PYC Therapeutics heeft ons een artikel toegestuurd waarin zij uitleggen met welk onderzoek, gericht op ADOA, zij op dit moment bezig zijn. De tekst bevat veel medische taal en kan moeilijk te begrijpen zijn.

Kort samengevat: PYC therapeutics is bezig met RNA- technieken waarbij een medicijn (PMO) het goedwerkende OPA1 gen versterkt en daardoor het tekort aan een bepaald eiwit, dat ontstaat door de mutatie in het andere OPA1 gen, opheft. Wanneer er een goed medicijn (PMO) ontwikkeld is, wordt de veiligheid en werkzaamheid getest op menselijke stamcellen van ADOA patiënten. Stamcellen bevatten het volledige DNA pakket van een individu en zijn daarom erg belangrijk bij het begrijpen en bestuderen van processen in de cel. Stamcellen kunnen bijvoorbeeld vanuit een stukje huid verkregen worden en zo de netvliescellen nabootsen. Het team van PYC wat hier aan werkt, heeft al meerder succesverhalen en zijn erg gedreven om een therapie voor ADOA te creëren. Hun streven is om binnen 5-7 jaar iets op de markt te zetten!

PYC Therapeutics: Article for ADOA (Autosomal Dominant Optic Atrophy) European Association

ADOA remains an area of significant unmet need, and with the advent of precision medicine there is increasing optimism around RNA and DNA therapies for ADOA. PYC Therapeutics, an RNA drug development company, is hoping to apply its RNA technology, known as PPMO, to many inherited retinal diseases. The company recently announced the development of a potential drug for certain sub-types of ADOA.

“ADOA is a monogenic disease, which is a disease caused by a mutation in a select gene. The gene OPA1, has been identified as a common driver of ADOA in patients,” PYC’s Chief Scientific Officer Professor Sue Fletcher said.

“Usually, people have 2 copies of the OPA1 gene – one from each parent. Some people have mutations in one copy of the OPA1 gene, which means some cells do not produce enough OPA1 protein. The lack of protein is what is believed to drive ADOA in these patients and is known as a haploinsufficiency.

PYC’s team is now working to develop a potential PPMO that can increase the amount of OPA1 protein produced by the healthy copy of the OPA1 gene. The concept is that if we can restore the level of OPA1 protein above the disease threshold, we may slow or even stop vision loss,” Prof Fletcher said.

PYC’s PPMOs are a combination of two critical components: 1) the ‘PMO’ (which stands for phosphorodiamidate morpholino oligomer), is the drug cargo and when delivered to the cells, will help correct the disease process; and 2) the peptide ‘P’ delivers the PMO to the target cell and helps carry it into the cell – where the PMO is needed. Together they form a ‘P-PMO’.

“We have designed a number of PMO candidates that show promising early results in correcting the OPA1 protein haploinsufficiency in cells derived from ADOA patients. We have seen more than 100% protein upregulation in patient fibroblasts, and this is exciting,” Dr Grainok, the scientist leading PYC’s ADOA program, said.

Patient-derived fibroblasts are cells widely used in the early stages of drug development because they are easily accessible and typically allow screening of multiple PMO candidates in the context of a patient’s individual genetic background.

Dr Janya Grainok is leading a team of five scientists to evaluate PYC’s ADOA candidate in several pre-clinical models. Dr Grainok is the co-inventor of VP-001 – PYC’s other leading drug candidate to treat RP11 – and experienced as both a medicinal biochemist and molecular geneticist working across retinal disease. Dr Grainok’s expertise spans PMO design and drug validation strategies.

Dr Grainok and her team are supported by Professor Fletcher, co-inventor of three FDA approved drugs for the treatment of Duchenne muscular dystrophy (DMD). PYC’s Scientific leadership team includes Dr Kim Rice, a molecular geneticist who has deep knowledge and experience of oligonucleotide design and Dr Carla Jackson who has vast experience with stem cells and retinal organoids.

Dr Grainok said that once the PMOs are designed, the research to test for the safety and effectiveness of the PMO is performed using human stem cells. 

“Stem cells can be used to make almost any of the cell types found within the organs of the human body, including the light-sensitive cells in the retina. A unique type of stem cell, called induced pluripotent stem cells (iPSCs), can be made from an adult’s own skin cells,” Dr Jackson said.

“As iPSCs contain all of the genetic information of the donor individual, the tissues that these stem cells can create allow the study of development and disease processes in that particular individual,” Dr Jackson said.

Dr Jackson said that stem cells can be instructed to make three-dimensional miniature versions of the human retina, called retinal organoids. “Retinal organoids are comparable to the light-sensitive tissue that grows naturally during human eye development, but they can be grown and studied entirely in the laboratory.

“This means that if iPSCs are made from a patient with inherited retinal disease, then the retinal organoids made from these can be used to directly study the events leading to visual loss in that patient. This allows the reasons underlying visual loss to be untangled, as well as the testing of new treatments.”

iPSC retinal models are becoming the gold standard in pre-clinical drug development and provide an extremely useful insight into a drug’s effectiveness before entering clinical studies in people.

Alongside these efficacy models, PYC will also evaluate safety, distribution, and duration of effect in animal models before entering clinical trials. This work is expected to occur across 2021 and 2022.

“Our goal is to develop a therapy to treat ADOA that is very safe and highly effective, obtain market authorisation for the therapy and get this treatment into patients with ADOA, alter the course of their disease and change lives,” Prof Fletcher said. 

“We are a purpose-driven company with scientists who are passionate and working around the clock to achieve these goals.”

Professor Fletcher said that in the past, the development of a drugs of this nature could take 15 to 20 years. In recent times advances in technology, data generation and sharing, has seen that treatments can be developed, approved, and delivered to patients much more rapidly.

“We would hope that the process of developing a drug from concept to being available in the clinic for patients would take a third of that time. This may be ambitious on our part, however we urgently want to develop safe and effective treatments for people living with ADOA.”