Patent Publication Number: US-2021187194-A1

Title: Use of Ultrasound to Guide Injection of Non-cytotoxic Protease

Description:
FIELD OF THE INVENTION 
     The present disclosure relates to a method and apparatus for guiding the treatment of non-cytotoxic proteases, and in particular to a medical or surgical apparatus, computer program and method for guiding the injection of at least one non-cytotoxic protease. 
     BACKGROUND 
     Cytotoxic proteins act by killing their natural target cells. This group of toxins is exemplified inter alia by plant toxins such as ricin, and abrin, and by bacterial toxins such as diphtheria toxin, and Pseudomonas exotoxin A. Cytotoxic toxins typically kill their target cells by inhibiting the cellular process of protein synthesis. This class of protein includes re-targeted cytotoxic proteins in which the natural binding ability of the protein has been modified by the introduction of a binding ligand (also known as a Targeting Moiety), thereby conferring new target cell binding properties on the modified protein. 
     In contrast, non-cytotoxic proteins act on target cells by incapacitating cellular function. Importantly, non-cytotoxic toxins do not kill the target cells upon which they act. Some of the best known examples of non-cytotoxic proteases include clostridial neurotoxins (e.g. botulinum neurotoxin, which is marketed under names such as Dysport™, Neurobloc™, and Botox™), IgA proteases (see, for example, WO99/032272), and antarease proteases (see, for example, WO2011/022357). Non-cytotoxic proteases act by proteolytically-cleaving and thus inactivating intracellular transport proteins known as SNARE proteins (e.g. SNAP-25, VAMP, or Syntaxin)—see Gerald K (2002) “Cell and Molecular Biology” (4th edition) John Wiley &amp; Sons, Inc. The acronym SNARE derives from the term Soluble NSF Attachment REceptor, where NSF means N-ethylmaleimide-Sensitive Factor. SNARE proteins are essential components of the vesicular secretion process in eukaryotic cells. Thus, non-cytotoxic proteases act by suppressing cellular secretion. This class of protein includes re-targeted non-cytotoxic proteins in which the natural binding ability of the protein has been modified by the introduction of a binding ligand (also known as a Targeting Moiety), thereby conferring new target cell binding properties on the modified protein. Applicant has pioneered the technology relating to the re-targeting of non-cytotoxic proteases, which dates back to the 1990s (see, for example, WO 94/21300, WO 96/33273 and WO 98/07864). Said re-targeted proteins are referred to (throughout the literature and scientific community) as Targeted Secretion Inhibitors (TSIs)—reference to TSIs includes structural equivalents such as those described in WO 2011/018665. 
     Non-cytotoxic proteases may be employed in their native or substantially native forms (i.e. as holotoxins, such as BOTOX™), in which case targeting of the proteases to specific cell-types is reliant on (i) localised administration of the protease and/or (ii) the inherent binding ability of the native protease. Alternatively, non-cytotoxic proteases may be employed in a re-targeted form in which the native protease is modified to include an exogenous ligand known as a Targeting Moiety (TM). The TM is selected to provide binding specificity for a desired target cell, and, as part of the re-targeting process, the native binding portion of the non-cytotoxic protease may be removed. Re-targeting technology has patent filings dating back to the early 1990s and include: EP-B-0689459; EP-B-0939818; U.S. Pat. Nos. 6,461,617; 7,192,596; EP-B-0826051; U.S. Pat. Nos. 5,989,545; 6,395,513; 6,962,703; EP-B-0996468; U.S. Pat. No. 7,052,702; EP-B-1107794; and U.S. Pat. No. 6,632,440; all of which are herein incorporated by reference thereto. 
     In view of the ubiquitous nature of SNARE proteins, non-cytotoxic proteases have been successfully employed in a plethora of therapies. 
     By way of example, we refer to William J. Lipham, Cosmetic and Clinical Applications of Botulinum Toxin (Slack, Inc., 2004), which describes the use of Clostridial toxins, such as botulinum neurotoxins (BoNTs), BoNT/A, BoNT/B, BoNT/C1, BoNT/D, BoNT/E, BoNT/F and BoNT/G, and tetanus neurotoxin (TeNT), to inhibit neuronal transmission in a wide variety of therapeutic and cosmetic applications—as an example, BOTOX™ is currently approved as a therapeutic for the following indications: achalasia, adult spasticity, anal fissure, back pain, blepharospasm, bruxism, cervical dystonia, essential tremor, glabellar lines or hyperkinetic facial lines, headache, hemifacial spasm, hyperactivity of bladder, hyperhidrosis, juvenile cerebral palsy, multiple sclerosis, myoclonic disorders, nasal labial lines, spasmodic dysphonia, strabismus and VII nerve disorder. In addition, Clostridial toxin therapies are described for treating neuromuscular disorders (see U.S. Pat. No. 6,872,397; for treating uterine disorders (see US2004/0175399); for treating ulcers and gastroesophageal reflux disease (see US2004/0086531); for treating dystonia (see U.S. Pat. No. 6,319,505); for treating eye disorders (see US2004/0234532); for treating blepharospasm (see US2004/0151740); for treating strabismus (see US2004/0126396); for treating pain (see U.S. Pat. Nos. 6,869,610, 6,641,820, 6,464,986, 6,113,915); for treating fibromyalgia (see U.S. Pat. No. 6,623,742, US2004/0062776); for treating lower back pain (see US2004/0037852); for treating muscle injuries (see U.S. Pat. No. 6,423,319); for treating sinus headache (see U.S. Pat. No. 6,838,434); for treating tension headache (see U.S. Pat. No. 6,776,992); for treating headache (see U.S. Pat. No. 6,458,365); for reduction of migraine headache pain (see U.S. Pat. No. 5,714,469); for treating cardiovascular diseases (see U.S. Pat. No. 6,767,544); for treating neurological disorders such as Parkinson&#39;s disease (see U.S. Pat. Nos. 6,620,415, 6,306,403); for treating neuropsychiatric disorders (see US2004/0180061, US2003/0211121); for treating endocrine disorders (see U.S. Pat. No. 6,827,931); for treating thyroid disorders (see U.S. Pat. No. 6,740,321); for treating a cholinergic influenced sweat Gland (see U.S. Pat. No. 6,683,049); for treating diabetes (see U.S. Pat. Nos. 6,337,075, 6,416,765); for treating a pancreatic disorder (see U.S. Pat. Nos. 6,261,572, 6,143,306); for treating cancers such as bone tumors (see U.S. Pat. Nos. 6,565,870, 6,368,605, 6,139,845, US2005/0031648); for treating otic disorders (see U.S. Pat. Nos. 6,358,926, 6,265,379); for treating autonomic disorders such as gastrointestinal muscle disorders and other smooth muscle dysfunction (see U.S. Pat. No. 5,437,291); for treatment of skin lesions associated with cutaneous cell-proliferative disorders (see U.S. Pat. No. 5,670,484); for management of neurogenic inflammatory disorders (see U.S. Pat. No. 6,063,768); for reducing hair loss and stimulating hair growth (see U.S. Pat. No. 6,299,893); for treating downturned mouth (see U.S. Pat. No. 6,358,917); for reducing appetite (see US2004/40253274); for dental therapies and procedures (see US2004/0115139; for treating neuromuscular disorders and c (see US2002/0010138); for treating various disorders and conditions and associated pain (see US2004/0013692) for treating pain (see WO96/33274); for treating conditions resulting from mucus hypersecretion such as asthma and COPD (see WO00/10598); for treating non-neuronal conditions such as inflammation, endocrine conditions, exocrine conditions, immunological conditions, cardiovascular conditions, bone conditions (see WO01/21213). All of the above publications are herein incorporated by reference thereto. 
     The use of non-cytotoxic proteases such as clostridial neurotoxins (e.g. BoNTs and TeNT) in therapeutic and cosmetic treatments of humans and other mammals is anticipated to expand to an ever-widening range of diseases and ailments that can benefit from the properties of these toxins. 
     Generally, therapeutic administration of a non-cytotoxic protease, including native botulinum neurotoxin clinical products, is well tolerated. However, administration in some applications can be challenging because of the larger doses required to achieve a beneficial effect. Larger doses can increase the likelihood that the protease may move, for example, through the interstitial fluids and the circulatory systems (such as the cardiovascular system and the lymphatic system) of the body, resulting in undesirable dispersal of the protease to areas not targeted for treatment. Said dispersal can lead to undesirable side effects, such as inhibition of cellular secretion in cells not targeted for treatment (e.g. inhibition of neurotransmitter release in neurons not targeted for treatment, or paralysis of a muscle not targeted for treatment). By way of specific example, a patient administered a therapeutically effective amount of a BoNT into the neck muscles for torticollis may develop dysphagia because of dispersal of the protease into the oropharynx. Similarly, a patient administered a non-cytotoxic protease to treat a neuromuscular disorder may suffer from undesirable muscle tissue inactivation due to dispersal of the protease into the muscle. 
     In common with any other drug substances, a therapeutic dosing range exists which identifies the lower and upper limits of safe, effective therapy. Often, the upper limit is determined by the increasing significance of off-target effects that lead to undesirable (e.g. potentially harmful) side-effects of drug treatment. In the case of non-cytotoxic proteases (notably BoNT), this could lead to the paralysis of cellular secretion in off-target cells, which, in turn, could be fatal. 
     The growing clinical, therapeutic and cosmetic use of non-cytotoxic proteases in therapies requiring larger doses places an ever-increasing requirement on the part of the pharmaceutical industry to develop means for minimising off-target effects, such that the therapeutic dose range can be increased and the patients thus provided with increased doses which will, in turn, lead to increased efficacy of treatment. 
     There is therefore a need in the art for addressing undesirable, off-site targeting effects. Embodiments of the disclosure may address the above-mentioned problems. 
     SUMMARY OF THE INVENTION 
     Aspects of the invention are as set out in the independent claims and optional features are set out in the dependent claims. Aspects of the invention may be provided in conjunction with each other and features of one aspect may be applied to other aspects. 
     In a first aspect there is provided a medical or surgical apparatus for guiding the injection of at least one non-cytotoxic protease, the apparatus comprising:
         an ultrasound imaging handheld scanner; and   a computer program comprising instructions which, when the program is executed by a computer, cause the computer to run an ultrasound imaging processing application;   wherein the ultrasound imaging handheld scanner comprises:
           at least one ultrasound transducer for transmitting and receiving ultrasound energy;   a processor coupled to the at least one ultrasound transducer and configured to receive ultrasound energy signals from the at least one ultrasound transducer; and   an interface coupled to the processer and configured to send data to the computer running the ultrasound imaging processing application, wherein the data is based on the received ultrasound energy signal from the at least one ultrasound transducer; and   
           wherein the ultrasound imaging processing application is configured to reference a database of treatment sites and dosage regimes for at least one non-cytotoxic protease, and is configured to provide treatment guidance to a user of the medical or surgical apparatus for guiding treatment based on the received data from the ultrasound imaging handheld scanner and the database of treatment sites and dosage regimes for the at least one non-cytotoxic protease.       

