As one of the major intrinsic impediments to axonal growth, PTEN is expressed in neurons and regenerating axons and plays a vital role in controlling the regeneration of corticospinal neurons via downregulating cytoplasmic mammalian target of rapamycin (mTOR) activity.

This mTOR pathway is intensely inhibited in axotomized adult neurons, restricting protein synthesis to sustain axonal growth. This unique activity makes PTEN a major homeostatic regulator and tumor suppressor protein, which function is absent or defective in a wide variety of tumors as a result of somatic alterations. The important role of the PI3K/AKT/mTOR signaling pathway in cell growth, regeneration and survival supports the rationale for the therapeutic targeting of PTEN.

Among the suggested PTEN inhibition-based therapeutic targets are nerve growth and regeneration after injury or damage, treatment of cardiac ischemia/reperfusion and associated disease, wound repair, and infertility.

Interestingly, the main paradigm of PTEN involvement in cancer is as a cancer suppressor, and it has been shown that PTEN inhibition may occur in brain metastases. PTEN is expressed preferentially in the neurons in adult brains, plays a critical role in controlling the regeneration of corticospinal neurons via downregulation of mammalian target of rapamycin (mTOR) activity. The mTOR activity is profoundly suppressed in axotomized adult neurons, limiting new protein synthesis required for sustained axon regeneration.

Several publications mention involvement of PTEN in suppression of nerve regeneration and others showed the positive effect of PTEN depletion on conditions related to axon damage or impairment. Effective inhibition of PTEN would be a candidate for increasing mTOR thereby promoting nerve regeneration.

The intranasal administration of ExoPTEN led to significant motor improvement, sensory recovery, and faster urinary reflex restoration. Functional recovery was accompanied by biological changes of reduced neuroinflammation and gliosis, increased axonal regeneration and angiogenesis, and structural and electrophysiological improvements.