Its purpose was to evaluate the phenotypic variability and natural history of ocular disease in a cohort of 28 individuals with MYO7A-related disease. Twenty-eight participants from 26 families participated. Conclusions from this study were published in the Ophthalmology Journal in February 2014.

It was concluded that MY07A-related ocular disease is variable. One observation was that central vision typically remains preserved at least until the third decade of life, with 50% of affected individuals reaching legal blindness by 40 years of age.

X-linked Retinoschisis (XLRS)

Clinical evaluation of patients with X-linked retinoschisis (XLRS)

This was a prospective natural history study led by Applied Genetic Technologies Corp (AGTC) in the US (ClinicalTrials.gov Identifier: NCT02331173). The objective of the study was to evaluate participants with XLRS in a clinical setting and gather data on disease progression.

 

Choroideremia

Nightstar Therapeutics – natural history of the progression of Choroideremia (NIGHT)

NIGHT is a prospective natural history study, led by Nightstar Therapeutics, which aims to examine the progression of choroideremia in 300 individuals diagnosed with the condition (ClinicalTrials.gov Identifier: NCT03359551). This study is being conducted at a number of locations across the world including the United States, Canada, Finland, Germany, England and France.

The study is due for completion in November 2019.

4D Molecular Therapeutics – natural history study of choroideremia.

Another prospective observational study is being led by 4D Molecular Therapeutics in the United States (ClinicalTrials.gov Identifier: NCT02994368). This study aims to understand the rate of progression of choroideremia in 50 participants. While on-going, this study is not recruiting at present and plans to be completed by December 2019.

 

Retinitis Pigmentosa (RP)

MeiraGTx – natural history study of individuals with mutations in RPGR

This is a prospective natural history study which is being led by MeriaGTx, recently acquired by Janssen, at two locations in the United States (ClinicalTrials.gov Identifier: NCT03349242). The team plan to recruit 55 participants with mutations in the RPGR gene and determine how the condition presents in such cases and how it progresses over time.

QLT – natural history study in subjects caused by mutations in RPE65 or LRAT

This was a retrospective natural history study, completed in 2016, which investigated the medical charts of people diagnosed Retinitis pigmentosa and Leber’s Congenital Amaurosis (caused by mutations in RPE65 or LRAT). A total of 59 people were recruited to the study, led by the QLT inc. group (ClinicalTrials.gov Identifier: NCT02575430).

XOLARIS – natural history of the progression of X-linked retinitis pigmentosa

This is a prospective, observational natural history study, supported by Nightstar Therapeutics, recently acquired by Biogen. The purpose of this study is to learn more about a condition called X-linked retinitis pigmentosa (XLRP). The study investigators want to gain a better understanding of disease progression over time in subjects with XLRP.

 

Leber Congenital Amaurosis (LCA)

Natural history study of subjects with LCA associated with mutations in RPE65

This is a prospective natural history study which aims to study this particular form of the condition over time (ClinicalTrials.gov Identifier: NCT02714816). It is being led by MeiraGTx UK II Ltd, which recently was acquired by Janssen. This study started in 2016 aims to include 40 individuals. It is hoped that this work will improve what is known about the condition and will help identify suitable individuals for a new therapeutic intervention. The study is due to complete in 2021.

Editas Medicine – natural history study of CEP290-related retinal degeneration

This is a prospective, observational natural history study of retinal degenerations associated with mutations in the CEP290 gene (ClinicalTrials.gov Identifier: NCT03396042). This study, supported by Editas Medicine aims to gather information which will guide future clinical trials. Approximately 40 participants will be recruited, with study completion expected in 2019.

 

Bardet-Biedl Syndrome (BBS)

Clinical registry investigating bardet-biedl syndrome (CRIBBS)

CRIBBS is an observational 10-year prospective study investigating the natural history of Bardet-Biedl syndrome (ClinicalTrials.gov Identifier: NCT02329210). The aim of the study, conducted by the Marshfield Clinic Research Foundation, is to gather comprehensive health information from individuals diagnosed with BBS in a single repository.

This information will be used to inform patients, families, and physicians about the complex features of BBS and will serve as a platform for researchers to develop effective and targeted treatment strategies for patients with BBS. The estimated enrollment for the study is 500 participants with a planned completion date of December 2025.

 

Age-related Macular Degeneration (Geographic Atrophy)

NEI – natural history of geographic atrophy secondary to age-related macular degeneration

A prospective natural history study, sponsored by the National Eye Institute in America aims to learn more about geographic atrophy (ClinicalTrials.gov Identifier: NCT02941263). This study commenced in 2016 and aims to recruit 25 individuals. It is due to complete in August 2020.

 

Glaucoma

Clinical and molecular studies in families with glaucoma and related diseases

This research, completed in 2016, was a prospective natural history study of glaucoma in a total of 484 individuals (ClinicalTrials.gov Identifier: NCT00272363). Supported by the National Eye Institute in America, this study aimed to learn more about the genetic basis and the presentation of the condition over time.

To learn more about natural history studies, please contact research@fightingblindness.ie or ring 01 6789004.