     The treatment site may correspond to any anatomical site and/or in any tissue type. For example the treatment site may be a treatment site in at least one of: muscle, organs (such as bladder), nerves (for the purpose of a nerve block) or may be percutaneous (for example for cosmetic applications). 
     The medical or surgical apparatus may comprise a controlled delivery device coupled to the ultrasound imaging handheld scanner, wherein the controlled delivery device is configured to deliver at least one controlled dose of at least one non-cytotoxic protease to a patient being imaged by the ultrasound imaging handheld scanner based on a location relative to the patient determined based on the received ultrasound energy signals. 
     Additionally or alternatively, the medical or surgical apparatus may comprise a guide for receiving at least a portion of an injection device, such as a needle, wherein the guide is coupled to the ultrasound imaging handheld scanner, and wherein the computer running the ultrasound imaging processing application is configured to display information to the user for enabling the user to position the guide at a determined position relative to the patient based on the database of treatment sites and dosage regimes for the at least one non-cytotoxic protease, so that the user can inject the non-cytotoxic protease into the patient at the correct treatment site for the selected non-cytotoxic protease being injected. 
     In some examples, a computer such as the computer running the ultrasound imaging processing application, or a separate computer (for example a handheld device such as a smartphone) that may or may not be in communication with the ultrasound imaging processing application running on another computer, may be configured to calculate and determine a dosage regime for a patient. For example, the computer may comprise a dosage application that is configured to receive a series of inputs from a user and in response display information to the user regarding the treatment sites and dosage regimes for the patient to assist in the delivery of treatment to a patient. 
     For example, the dosage application may be configured to receive information regarding the patient (such as age, weight, region and/or part of the anatomy (for example muscle type)) and determine a recommended treatment regime and/or dosage range for the patient. The recommended dosage range may be determined, for example, on the basis of the information regarding the patient. The recommended dosage range may be calculated per region and/or part of the anatomy (for example, muscle type) based on a determined total dose for the patient. The dosage application may provide a warning indication to the user if a dose outside of the recommended dosage range is selected. 
     The dosage application may also be configured to assist in preparing samples for injection. For example, the dosage application may be configured to receive inputs regarding the type and concentration of treatment, and calculate the necessary volume of treatment to be injected based on a determined or selected dose for a particular treatment site, which is then displayed to the user. Calculating the necessary volume of treatment to be injected may comprise calculating the number of vials of a particular treatment that are necessary to deliver the desired treatment at a treatment site. 
     In another aspect there is provided a medical or surgical apparatus for guiding the injection of at least on non-cytotoxic protease, the apparatus comprising:
         an ultrasound imaging handheld scanner; and   a controlled delivery device coupled to the ultrasound imaging handheld scanner;   wherein the ultrasound imaging handheld scanner comprises:
           at least one ultrasound transducer for transmitting and receiving ultrasound energy;   a processor coupled to the at least one ultrasound transducer and configured to receive ultrasound energy signals from the at least one ultrasound transducer; and   
           wherein the controlled delivery device is configured to deliver a controlled dose of at least one non-cytotoxic protease to a patient being imaged by the ultrasound imaging handheld scanner based on a location relative to the patient determined based on the received ultrasound energy signal.       

