Genetic New Cure for Retinitis Pigmentosa and other Blinding disease associated with Gene RPE65: Cure for Stargardt's Disease may be coming soon.

Blinding diseases are heart breaking, especially if they affect young children. I have seen many patients with Retinitis Pigmentosa who are thrilled about the new genetic treatment which may prove to help thousands who have RP.

I have also seen many patients with Stargardt's disease which is also a blinding disease. Most of these patients are young children. They often have very poor retina function noted on their ERG. But there is great hope! 

Recently, the first gene restoring therapy was approved by the FDA for patients with Retinitis Pigmentosa which is a mutation of gene RPE65. More about this below.

Hopefully the genes for Stargardts are on their way to being treated. Startgardt's disease is named after a German eyeMD named Karl Stargardt who reported the first case in 1901. Stargardt's disease affects about 1 in 20,000 kids with a form of macular degeneration. It can affect both eyes and usually develops between ages 6-20. Kids first notice difficulty reading or difficulty adapting to bring light. 

Stargardt disease is due to a genetic mutation primarily in gene ABCA4 and is usually a recessive trait. When both parents carry the ABCA4 mutation, there is a 25%chance their children will have Stargardt disease.

ABCA4 is a genetic code that tells your body to produce a protein (lipofuscin) which blocks the normal transportation of food and waste to the retina's delicate photoreceptor cells.  which tells the body to produce a protein which blocks normal transportation of food and waste to the retina’s photoreceptor cells. Flecks of lipofuscin, or these waste deposits, build up in the retinal pigment epithelium (RPE), which is the nutritional support layer for the rods and cones of the retina. The RPE and the rods and cones break down in the presence of these waste deposits.

A rarer disease called autosomal dominant Stargardt-like macular dystrophy, similar to Stargardt, is caused by the gene ELOVL4.

While there is no cure for Stargardt disease yet, the hope of genetic therapy is real. Also if new blood vessels form under the macula because of Stargardt's disease, this can be treated with Anti-VEGF intraocular injections like is currently treated for age related macular degeneration. 

Currently, to prevent further macular degeneration from Stargardts, the following is recommended:

1. Always wear sunglasses (especially sunglasses which block UV A and B and blue light) & hat

2. Never smoke or be around smokers.

3. Avoid high dose Vitamin A: which is different from patients with Retinitis Pigmentosa. In patients with Stargardt's, Vitamin A can actually be toxic to the eyes because the vitamin is not metabolized by cells in the eye.

So what are the next steps to be in line to get treated from a blinding disease.

1. Be in the best shape you can possibly be in: avoid getting diabetes as patients who have diabetes will not be in the first round of trials or treatment most likely as companies who are investing millions want to try these therapies on those who have the best chance of improvement. 

2. Exercise, eat a low carb, gluten free diet. Avoid sugar. Avoid sodas.

3. Wear sunglasses and a hat.

4. Avoid smokers & smoking.

5. If you have Retinitis Pigmentosa, look into high dose Vitamin A Palmitate. If you have Stargardt's disease, avoid high dose Vitamin A.

6. Find out which genetic mutation you have. 

a. Either ask you MD or find a genetic counselor

https://www.genome.gov/19516567/faq-about-genetic-testing/

b. Contact a genetic testing company to see if they test for common eye disease mutations & see how much it costs.

https://www.genedx.com/test-catalog/available-tests/rpe65-gene-sequencing/

Genes that can have a Mutation which is associated with Eye Diseases:

1. Retinitis Pigmentosa: 
a. RPE65
b. RP1, RP2, RPGR, PRPH2, IMPDH1, PRPF31, CRB1, PRPF8, TULP1, CA4, HPRPF3, ABCA4, EYS, CERKL, FSCN2, TOPORS, SNRNP200, PRCD, NR2E3, MERTK, USH2A, PROM1, KLHL7, CNGB1, TTC8, ARL6, DHDDS, BEST1, LRAT, SPARA7, CRX
2. Stargardt disease:
a. ABCA4 
b. CNGB3
b. ELOVL4
c. PROM1

