Our Pipeline
Niemann Pick Disease
Unmet Need
Niemann-Pick disease (NPD) is a rare genetic disease belonging to the lysosomal storage disorder (LSD) group. It is an inherited metabolic disorder in which abnormal amounts of lipids (fatty materials such as waxes, oils, and cholesterol) build up in the brain, spleen, liver, lungs, and bone marrow. Symptoms may include:
- Brain degeneration
- Ataxia (lack of muscle control during voluntary movements such as walking)
- Loss of muscle tone
- Increased sensitivity to touch
- Spasticity (stiff muscles and awkward movement)
- Slurred speech
- Swallowing and feeding difficulties
Despite the significant medical need, there are no commercial options to deliver enzyme replacement therapy (ERT) across the blood brain barrier, including NPD. ERT using recombinant acid sphingomyelinase (ASM; Olipudase alfa; Xenpozyme®) was approved by the FDA for the non-neurologic symptoms of NPD in 2022. However, this ERT does not address the neurologic involvement in type A and A/B patients. Moreover, since only ~2% of the systemically infused enzyme reaches the lung, high doses of the recombinant ASM must be used to impact this organ, leading to potential toxicity and the need for a dose escalation protocol that can be difficult to implement.
Our Innovative Approach
Our approach is to target the CNS and peripheral delivery of the optimal enzyme through the ICAM-1 receptor. ICAM-1 is overexpressed in all tissues during pathological states, including NPD and other LSDs making ICAM-1 an ideal, self-regulated target. The ICAM pathway, in which the cellular receptor ICAM-1 delivers molecules to lysosomes via clathrin and caveolae-independent mechanisms, is an elegant means whereby therapeutic ASM can be delivered to the brain, thereby extending the ERT treatment to neurological NPD-A and A/B patients. In addition, since it is known that recombinant ASM reaches the lungs less efficiently than other systemic organs (e.g., liver and spleen), our ICAM-1-ASM fusion protein could also be more effective for the pulmonary complications of NPD and allow for lower dosing to avoid toxicities.
Preclinical Results in NP ASM Knock-out Model
We recently demonstrated significant improvement in the physiological and clinical outcomes using an ICAM-1-ASM fusion protein delivered in an ASM knock-out (ASMKO) model of NPD. Specifically, our ICAM-1 approach enhanced ASM tissue-over-blood localization ratio for all organs, including the brain and lungs in mice.
Brain levels for substrate & secondary storage
Six (6) I.V. injections, given every other day.
• 0.6 mg/kg
ICAM-1 targeting reduced brain storage of sphingomyelin substrate and secondary cholesterol in ASM knockout mice.
No apparent side effects were observed regarding hematology (B), liver/kidney markers (C), body weight (D), or behavioral (grooming, activity) patterns.
Preclinical trials with olipudase (Xenoozyme) in the same animal model showed no lung/brain activity with 3 mg/kg.
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