     The medical or surgical apparatus may comprise an interface coupled to the processer and configured to send data to a computer running an ultrasound imaging processing application, wherein the data is based on the received ultrasound energy signals from the at least one ultrasound transducer. The ultrasound imaging processing application may comprise a database of treatment sites and dosage regimes for at least one non-cytotoxic protease, and may be configured to provide treatment guidance to a user of the medical or surgical apparatus for guiding treatment based on the received data from the ultrasound imaging handheld scanner and the database of treatment sites and dosage regimes for the at least one non-cytotoxic protease. 
     The treatment guidance may comprise an indication of at least one of:
         (i) where to inject the non-cytotoxic protease relative to the patient being scanned; and   (ii) a quantity of non-cytotoxic protease to inject.       

     The treatment guidance may additionally or alternatively comprise at least one of: a recommended dose range for a selected region of the anatomy (such as a tissue type, for example a muscle type), a recommended total patient dose, guidance as to how to prepare the treatment for injection such as the concentration and volume of treatment needed, and the number of vials or syringes needed to deliver the treatment. 
     The treatment guidance may comprise an indication of where to inject the non-cytotoxic protease relative to the patient being scanned, and the indication may be overlaid on a graphical representation of the patient being scanned based on the data received from the ultrasound imaging handheld scanner. 
     The ultrasound imaging processing application may be configured to determine the position of a controlled delivery device coupled to the ultrasound imaging handheld device, or an injection device positioned in a guide coupled to the ultrasound imaging handheld device, relative to the patient based on the received data from the ultrasound imaging handheld device. The treatment guidance may comprise an indication to the user of how to position the ultrasound imaging handheld scanner with respect to the patient so that the non-cytotoxic protease can be injected from the controlled delivery device or injection device positioned in the guide at the correct treatment site. 
     The ultrasound imaging processing application may be configured to process the data received from the ultrasound imaging handheld device to provide a graphical representation of the patient being scanned to the user. 
     The processor of the ultrasound imaging handheld scanner may be configured to process the received ultrasound energy signals from the at least one ultrasound transducer to provide data signals comprising information indicative of a graphical representation of the patient being scanned. 
     In another aspect there is provided a medical or surgical kit comprising:
         an ultrasound imaging handheld scanner;   an injectable device comprising a selected quantity of at least one non-cytotoxic protease; and   a computer program comprising instructions which, when the program is executed by a computer, cause the computer to run an ultrasound imaging processing application;
 
wherein the ultrasound imaging processing application is configured to reference a database of treatment sites and dosage regimes for at least one non-cytotoxic protease, and is configured to provide treatment guidance to a user of the medical or surgical apparatus for guiding treatment based on the received data from the ultrasound imaging handheld scanner and the database of treatment sites and dosage regimes for the at least one non-cytotoxic protease, for enabling the user to inject the correct quantity of non-cytotoxic protease at the correct treatment site.
       

