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Advanced Neurology Brain bioavailability of targeted protein degraders

or 5 mg/kg IV, penetrates the BBB through disruption- (iii) The passive diffusion potential of TPDs may also be
driven mechanisms, breaching the neurotoxicity threshold, assessed in vivo by comparing brain concentrations of
or enters the brain through permeability-driven pathways. TPDs in young (2 months) versus aged (16 months)
However, simply crossing the BBB is not sufficient for rats. In aged rats, the number of tight-junction
TPDs to disease conditions. Efficient penetration into brain proteins and the total length per capillary decrease.
cells, which are typically difficult to transfect, is necessary. Alternatively, 1 week old neonatal mice may be used
Furthermore, enhancing the selective accumulation of to determine the passive diffusion ability of TPDs.
TPD in the affected brain regions remains a challenge. We The route of administration however will be limited to
have yet to conclusively demonstrate that TPD activity is intraperitoneal or subcutaneous only, as it is relatively
region-specific, that is, concentrated in the affected areas of difficult to administer through oral or IV route in
the brain. Finally, a major obstacle in achieving the desired 1 week old mice.
therapeutic benefit is overcoming the downregulation of (iv) The novel mechanism(s) of BBB permeation by TPDs
proteasome machinery in various CNS diseases. Thus, could be investigated using a unilateral internal carotid
in vitro efficacy screening should encompass a cellular artery ligation rat model. Specific brain regions could
environment that mimics the senile state (e.g., neurons and be isolated, and free fractions of TPDs measured to
astrocyte primary cultures derived from 16-week-old rats assess region-specific distribution. In addition, the
or 24-week-old mice), and establish a PK-PD correlation BBB membrane may be subjected to next-generation
in experimental animals. sequencing for differential gene expression profiling,
with gene regulation confirmed through reverse
21. Discussion transcription polymerase chain reaction.
(v) The ability of OATP1A2, OATP2B1, and OATP1B1 to
The limitations posed by the BBB present an enduring transport TPDs across the plasma membrane could be
challenge in delivering macromolecular therapeutics evaluated using transporter-overexpressing cell lines.
to the CNS. TPDs are large molecules that belong to the (vi) To assess the brain-specific turnover of TPDs, the
“beyond rule of 5” chemical space. Due to their size and liability of CYP1B1 can also be evaluated. CYP1B1
composition, achieving reasonable BBB permeability is a metabolizes several endogenous substances, including
major roadblock. Nonetheless, TPDs are being considered as retinol, prostanoids, estradiol, and melatonin.
effective CNS therapeutics. In our preliminary experiments,
we found quantifiable concentrations (K ) of TPDs despite Assessing the CYP1B1 liability of investigational TPDs
p
demonstrating poor MDCK-MDR1 cell permeability, high will provide insights into their metabolic stability
efflux potential, and >98% plasma protein binding in in in the CNS and offer a comprehensive view of brain
vitro studies. Therefore, it would be valuable to investigate pharmacokinetics.
the mechanism(s) and route(s) by which TPDs cross the 22. Conclusion
BBB. Several approaches could be explored:
(i) Although the likelihood of passive diffusion of The clinical therapeutic efficacy of drug candidates relies
macromolecule TPDs is low, the parallel artificial in part on the earliest possible detection of neurological
membrane permeability assay can be employed as a diseases and the initiation of therapy. Most CNS diseases
Tier 1 assay to assess the passive diffusion potential have a poor prognosis once they reach advanced stages. Early
of TPDs. Molecules with an apparent permeability treatment of neuroinflammation or neurodegeneration
value of >4.0 × 10 cm/s can be considered to possess may help prevent or slow the progression of BBB
−6
passive diffusion potential. deterioration to an irreversible stage. In addition, early
(ii) The possibility of passive diffusion of TPDs through intervention could restore the BBB’s protective function,
PCVs should be evaluated, as PCVs offer less shielding the brain from inflammatory cytokines, toxins,
resistance at the BBB. Compared to capillaries, they metastatic cancer cells, and xenobiotics. With the advent
are the primary site for transcytosis-mediated brain of advanced imaging techniques, artificial intelligence-
delivery of therapeutic nanoparticles. Moreover, powered technologies for detecting pathological changes
there is substantial evidence supporting the notion in the CNS, improved diagnostic tools, and an expanded
that PCVs are the preferred site of extravasation for battery of biomarkers, it has become relatively easier to
leukocytes, tumor cells, and parasites. Capillaries’ identify CNS diseases at early stages. TPDs are making
slower blood velocity may increase the time that TPDs significant inroads into the CNS disease space, with high
interacting with venular endothelial cells, which hopes pinned on advanced pre-clinical leads. Compared to
contain intracellular machinery that could aid in TPD late-stage diseases, TPD delivery across the BBB in younger
internalization. subjects exhibiting early-stage disease manifestations

Volume 4 Issue 2 (2025) 70 doi: 10.36922/an.5140