Phenylketonuria (PKU)

Our lead integrative gene therapy indication is PKU. This rare, monogenic, liver disease is caused by the lack of the enzyme PAH, which results in high levels of serum phenylalanine. If untreated, elevated phenylalanine in infancy and childhood leads to neurotoxicity and developmental delays. Adults with PKU may experience neurocognitive dysfunction, psychiatric disorders, and behavioral disturbances. Given the growing evidence of the detrimental effects of elevated phenylalanine in later life, US guidelines recommend patients achieve target levels of low phenylalanine for life. There are approximately 14,000 patients with PKU in the US.

PKU is currently treated with a low phenylalanine diet and medical foods with or without medical therapy. Despite these treatments, there remains a strong need for a treatment that both normalizes phenylalanine levels and allows patients to liberalize their diet. Our approach to PKU is to insert a healthy copy of the PAH gene in its natural genomic location using our I-PGI technology. This approach has the potential to normalize phenylalanine levels for the vast majority of the patient population, including pediatric patients, which could allow patients to liberalize their diets.

ApoA-1 for atherosclerotic cardiovascular disease (ASCVD)

ASCVD is the leading cause of death globally. It is caused by plaque build-up in arterial walls which if not adequately treated can lead to heart attacks and strokes. There are approximately 24 million patients in the US with ASCVD.

Most treatments for ASCVD are focused on lowering LDL cholesterol. However, even when patients achieve target LDL levels, a 60-80% risk of ASCVD still remains. Cholesterol efflux represents a distinct, and potentially complementary, pathway from LDL-lowering therapies, which has the potential to further reduce the risk of ASCVD.

Based on human genetics and clinical trials, we have chosen ApoA-1 as our target to increase the cholesterol efflux pathway. In 1980, the ApoA-1 Milano mutation was discovered in a family who had no clinical evidence of ASCVD despite high triglycerides and low HDL levels. Since then, recombinant ApoA-1 wild-type or Milano has been tested in clinical trials with evidence suggesting that ApoA-1 can reduce atherosclerosis, though significant challenges with limited pharmacokinetics of recombinant ApoA-1 and challenges with manufacturing have hindered fulsome development. We believe PGI is uniquely suited to provide patients with continuous overexpression of ApoA-1 that could protect patients from ASCVD. We are currently evaluating which PGI technology is best suited to result in an overexpression of this cardioprotective protein.

Homocystinuria (HCU)

HCU is a rare, monogenic liver disorder caused by mutations in the CBS gene that result in high levels of homocysteine in urine and blood. High homocysteine levels affect the eye, brain, skeleton and circulatory systems. If untreated, HCU can lead to many serious diseases including optic lens dislocation, developmental delay, intellectual disability, osteoporosis, skeletal deformations, cardiovascular disease, and a high risk of developing blood clots leading to strokes. There are more than 3,500 patients in the US.

HCU is currently treated with diet, medical foods and supplements. The diet is challenging to follow, leaving patients at risk of a thrombotic event and other medical problems throughout their life. Therefore, there is a need for a treatment which normalizes homocysteine levels and allows patients to liberalize their diets. Our approach to HCU is to insert a healthy copy of the CBS gene in its natural or a defined genomic location using our I-PGI technology. This approach has the potential to normalize homocysteine levels for the vast majority of the patient population, including pediatric patients, which could allow patients to liberalize their diets.

Hereditary Hemochromatosis

Hereditary hemochromatosis is a condition of iron overload that can lead to multi-organ damage. If untreated, patients experience serious clinical consequences, such as liver cirrhosis, cardiac dysfunction, diabetes and growth retardation. The most common cause of hereditary hemochromatosis is due to mutations in the HFE gene. There are approximately 600,000 patients in the US.

Hemochromatosis is currently treated by therapeutic phlebotomy or iron chelation. However, there remains a need for a safe and long-lasting therapy for these patients. We believe a gene editing approach has the potential to provide patients with a one-and-done treatment for hemochromatosis and are currently evaluating which PGI technology is best suited for this indication.

B cell-driven autoimmune diseases

There are more than 80 identified autoimmune disorders, affecting as many as 50 million people in the US alone. Autoimmune diseases occur when the immune system fails to recognize the body’s own cells and begins attacking itself. These diseases can affect multiple different organs, tissues and cells and can become life-threatening.

B cells and plasma cells both contribute to the pathogenesis and persistence of autoimmune diseases and have been a therapeutic target for quite some time. However, it’s proven challenging to adequately target these cells with traditional biologic or small molecule methods. Cell therapy has recently emerged as a method to target and remove the self-reacting B and plasma cells, thereby resetting a part of the patient’s immune system.

We are developing two different best-in-class allogeneic iNK cells for the treatment of patients with humoral autoimmune diseases. We’ve designed our cells as bespoke cell therapies with the autoimmune patient population in mind, focusing on efficacy, reversibility, convenience and redosability. We plan to initially develop our iNK cells for autoimmune diseases of the kidney: lupus nephritis, IgA nephropathy, membranous nephropathy and minimal change disease. However, we believe these cell therapies could be applied to more than 15 additional autoimmune indications.

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