     The kit may further comprise a controlled delivery device coupled to the ultrasound imaging handheld scanner, wherein the controlled delivery device is configured to deliver a controlled dose of at least one non-cytotoxic protease to a patient being imaged by the ultrasound imaging handheld scanner based on a location relative to the patient determined based on the received ultrasound energy signal. 
     Additionally or alternatively, the kit may further comprise a guide for receiving at least a portion of an injection device, such as a needle, wherein the guide is coupled to the ultrasound imaging handheld scanner. The computer running the ultrasound imaging processing application may be configured to display information to the user for enabling the user to position the guide at a determined position relative to the patient based on the database of treatment sites and dosage regimes for the at least one non-cytotoxic protease, so that the user can inject the non-cytotoxic protease into the patient at the correct treatment site for the selected non-cytotoxic protease being injected. 
     In another aspect there is provided a computer program comprising instructions which, when the program is executed by a computer, cause the computer to run an ultrasound imaging processing application, wherein the ultrasound imaging processing application is configured to:
         receive and process data obtained from an ultrasound imaging handheld scanner; reference a database of treatment sites and dosage regimes for at least one non-cytotoxic protease; and   provide treatment guidance to a user of the medical or surgical apparatus for guiding treatment based on the received data from the ultrasound transducer and the database of treatment sites and dosage regimes for the at least one non-cytotoxic protease, for enabling the user to inject the correct quantity of non-cytotoxic protease at the correct treatment site.       

     The ultrasound imaging processing application may be configured to process the data received from the ultrasound imaging handheld device to provide a graphical representation of the patient being scanned to the user. 
     The treatment guidance may comprise an indication of where to inject the non-cytotoxic protease relative to the patient being scanned. The indication may be overlaid on a graphical representation of the patient being scanned based on the data received from the ultrasound imaging handheld scanner. 
     The ultrasound imaging processing application may be configured to determine the position of at least one of: (i) a controlled delivery device coupled to the handheld ultrasound imaging scanner, and (ii) an injection device positioned in a guide and coupled to the handheld ultrasound imaging scanner, relative to the patient based on the received data from the ultrasound imaging handheld device. The treatment guidance may comprise an indication to the user of how to position the ultrasound imaging handheld scanner with respect to the patient so that the non-cytotoxic protease can be injected from the controlled delivery device or injection device positioned in the guide at the correct treatment site. 
     In another aspect there is provided a method of administering a controlled dose of non-cytotoxic protease to a patient, the method comprising:
         scanning a region of a patient&#39;s anatomy with an ultrasound imaging handheld scanner to obtain a graphical representation of the region of the patient&#39;s anatomy being scanned;   referencing a database of treatment sites and dosage regimes for the non-cytotoxic protease being administered;   determining at least one of:
 
(i) the correct location to inject the non-cytotoxic protease being administered based on the graphical representation of the region of the patient&#39;s anatomy and the reference with the database of treatment sites and dosage regimes; and
 
(ii) the correct dose of the non-cytotoxic protease to administer based on the graphical representation of the region of the patient&#39;s anatomy and the reference with the database of treatment sites and dosage regimes;
   administering a controlled dose of the non-cytotoxic protease at the correct location based on the determination.       

     Determining the correct dose of the non-cytotoxic protease to administer based on the graphical representation of the region of the patient&#39;s anatomy and the reference with the database of treatment sites and dosage regimes may comprise determining the position of at least one of (i) a controlled delivery device coupled to the handheld ultrasound imaging scanner relative to the patient, and (ii) an injection device positioned in a guide and coupled to the handheld ultrasound imaging scanner relative to the patient. 
    
    
     
       DRAWINGS 
       Embodiments of the disclosure will now be described, by way of example only, with reference to the accompanying drawings, in which: 
         FIG. 1  shows an example medical or surgical apparatus for guiding the injection of non-cytotoxic proteases; 
         FIG. 2  shows another example medical or surgical apparatus for guiding the injection of non-cytotoxic proteases; 
         FIG. 3  shows another example medical or surgical apparatus for guiding the injection of non-cytotoxic proteases; 
         FIG. 4  shows an example flow-chart for use in administering a dose of non-cytotoxic protease to a patient; 
         FIG. 5  shows another example medical or surgical apparatus for guiding the injection of non-cytotoxic proteases; 
         FIG. 6  shows two screenshots of an example computer program for use with the medical or surgical apparatus of any of  FIGS. 1 to 3 and 5 ; 
         FIG. 7  shows two further screenshots of the example computer program of  FIG. 6  for use with the medical or surgical apparatus of any of  FIGS. 1 to 3 and 5 ; and 
         FIG. 8  shows another screenshot of the example computer program of  FIGS. 6 and 7  for use with the medical or surgical apparatus of any of  FIGS. 1 to 3 and 5 . 
     
    
    
     SPECIFIC DESCRIPTION 
       FIG. 1  shows an example medical or surgical apparatus for guiding the treatment, for example the injection, of at least one non-cytotoxic protease. The at least one non-cytotoxic protease may be supplied as part of a medical composition, for example at least one polypeptide. In some examples, the medical composition (such as a polypeptide) comprises:
         (i) at least one non-cytotoxic protease, which protease is capable of cleaving a SNARE protein in a cell—for example, the non-cytotoxic protease may be a clostridial neurotoxin such as BoNT and/or TeNT;   (ii) at least one Targeting Moiety (TM) that is capable of binding to a Binding Site on a cell, which Binding Site is capable of undergoing endocytosis to be incorporated into an endosome within the cell, and wherein said cell expresses said SNARE protein; and   (iii) at least one translocation domain that is capable of translocating the protease from within an endosome, across the endosomal membrane and into the cytosol of the cell.       

