The National Institutes of Health’s (NIH) National Eye Institute (NEI) has awarded two researchers—one from Columbia University and another from the Rensselaer Polytechnic Institute $6.4 million to find their co-clinical development of an investigational compound for the treatment of two retinal diseases:
- Dry age-related macular degeneration (AMD)
- Stargardt disease (SD)
First up, this grant.
The multimillion-dollar grant will be dispersed over a 5-year period to support drug development activities and an investigational new drug (IND)-enabling toxicology studies.
Nice! Now before we get to this drug, some background on these diseases.
AMD is, most notably, one of the most common culprits behind vision loss in adults, with 12.6% of Americans aged 40+ living with the vision-threatening condition (as of 2019).
Even further: Dry AMD—occurring when there’s a build up of lipofuscin within the retina—is referred to as “the most prevalent form” of this disease, with 6.9% of adults aged 40+ living with it in 2019 (a 5.1% increase).
- Keeping with the theme: In the presence of Stargardt macular degeneration, lipofuscin buildup occurs within the macula.
Remind me: What exactly is lipofuscin?
Lipofuscin consists of yellow-brown pigment granules that naturally accumulate in aging cells (such as retinal pigment epithelium [RPE]) as a direct result of the body’s aging process—or, in some cases, disease.
Specifically, these granules include pyridinium bisretinoids, which comprise the primary cytotoxic elements of retinal lipofuscin (i.e., dry AMD and SD).
And in relation to this research?
The investigators—Konstantin Petrukhin, PhD, professor of Ophthalmic Science at Columbia University as well as Christopher Cioffi, PhD, the Thomas and Constance D’Ambra professor in Organic Chemistry at Rensselaer Polytechnic Institute—are looking to block the synthesis of these bisretinoids in order to treat dry AMD.
And how might they do that?
By focusing in on this bisretinoid synthesis, which is determined by retinol traffic passing through the bloodstream to the retina and a retinol binding protein (RBP4) - Transthyretin (TTR) complex operating as the main carrier that delivers retinol to the eye.
From there: RBP4 antagonists displace this retinol from RBP4, resulting in the RBP4-TTR complex to separate and lipofuscin bisretinoid synthesis to become suppressed.
Any potential issues associated with this?
The investigators noted that “disrupting the RBP4-TTR interaction could potentially destabilize wild-type TTR tetramers and promote TTR aggregation in individuals with age-related predisposition to TTR amyloidosis disease (ATTR).”
- Note: A “tetramer” is a transport protein within the plasma and cerebrospinal fluid that delivers both the thyroid hormone thyroxine (T4) as well as retinol via its association with retinol-binding protein.
So, what’s their plan?
Cioffi and Petrukhin have introduced a new class of investigational compounds—specifically referred to as “orally bioavailable bispecific drugs”—that act as “both RBP4 antagonists and TTR tetramer kinetic stabilizers.”
Their purpose: To reduce serum RBP4 levels along with suppressing bisretinoid synthesis and binding to TTR’s thyroxine binding sites.
- And, as a result of this TTR binding, TR amyloid formotion is also blocked.
And how might this help dry AMD patients?
This research resulted in the discovery of an advanced preclinical candidate that targets treatment for dry AMD patients with age-related predisposition to TTR amyloidosis, according to the investigators.
- The details: Developed as an oral pill (compared to standard injections often used to treat AMD), Cioffi stated that the candidate would “avoid compliance issues associated with intravitreal injections.”
What about for SD patients?
Cioffi added that the bispecific compounds have shown “therapeutic potential to treat atrophic age-related dry AMD and (SD).”
Plus, Petrukhin noted that the candidate combines optimal safety and efficacy and is intended to “emerge as a new and improved therapy for macular degeneration, benefiting diverse patient populations in need of enhanced treatment options.”