3. Glaucoma: This is more complex: Reference: https://www.glaucoma.org/glaucoma/the-genetics-of-glaucoma-what-is-new.php

Primary open-angle glaucoma (POAG) is the most common type of glaucoma and has no obvious abnormality in the eye that points to a cause. Although mutations in several genes, including myocilin, optineurin, and CYP1B1, have been reported to cause POAG, these genes account for less than 10% of cases worldwide. In the past 2 years, large scale genetic studies that have examined the blood samples of thousands of glaucoma patients have been instrumental in the discovery of more common genetic risk factors for POAG. A risk factor is something that doesn’t always lead to a condition but increases the risk of having that condition. For glaucoma, these genetic factors include changes in the DNA sequences (near or in the genes such as caveolin 1 and 2 (CAV1/CAV2), CDKN2B antisense RNA, TMCO1, SIX1/SIX6, and LRP12/ZFPM2 genes) or actual loss of DNA (TBK1 and GALC), and several different genes have been implicated. How these genes cause or influence the likelihood of developing POAG is of major interest.

Glaucoma is often thought of as a disease of middle age or older adults. However there are many inherited forms of glaucoma that affect young children. Primary congenital glaucoma (PCG) is the most common childhood glaucoma affecting children from birth to age 3 and is a major cause of blindness in this young population. Mutations in the CYP1B1 gene have been found to cause PCG in children worldwide and are the dominant genetic cause for glaucoma in children in the Middle East and central Europe. In the United States only 15% of children with PCG have a mutation in CYP1B1, so there are ongoing efforts to identify additional causes in these young patients. Other types of glaucoma related to maldevelopment of the eye occur in older children - the genes implicated in these forms of glaucoma play a key role in the development of the eye, so when they malfunction they cause abnormalities in the eye's fluid drainage system which leads to elevated eye pressures and glaucoma. The genes currently known to be associated with these forms of glaucoma include PITX2, PITX3, FOXC1, FOXE3, PAX6, LMX1B, and MAF.

Primary angle-closure glaucoma (PACG) is the second most common form of glaucoma and affects over 16 million people globally. In this form of glaucoma the drainage angle closes over time, blocking the pathway to the drainage system and causing high eye pressures. Very recently a large scale genetics study identified genetic variants that are associated with this form of glaucoma. These variants are in or near PLEKHA7, PCMTD1/ST18, and COL11A1. How these genes contribute to this form of glaucoma is not clear.

Exfoliation glaucoma (XFG), also called pseudoexfoliation glaucoma, affects millions and is the most common identifiable form of open-angle glaucoma in the world. XFG results from exfoliation syndrome, a common condition characterized by the deposit of white protein-like material that forms on the lens and within the fluid drainage system of the eye, as well as tissues throughout the body. Genetic variants of LOXL1 and CNTNAP2 genes have been associated with XFG.Researchers are currently working on how these genes contribute to the formation of these protein deposits and how these cause glaucoma.

Stargardt disease (macular degeneration)

ABCA4, CNGB3, ELOVL4, PROM1

References: 

https://www.macular.org/stargardt-disease

Stargardt Disease Support Groups

Royal National Institute of Blind People

Stargardt Argentina
Contact: Florencia Braga Menendez
Humboldt 1574
Mariano Moreno 465
Buenos Aires, Argentina
0054.9.11.4174.8230

Stargardt’s Australia

Stargardt Disease: Hope for a Cure

With the passing of the Orphan Drug Act in 1983, the FDA established the Office of Orphan Product Development (OOPD), which gives incentives to biotech companies to develop promising products for the diagnosis, treatment, and cure of rare diseases. Orphan Drug Status provides tax reductions and the exclusive rights to the cure for a specific condition for a period of seven years post-approval. It encourages companies to enter a market where high costs of drug development are less likely to be recouped quickly, due to the smaller pool of individuals needing the cure.

By definition, an orphan drug is one for a disease which affects less than 200,000 Americans, or less than 5 per 10,000 people in a community. During approval of an orphan drug, the FDA recognizes that Phase III clinical trials on 1000 people might not always be possible, due to a lack of individuals with the condition in question. It provides incentive to continue the research, even when a drug doesn’t prove to be the miracle cure it was initially thought.

The OOPD administers the Orphan Products Grants Program which provides funding for clinical research in rare diseases. For example, in 2014, the biotech company Makindus received orphan designation for its lead product, MI-100, from OOPD for the treatment of Stargardt disease, a hopeful sign that progress may be made toward a cure for this debilitating juvenile illness.