       FIG. 1  shows an ultrasound imaging handheld scanner  100  comprising an ultrasound transducer  106 , a processor  108  and an interface  110 , such as a wired or wireless interface, for example a Bluetooth® interface. The ultrasound imaging handheld scanner  100  may also be known as an ultrasound wand. The processor  108  is coupled to the ultrasound transducer  106  and the interface  106 . Although only one ultrasound transducer  106  is shown in  FIG. 1 , it will be understood that in other examples there may be a plurality of ultrasound transducers  106 , for example an array of ultrasound transducers  106 . 
     Also shown in  FIG. 1  is a computer  200  operating an ultrasound imaging processing application. It will be understood that the medical or surgical apparatus may comprise a computer program comprising instructions which, when run on the computer, cause the computer to run the ultrasound imaging processing application. The computer  200  comprises an interface  210 , such as a wired or wireless interface, for example a Bluetooth® interface. It will be understood that in some examples the computer  200  may be a desktop or laptop computer, or in other examples may be a portable electronic device, for example a handheld device such as a tablet or mobile/cell phone. 
     In use, the ultrasound transducer  106  is operable to transmit and receive ultrasound energy for the purpose of ultrasound scanning, for example to create a graphical representation of a region of a patient, such as a sonogram. The processor  108  is configured to receive the signals from the ultrasound transducer  106 . 
     In some examples, the processor  108  is configured to process the received ultrasound energy signals from the at least one ultrasound transducer to provide data signals comprising information indicative of a graphical representation of the patient being scanned. However, in other examples, minimal (if any) processing is performed by the processor  108 . The interface  110  is configured to receive data from the processor  108  and send data based on the received ultrasound energy signal from the at least one ultrasound transducer  106  to the computer. 
     The interface  210  of the computer  200  is configured to receive signals comprising the data from the ultrasound imaging handheld scanner  100 . The ultrasound imaging processing application running on the computer  200  is configured to reference a database of treatment sites and dosage regimes for at least one non-cytotoxic protease, and is configured to provide treatment guidance to a user of the medical or surgical apparatus for guiding treatment based on the received data from the ultrasound imaging handheld scanner and the database of treatment sites and dosage regimes for the at least one non-cytotoxic protease. The database could be a local database (for example, stored on the computer  200 ) or could be a remote database (for example, the database could be a cloud-based database, for example accessed via the Internet). 
     The treatment guidance may comprise an indication of at least one of:
         (i) where to inject the, or a plurality of, non-cytotoxic protease(s) relative to the patient being scanned; and   (ii) a quantity of each of the non-cytotoxic protease(s) to inject.       

     In some examples, the ultrasound imaging processing application is configured to process the data received from the ultrasound imaging handheld device  100  to provide a graphical representation of the patient being scanned to the user, for example in the form of a sonogram. In such examples, the treatment guidance may comprise an indication of where to inject the non-cytotoxic protease relative to the patient being scanned, and the indication may be overlaid on a graphical representation of the patient being scanned based on the data received from the ultrasound imaging handheld scanner. For example, the treatment guidance may indicate on a sonogram where the non-cytotoxic protease should be injected to have increased efficacy and minimise off-target effects. 
     In some examples, processing the data received from the ultrasound imaging handheld device  100  to provide a graphical representation of the patient being scanned to the user may comprise performing image recognition on a graphical representation of the patient being scanned. For example, the ultrasound imaging processing application may comprise algorithms for performing image recognition. For example, the ultrasound imaging processing application may be configured to detect which region and/or part of the anatomy is being scanned and to use this information when referencing the database for determining treatment guidance. 
     In some examples, the image processing application may additionally or alternatively comprise an interface for enabling a user to enter patient-specific details, for example regarding the patient&#39;s weight, age, symptoms, region and/or part of the anatomy being imaged, for example to aid in the image recognition process and/or for use in performing the reference with the database for determining treatment guidance, for example as described below with reference to  FIGS. 6 to 8 . 
     In some examples, the image processing application may be configured to receive patient-specific data from the patient, and make a determination of the treatment site and/or treatment dose based on the received patient-specific data (as well as, for example, the database of treatment sites and dosage regimes). The treatment dose may be a dose for a particular treatment site, and/or a total dose for a patient. The treatment dose may also comprise a preferred or recommended dose range. The treatment dose may be specific to a particular non-cytotoxic protease, or may be a dose determined irrespective of non-cytotoxic protease type (i.e. a dose for all non-cytotoxic proteases). Such examples may provide for “personalised medicine” where the treatment can be tailored for each specific patient. The patient-specific data may comprise at least one of: patient&#39;s age, patient&#39;s weight, patient&#39;s symptoms, tissue type to be treated, non-cytotoxic protease being used, degree of disability, and time since injury/disabilitating event. For example, the patient&#39;s degree of disability, for example degree of spasticity, may be used in determining the treatment dose and/or treatment site. For example, the patient may be given a score based on the severity of their symptoms to determine their degree of disability, and may be used in determining the treatment dose and/or treatment site. Additionally or alternatively, the time since a disabilitating event, such as a stroke, may be used in determining the treatment dose and/or treatment site. For example, it may be envisaged that the treatment dose may decrease as a function of increasing time since the disabilitating event. 
     In some examples, the medical or surgical apparatus may comprise an injectable device comprising a selected quantity of at least one non-cytotoxic protease. For example, the medical or surgical apparatus may be provided as part of a kit, comprising the ultrasound imaging handheld scanner, a computer program comprising instructions which, when the program is executed by a computer, cause the computer to run the ultrasound imaging processing application, and the injectable device comprising a selected quantity of at least one non-cytotoxic protease. The injectable device may be a syringe, or may be a vial or other storage medium for holding a selected quantity of the non-cytotoxic protease. A selected quantity may comprise at least one of a selected volume and a selected concentration. 
     In some examples, such as the example shown in  FIG. 2 , the ultrasound imaging handheld scanner  100  may comprise a controlled delivery device  150  coupled to the ultrasound imaging handheld scanner  100 . The controlled delivery device  150  may be configured to deliver a controlled dose of at least one non-cytotoxic protease to a patient being imaged by the ultrasound imaging handheld scanner  100 , for example based on a location relative to the patient. The location relative to the patient may be determined based on ultrasound energy signals received from the ultrasound imaging handheld scanner  100 . The ultrasound imaging processing application may be configured to operate the controlled delivery device  150  to administer (for example, inject) a selected quantity of non-cytotoxic protease to the patient. The ultrasound imaging processing application may be configured to operate the controlled delivery device  150  based on a determination of the correct treatment dose and treatment site made based on a reference with the database of treatment sites and dosage regimes for the selected non-cytotoxic protease in the controlled delivery device  150 . 
     In some examples, the ultrasound imaging processing application is configured to determine the position of the controlled delivery device  150  relative to the patient based on the received data from the ultrasound imaging handheld device  100 . The treatment guidance may comprise an indication to the user of how to position the ultrasound imaging handheld scanner  100  with respect to the patient so that the non-cytotoxic protease can be injected from the controlled delivery device  150  at the correct treatment site. 
     For example, the controlled delivery device  150  may be attached to an outer surface of the housing/casing of the ultrasound imaging handheld scanner  100 . The position of the controlled delivery device  150  relative to the ultrasound transducer  106  and/or the ultrasound imaging handheld scanner  100  may be known. For example, the ultrasound imaging processing application may be programmed with information relating to the position of the controlled delivery device  150  relative to the ultrasound transducer such that the position of the controlled delivery device  150  is known. For example, the position of controlled delivery device  150  can be shown on a graphical representation of the patient&#39;s anatomy being imaged by the ultrasound imaging handheld scanner  100 . 
     In some examples, such as the examples shown in  FIGS. 3 and 5 , the ultrasound imaging handheld scanner  100  may comprise a guide  160  for receiving at least a portion of an injection device  170 , such as a syringe. The guide  160  may be coupled to the ultrasound imaging handheld scanner  100 , and the computer running the ultrasound imaging processing application may be configured to display information to the user for enabling the user to position the guide at a determined position relative to the patient based on the database of treatment sites and dosage regimes for the at least one non-cytotoxic protease, so that the user can inject the non-cytotoxic protease into the patient at the correct treatment site for the selected non-cytotoxic protease being injected from the injection device  170 . 
     For example, the guide  160  may be attached to an outer surface of the housing/casing of the ultrasound imaging handheld scanner  100 . The guide  160  may comprise a slot or other means for receiving at least a portion of an injection device, such as a needle. The position of the guide  160  relative to the ultrasound transducer  106  and/or the ultrasound imaging handheld scanner  100  may be known. For example, the ultrasound imaging processing application may be programmed with information relating to the position of the guide  160  relative to the ultrasound transducer such that the position of an injectable device such as a needle inserted into the guide  160  is known. For example, the position of a needle located in the guide  160  can be shown on a graphical representation of the patient&#39;s anatomy being imaged by the ultrasound imaging handheld scanner  100 . 
     In some examples, the ultrasound imaging processing application is configured to determine the position of an injection device  170  positioned in the guide  160 , relative to the patient based on the received data from the ultrasound imaging handheld scanner  100 . In such examples, the treatment guidance may comprise an indication to the user of how to position the ultrasound imaging handheld scanner  100  with respect to the patient so that the non-cytotoxic protease can be injected from the injection device  170  positioned in the guide  160  at the correct treatment site. 
     In some examples, such as the example shown in  FIG. 5 , the guide  160  will be configured to direct the injection device  170  at least partially into a field of view of the ultrasound transducer(s)  106 . For example, the guide  160  will be configured so that when an injection device  170 , such as a syringe, is inserted into the guide  160 , it will at least partially pass into the field of view of the ultrasound transducer(s)  106 . For example, as shown in  FIG. 5 , the needle  510  of the syringe  170  can be seen passing into the field of view  520  of the ultrasound transducer  106 . In this example the ultrasound imaging processing application running on the computer  200  displays a sonogram obtained from the ultrasound transducer  106 . Because the needle  510  extends at least partially into the field of view of the ultrasound transducer  106 , the needle  510  can be seen in the sonogram. In this way, a user of the ultrasound imaging handheld scanner  100  can scan and identify the treatment site, introduce the syringe  170  and needle  510  into the guide  160 , check the site again, advance the needle  510 , check it can be seen in the field of view  520 , inject the non-cytotoxic protease at the correct treatment site, withdraw the syringe  170  and check the site again. 
       FIG. 4  shows a flow-chart for a method of administering a controlled dose of non-cytotoxic protease to a patient, for example using the apparatus and/or ultrasound imaging processing application described above with reference to  FIGS. 1 to 3 . 
     The method comprises the steps of:
         scanning  410  a region of a patient&#39;s anatomy with an ultrasound imaging handheld scanner to obtain a graphical representation of the region of the patient&#39;s anatomy being scanned;   referencing  420  a database of treatment sites and dosage regimes for the non-cytotoxic protease being administered;   determining  430  at least one of:
           (i) the correct location to inject the non-cytotoxic protease being administered based on the graphical representation of the region of the patient&#39;s anatomy and the reference with the database of treatment sites and dosage regimes; and   (ii) the correct dose of the non-cytotoxic protease to administer based on the graphical representation of the region of the patient&#39;s anatomy and the reference with the database of treatment sites and dosage regimes;   
           administering  440  a controlled dose of the non-cytotoxic protease at the correct location based on the determination.       