History Is Made: FDA Approves Spark’s Vision-Restoring Gene Therapy

By Ben Shaberman on December 20, 2017

Spark Therapeutics’ vision-restoring RPE65 gene therapy has received marketing approval from the U.S. Food and Drug Administration, becoming the first gene therapy to gain regulatory approval in the U.S. for the eye or any inherited condition.

Known as LUXTURNA™ (voretigene neparvovec), the gene therapy restored vision in a clinical trial for people between the ages of 4 and 44 with Leber congenital amaurosis (LCA) caused by mutations in the gene RPE65. Study participants with severe vision loss reported putting away their navigational canes, seeing stars, being able to read, and recognizing faces of loved ones. Vision restoration has persisted for at least three years. The treatment is also designed to work for people with retinitis pigmentosa (RP) caused by RPE65 mutations.

On October 12, 2017, an FDA Advisory Committee voted 16 to 0 in recommending marketing approval for LUXTURNA.

The Foundation Fighting Blindness invested about $10 million in more than a decade of lab research that made possible the RPE65 gene therapy clinical trial at the Children’s Hospital of Philadelphia (CHOP). FFB-funded research included: studies to understand the role of RPE65 in vison and retinal disease, development of animal models with RPE65 mutations, RPE65 gene therapy testing and development, and support for early clinical research at CHOP.

“This is truly a historical moment in the fight against blindness. We are delighted by the FDA’s approval of LUXTURNA for people with RPE65 mutations,” says Stephen Rose, PhD, chief research officer at FFB. “LUXTURNA’s approval also provides affirmation that gene therapies can be a safe, effective, and commercially viable approach to treating many forms of blindness, providing a big boost to an already burgeoning field. The approval is great news for a broad spectrum of people with inherited retinal diseases.”

Retinal gene therapy clinical trials are underway for people with a wide range of retinal diseases including: X-linked RP, choroideremia, Usher syndrome type 1B, Stargardt disease, X-linked retinoschisis, and achromatopsia.

More than 10 million people in the U.S., and millions more around the world, have retinal degenerative diseases.

“We are thrilled for the patients whose lives will change because of this treatment,” says David Brint, Foundation Fighting Blindness chairman. “And we are also pleased to have this concrete example of the strength of the Foundation’s strategy of investing early in promising treatments in order to attract later industry investment that can usher the treatments through clinical trials and FDA approval.”

“LUXTURNA will be life changing for people with RP and LCA caused by RPE65 mutations. For them, the treatment may well mean the difference between relying on assistive technologies or other people and living a life of independence. Also important is the momentum this approval provides to other gene-based therapies — for the eye and other diseases — now in the pipeline,” says Benjamin Yerxa, PhD, Foundation chief executive officer.

The LUXTURNA gene therapy involves injection of healthy copies of RPE65 underneath the retina. The RPE65 copies are contained in a human-engineered virus — known as an adeno-associated virus or AAV — which is designed to readily penetrate retinal cells to deliver the therapeutic genetic cargo. A single treatment is expected to last several years.

Spark Therapeutics, which holds the biologics license for LUXTURNA and conducted the clinical trials that showed its safety and efficacy, will also manage the treatment rollout. Spark has announced that in order to ensure the treatment is safely administered, it will only be available through a small number of centers of clinical excellence around the country. Spark has also expressed its commitment to educate third-party payers about the value of LUXTURNA and to work to help ensure treatment access to all eligible patients.

Anyone in need of more information about LUXTURNA should contact Spark Therapeutics at 1-833-SPARK-PS (833-772-7577). Another resource for information is www.luxturna.com.

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Spark Therapeutics’ Biologics License Application for Investigational Voretigene Neparvovec Accepted for Filing by FDA

FDA grants Priority Review with Prescription Drug User Fee Act (PDUFA) date of Jan. 12, 2018

LUXTURNA™ (voretigene neparvovec) unveiled as proposed trade name

PHILADELPHIA , July 17, 2017 (GLOBE NEWSWIRE) -- Spark Therapeutics (NASDAQ:ONCE), a fully integrated gene therapy company dedicated to challenging the inevitability of genetic disease, announced today that the U.S. Food and Drug Administration ( FDA ) has accepted for filing the Biologics License Application (BLA) and granted Priority Review for voretigene neparvovec, an investigational, potential one-time gene therapy candidate for the treatment of patients with vision loss due to confirmed biallelic RPE65-mediated inherited retinal disease (IRD). The investigational gene therapy, which has the proposed trade name LUXTURNA™ (voretigene neparvovec), has the potential to be both the first pharmacologic treatment for IRD and the first gene therapy for a genetic disease in the United States .