     As described above in relation to  FIG. 1 , the database could be a local database (for example, stored on a computer  200 ) or could be a remote database (for example, the database could be a cloud-based database, for example accessed via the Internet). 
     In some examples, determining  430  the correct dose of the non-cytotoxic protease to administer based on the graphical representation of the region of the patient&#39;s anatomy and the reference with the database of treatment sites and dosage regimes comprises determining the position of at least one of (i) a controlled delivery device coupled to the handheld ultrasound imaging scanner relative to the patient (such as the controlled delivery device  150  described above in relation to  FIG. 2 ), and (ii) an injection device positioned in a guide and coupled to the handheld ultrasound imaging scanner relative to the patient (such as the injection device  170  and guide  160  described above in relation to  FIG. 3 ). 
     Administering  440  a controlled dose of the non-cytotoxic protease may comprise injecting a controlled dose of the non-cytotoxic protease into the patient. This may be aided, for example, via the provision of a guide  160  as illustrated in  FIG. 3 , or may be performed automatically/electronically, for example by the ultrasound imaging processing application, via the use of a controlled delivery device  150 , as illustrated in  FIG. 2 . 
     It will be understood that in some examples, the interface  110  of the ultrasound imaging handheld scanner  100  is optional. For example, the processor  108  of the ultrasound imaging handheld scanner  100  may be configured to run the ultrasound imaging processing application. In addition, the processor  108  may be coupled to a memory that comprises the reference database of treatment sites and dosage regimes for the at least one non-cytotoxic protease. 
     As with the examples described above in relation to  FIGS. 2 and 3 , in some examples the processor  108  of the ultrasound imaging handheld scanner  100  may be configured to run the ultrasound imaging processing application and may be configured to use the interface  110  to access and reference a remote database of treatment sites and dosage regimes for the at least one non-cytotoxic protease. 
     In some examples, the ultrasound imaging handheld scanner  100  may comprise a display or other display means to display treatment guidance to a user. For example, the ultrasound imaging handheld scanner  100  may comprise one or a plurality of lights, such as LEDs, operable to display information such an indication of an orientation in which to hold the scanner  100  and/or in which direction to move the scanner  100  for guiding treatment, such as the injection, of the non-cytotoxic protease. 
     In some examples, the ultrasound imaging handheld scanner  100  may comprise a display, such as an LED display, for example operable to provide a graphical representation of the region of the part of the anatomy being imaged. For example, the processor  108  of the ultrasound imaging handheld scanner  100  may be configured to process the data received from the ultrasound imaging handheld device  100  to provide a graphical representation of the patient being scanned to the user on the in-built display, for example in the form of a sonogram. It will be understood that in such examples, the user may advantageously be able to better treat a patient with a dose of non-cytotoxic protease without the need for additional computing equipment. In such examples, the treatment guidance may comprise an indication of where to inject the non-cytotoxic protease relative to the patient being scanned, and the indication may be overlaid on a graphical representation of the patient being scanned based on the data received from the ultrasound imaging handheld scanner. For example, the treatment guidance may indicate on a sonogram where the non-cytotoxic protease should be injected to have increased efficacy and minimise off-target effects. 
     Such examples may enable a non-skilled user of the ultrasound imaging handheld scanner  100  to self-administer treatment accurately and safely, thus avoiding the need for skilled clinical intervention (for example avoiding the need for a skilled radiographer). 
     In examples where the medical or surgical apparatus comprises an injectable device (such as the controlled delivery device  150  or injection device  170  described above with reference to  FIGS. 2 and 3 ) comprising a selected quantity of at least one non-cytotoxic protease, and the processor  108  of the ultrasound imaging handheld scanner  100  is configured to run the ultrasound imaging processing application, then the medical or surgical apparatus may be supplied as a kit, for example in a sealed sterile container, comprising both the ultrasound imaging handheld scanner  100  and the injectable device containing the non-cytotoxic protease. This may be advantageous not only for hygiene reasons but also because it may mean that the dosage of non-cytotoxic proteases may be better controlled. This may be because a controlled dose/quantity of non-cytotoxic protease can be supplied with a device that has been programmed (for example the processor  108  may be programmed, or a memory coupled to the processor  108  may be programmed) with information relating to at least one of (i) the concentration and (ii) the volume of non-cytotoxic protease supplied with it so that the application can carefully control its dose, for example by controlling operation of a controlled delivery device such as the controlled delivery device  150  described above in relation to  FIG. 2 . 
     In some examples, the medical or surgical apparatus may be configured to deliver a plurality of non-cytotoxic proteases, for example different serotypes of non-cytotoxic protease, such as different serotypes of clostridial neurotoxins, such as BoNTs and/or TeNTs. This may be beneficial, for example, to inhibit host immunogenicity. 
     In some examples, the medical or surgical apparatus may be configured to deliver different medical compositions, wherein each medical composition may comprise a different polypeptide. Each medical composition (for example polypeptide) may comprise at least one non-cytotoxic protease (in some examples the non-cytotoxic protease may be the same between compositions, but in other examples the compositions may comprise one or more different non-cytotoxic proteases). Each composition, for example each polypeptide, may comprise different targeting moieties and/or different translocation domains. In some examples the different medical compositions, for example different polypeptides, may comprise different TSIs that bind to different receptors on the same target cell. 
     In some examples, the medical or surgical apparatus may be configured to deliver a plurality of doses. For example, the ultrasound imaging processing application may be configured to deliver a plurality of doses, for example by control of the controlled delivery device  150  of  FIG. 2 . The plurality of doses may be of the same type of non-cytotoxic protease, or may be of different serotypes, for example to inhibit host immunogenicity. 
     For example, the ultrasound imaging processing application may comprise a user interface allowing the user to enter details of the desired treatment (such as the serotype(s) of non-cytotoxic protease(s)) and/or details regarding the patient (such as age, weight, clinical symptoms etc.), and the application may be configured to reference the database of treatment sites and dosage regimes to determine a treatment regime for the patient. 
     In some examples, the ultrasound imaging processing application may also be configured to determine which serotypes (and optionally quantities of each of those serotypes) to administer to the patient (and in some cases the locations of where to inject those serotypes). Information regarding the serotypes and at least one of the treatment regime, doses and sites for each of the serotypes may be provided as part of the treatment guidance. 
     In some examples, therefore, the ultrasound imaging processing application may be configured to provide treatment guidance that comprises an indication of at least one of:
         (i) where to inject each of the plurality of non-cytotoxic proteases relative to the patient being scanned;   (ii) which particular serotype of non-cytotoxic protease to inject at a selected treatment site; and   (iii) a quantity of each of the non-cytotoxic proteases to inject at a selected treatment site.       