Priority Review is granted to therapeutics that would offer major advances over existing therapies or would provide a treatment where no adequate therapy exists. FDA's goal for taking an action on Priority Review applications is six months. For the review of LUXTURNA, FDA has assigned a PDUFA date of Jan. 12, 2018 .

"FDA acceptance for filing of our BLA for LUXTURNA is an important development for people living with RPE65 -mediated IRD, a significant milestone for the gene therapy field, and a strong testament to the dedication of our collaborators and employees," saidJeffrey D. Marrazzo, chief executive officer of Spark Therapeutics . "As we work closely with FDA in the months ahead, we will remain steadfast in our commitment to bring this important investigational therapy to people living with RPE65-mediated IRD who currently have no pharmacologic treatment options."

Investigational LUXTURNA is intended to be administered one time per eye in patients with vision loss due to biallelic RPE65-mediated IRD. A natural history study has shown that people with this IRD eventually progress to complete blindness.

"Today's announcement is an important and exciting step forward in the effort to treat blindness caused by inherited retinal diseases," commentedGordon Gund, co-founder and chairman emeritus, Foundation Fighting Blindness (FFB), a nonprofit organization focused on research for preventing and treating blindness caused by IRDs. "While we await the FDA review process, it is fitting to note that FFB is proud to have been a part of the early support of the research that led to the development of this potential therapy."

LUXTURNA Clinical Trial Overview
The safety and efficacy of LUXTURNA were assessed in two open-label Phase 1 trials, which continue to follow participants who received LUXTURNA between 2007 and 2012, and one open-label, randomized, controlled Phase 3 trial. Following the one-year control period of the Phase 3 study, all control participants elected to cross over and received LUXTURNA; long-term safety and efficacy continue to be assessed in the Phase 3 participants who received LUXTURNA between 2013 and 2015. The clinical trial program included 41 participants with vision loss aged four to 44 at the time of first administration. Confirmed biallelic RPE65 mutations and the presence of sufficient viable retinal cells were established in all participants.

LUXTURNA Phase 3 clinical trial data, including data from the intent-to-treat population of all randomized participants through the one-year time point, were published in The Lancet. Results showed a statistically significant and clinically meaningful difference between intervention (n=21) and control participants (n=10) at one year, per the clinical trial's primary endpoint, mean bilateral multi-luminance mobility testing (MLMT) change score (difference of 1.6; 95% CI, 0.72, 2.41; p=0.001). In addition, participants who received LUXTURNA showed a marked difference compared to control participants across the first two secondary endpoints: full-field light sensitivity threshold (FST) testing (p<0.001) and the mobility test change score for the first injected eye (p=0.001). A third secondary endpoint, the change in visual acuity (VA) averaged over both eyes, was not statistically significant between intervention and control participants (p=0.17).

On average, participants in the original Phase 3 intervention group maintained functional gains observed by the day-30 visit through at least two years, as measured by MLMT and FST. The more than 100-fold (or greater than two log units) average improvement in FST testing observed in the original intervention group at one year, similarly, was maintained through at least two years.

In continuation of the trial to include crossover of the control group to receive LUXTURNA, 93 percent (27 of 29) of all treated Phase 3 trial participants saw a gain of functional vision as assessed by bilateral MLMT over the follow-up period of at least one year from administration of LUXTURNA to each eye. Additionally, 72 percent (21 of 29) of all Phase 3 trial participants receiving LUXTURNA successfully completed MLMT at the lowest light level evaluated (1 lux) at one year.

Data from a cohort of the Phase 1 clinical trial, in which investigational LUXTURNA was administered to the contralateral, or second previously uninjected eye, showed mean improvements in functional vision and visual function. These improvements were maintained through at least three years, as measured by both MLMT and FST testing. This cohort of participants (n=8) received the same dose of LUXTURNA that was administered in the Phase 3 trial and would have met the Phase 3 eligibility criteria.