     In some examples, the ultrasound imaging handheld scanner  100  and/or ultrasound imaging application may be calibrated so that the location of an injectable device, for example a controlled delivery device  150  (as described above in relation to  FIG. 2 ) or an injectable device  170  inserted into a guide  160  (as described above in relation to  FIG. 3 ) is determined. Calibration may involve taking a reference scan at a first position and marking the position of the injectable device/controlled delivery device on the patient&#39;s skin at the first position. A second scan may then be taken with the ultrasound transducer  106  located on the patient&#39;s skin at the first position, so that the distance between the ultrasound transducer  106  and the injectable device can be determined by comparison of the ultrasound data obtained at the first position and the second position. 
       FIGS. 6 to 8  show example screenshots of a computer program operating to provide a dosage application. In the examples shown the computer program is operating a handheld device (in this case a smartphone), although it will be understood that the computer program may be running on other types of device, for example a computer running the ultrasound imaging processing application as described above and/or on a device in communication with a computer running the ultrasound imaging processing application. 
       FIG. 6  shows two similar screenshots of the computer program operating to provide the dosage application. The dosage application allows a user to select a muscle type and to select a dose for that muscle type. For each muscle type the dosage application shows a recommended dose range for the patient. If a dose outside of the recommended range is selected a warning may be presented to the user. The recommended dose range may be calculated based on information relating to the patient—such as their age and weight. The dosage application also determines the total dose that may be administered to a patient based on the selected doses for each muscle type, and a total approved dose for the patient. If the total dose is above the total approved dose a warning may be provided to the user. The total approved dose may also be calculated based on information relating to the patient—such as their age and weight. 
       FIG. 7  shows two more similar screenshots of the computer program operating to provide the dosage application. In the screenshots of  FIG. 7  it can be seen how the dosage application can determine the volume of injection to be administered based on the desired dose and the concentration of treatment solution that is to be used. The dosage application can therefore display an indication to the user of the volume of injection to be administered to a patient at each treatment site. 
       FIG. 8  shows another screenshot of the computer program operating to provide the dosage application. As can be seen in  FIG. 8 , the dosage application can display an indication of the doses and volumes of treatment solutions to be injected at each treatment site. 
     EXAMPLES 
     A region of a patient&#39;s anatomy is scanned with an ultrasound imaging handheld scanner (such as the scanner  100  described above in relation to  FIGS. 1 to 3 ) to obtain a graphical representation of the region of the patient&#39;s anatomy being scanned. A database of treatment sites and dosage regimes is referenced, for example, for the non-cytotoxic protease being administered. At least one of: (i) the correct location to inject the non-cytotoxic protease being administered based on the graphical representation of the region of the patient&#39;s anatomy and the reference with the database of treatment sites and dosage regimes; and (ii) the correct dose of the non-cytotoxic protease to administer based on the graphical representation of the region of the patient&#39;s anatomy and the reference with the database of treatment sites and dosage regimes is determined. A controlled dose of the non-cytotoxic protease is administered at the correct location based on the determination. 
     Example 1 
     A 45 year-old female patient presents with hemifacial spasm. The patient&#39;s face is scanned using the ultrasound imaging handheld scanner  100  connected to a computer running an ultrasound imaging processing application. The ultrasound imaging processing application references a database of treatment sites and dosage regimes for at least one non-cytotoxic protease, and provides treatment guidance for guiding treatment based on the received data from the ultrasound imaging handheld scanner and the database of treatment sites and dosage regimes for the at least one non-cytotoxic protease. 
     Example 2 
     A 55 year-old male patient presents with spasticity of the right arm following from a stroke. The patient&#39;s degree of disability due to the spasticity is given a score based on the patient&#39;s symptoms. The patient&#39;s arm is scanned using the ultrasound imaging handheld scanner  100  connected to a computer running an ultrasound imaging processing application. The ultrasound imaging processing application references a database of treatment sites and dosage regimes for at least one non-cytotoxic protease, and provides treatment guidance for guiding treatment based on the received data from the ultrasound imaging handheld scanner, the database of treatment sites and dosage regimes for the at least one non-cytotoxic protease, and the patient&#39;s degree of spasticity and time since the disabilitating event (in this case the stroke). 
     It will be appreciated from the discussion above that the embodiments shown in the Figures are merely exemplary, and include features which may be generalised, removed or replaced as described herein and as set out in the claims. In the context of the present disclosure other examples and variations of the apparatus and methods described herein will be apparent to a person of skill in the art.