No serious adverse events (SAEs) associated with LUXTURNA or deleterious immune responses have been observed. Two ocular SAEs were reported in the clinical program. There was one SAE related to the surgical procedure in one eye of a Phase 3 participant, in which there was foveal thinning and a sustained reduction in VA. One additional ocular SAE was reported in one eye of a Phase 1 participant in which the treatment for bacterial endophthalmitis led to elevated intraocular pressure and subsequent optic atrophy. There were three non-serious AEs of retinal deposit (subretinal precipitate) in three participants (three eyes) that were considered to be related to LUXTURNA. All three of these events were mild in intensity, transient in nature and resolved without consequences. The most common adverse reactions related to LUXTURNA reported in 10 percent or greater of the combined Phase 1 and Phase 3 trial participants included conjunctival hyperemia, cataract, intraocular pressure increased, and retinal tear.

About RPE65-mediated Inherited Retinal Disease (IRD)
Inherited retinal diseases (also known as inherited retinal dystrophies) are a group of rare blinding conditions caused by one of more than 220 different genes. People living with IRD due to biallelic RPE65 gene mutations often experience night blindness (nyctalopia) due to decreased light sensitivity in childhood or early adulthood and involuntary back-and-forth eye movements (nystagmus). As the disease progresses, individuals may experience loss in their peripheral vision, developing tunnel vision, and eventually, they may lose their central vision as well, resulting in total blindness. Independent navigation becomes severely limited, and vision-dependent activities of daily living are impaired. There are currently no approved pharmacologic treatment options for this disease.

About Gene Therapy
Gene therapy is an investigational approach to treat or prevent genetic disease by seeking to augment, replace or suppress one or more mutated genes with functional copies. It addresses the root cause of an inherited disease by enabling the body to produce a protein or proteins necessary to restore health or to stop making a harmful protein or proteins, with the potential of bringing back function in the diseased cells and slowing disease progression. To deliver the functional gene into the cell, a vector is used to transport the desired gene and is delivered either intravenously (IV) or injected into specific tissue. The goal is to enable, through the one-time administration of gene therapy, a lasting therapeutic effect.

About Spark Therapeutics
Spark Therapeutics , a fully integrated company, strives to challenge the inevitability of genetic disease by discovering, developing, and delivering gene therapies that address inherited retinal diseases (IRDs), neurodegenerative diseases, as well as diseases that can be addressed by targeting the liver. Our validated platform successfully has delivered proof-of-concept data with investigational gene therapies in the retina and liver. Our most advanced investigational candidate, with proposed trade name LUXTURNA™ (voretigene neparvovec), is currently under Priority Review with FDA for the treatment of biallelic RPE65-mediated IRD. It previously received breakthrough therapy and orphan product designations from FDA and orphan product designations from the European Medicines Agency (EMA). The pipeline also includes SPK-7001 in a Phase 1/2 trial for choroideremia, and two hemophilia development programs: SPK-9001 (which also has received both breakthrough therapy and orphan product designations by FDA , and access to the PRIority MEdicines (PRIME) Program by the EMA) in a Phase 1/2 trial for hemophilia B being developed in collaboration with Pfizer, and SPK-8011, in a Phase 1/2 trial for hemophilia A to which Spark Therapeutics retains global commercialization rights. For more information, visit www.sparktx.com.

Cautionary note on forward-looking statements
This release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding the company's product candidate LUXTURNA™ (voretigene neparvovec). Any forward-looking statements are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in, or implied by, such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk that: (i) our BLA submitted for LUXTURNA to the FDA may not be approved; (ii) the data from our Phase 3 clinical trial of LUXTURNA may not support labeling for all biallelic RPE65 mutations other than Leber congenital amaurosis (LCA); and (iii) the improvements in functional vision demonstrated by LUXTURNA in our clinical trials may not be sustained over extended periods of time. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the "Risk Factors" section, as well as discussions of potential risks, uncertainties and other important factors, in our Annual Report on Form 10-K, our Quarterly Reports on Form 10-Q and other filings we make with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Spark undertakes no duty to update this information unless required by law.

Investor Contact: 
Ryan Asay 
Ryan.asay@sparktx.com
(215) 239-6424 

Media Contact:
Monique da Silva
Monique.dasilva@sparktx.com
(215) 282-7470